Fibroblast Growth Factors in Neurodevelopment and Psychopathology

Abstract

In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology-directed treatments for psychopathology.

Keywords

schizophrenia mood disorder behavior psychopathology brain development neurotrophic growth factor neurogenesis gliogenesis

Introduction

Psychiatric disorders, such as schizophrenia, mood disorders, and autism, are heterogeneous disorders in which many genetic and environmental factors are involved. Searching for common pathways that are affected by the different etiological factors is a prominent strategy to investigate the pathology of these disorders.

Growth factor functioning may be one of those convergent molecular pathways. Glial growth factors were first hypothesized to be involved in schizophrenia (Moises and others 2002), but have been related to autism and mood disorders as well (Bellon and others 2011; Vaccarino and others 2008). Glial growth factors are neurotrophic factors produced by glial cells. Well-known examples of these are neuregulin 1 (NRG1) and brain derived neurotrophic factor (BDNF) (Favalli and others 2012; Shamir and others 2012), but many more exist, including nerve-, insulin-like-, epidermal-, and fibroblast growth factors (FGFs). FGFs are particularly interesting, because they are one of the few growth factors involved in early brain development as well as maintenance and repair through adult life (Stevens and others 2010b). Although a role for NRG1 and BDNF in psychiatric disorders has been much investigated, the interest for the role of FGFs in psychopathology has been growing relatively recently.

In this review, we will explore the wealth of literature on the role of FGFs in psychopathology. There are 22 FGF ligands, which can be divided in several subfamilies based on homology in structure and function, as previously reviewed (Itoh and Ornitz 2011). Endocrine FGFs (FGF19, FGF21, and FGF23) can act over long distances as endocrine hormones and modulate binding of other FGFs. Intracrine FGFs (FGF11-14) act as receptor-independent intracellular molecules that regulate the function of sodium channels. All other FGFs are paracrine and modulate development by influencing intracellular signaling of neighboring cells. They do so by binding to one of the four FGF membrane-bound receptors (FGFRs), which induce dimerization, receptor phosphorylation, and activation of four key downstream signaling pathways: RAS/mitogen-actived protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3)/AKT, signal transducer and activator of transcription (STAT), and phospholipase gamma (PLCγ) (Itoh and Ornitz 2011).

The FGF family is crucial for the development of the brain, cranium, organs, limbs, and inner ear and for metabolism. The phenotypes of knock-out mice and diversity of human diseases caused by FGF(R) mutations have been described in several reviews and include skull malformations, achondroplasia, and several cancers (Beenken and Mohammadi 2009; Kan and others 2002; Krejci and others 2009). In addition, other reviews have specifically focused on the role of the FGF family in neurodevelopment (Bansal 2002; Iwata and Hevner 2009; Mason 2007; Reuss and von Bohlen und Halbach 2003; Stevens and others 2010b). Therefore, we will not attempt to give an extensive summary of these functions here. In short, FGFs control growth and patterning of the brain during development, whereas in adulthood they remain involved in neurogenesis and gliogenesis, axon outgrowth, myelinogenesis, and tissue repair.

In this review, the role of selected FGFs and receptors in psychopathology is described. We focus on four of the FGF family members, namely, FGF receptors 1 and 2, FGF2, and FGF17. These were chosen based on available evidence of their association with human psychopathology and evidence of their functions in animal behavior and brain development. These FGFs share a role in neurogenesis, axon outgrowth, brain volume, and the excitatory/inhibitatory balance. However, their target regions differ and so do the behaviors that they affect most, ranging from hyperactivity and increased anxiety to disturbed social and cognitive behavior.

Although all FGFRs drive essentially the same signaling pathways, they do act in a highly tissue- and time-specific manner. Specificity is derived by differential expression of binding proteins such as heparan sulfate proteoglycans and signaling adapters (Krejci and others 2009). Heparan sulfate proteoglycans act as co-receptors in the FGF–FGFR complex, form a storage reservoir for FGF ligands, and determine the radius of ligand diffusion (Beenken and Mohammadi 2009). So, although FGFs may be widely released, the distribution of heparan sulfate proteoglycans may help stimulate activation of targeted cells. Moreover, there may be differences in kinase activity depending on which molecule triggered the signal (Turner and others 2012).

The same signaling pathways can be induced by other growth factors, including insulin-like growth factor (IGF), transforming growth factor β (TGFβ), bone morphogenic protein (BMP), and vertebrate homologs of Drosophila wingless (WNT) (Szebeni, 1999). In addition, noncanonical ligands such as neuronal cell adhesion molecule (NCAM), L1, N-cadherin, and Ephrin A4 can bind to FGFRs (Hansen and others 2008; Polanska and others 2009). Thus, the final action depends on the combined activity of these ligands and receptors.

Human Genetic Studies

There are numerous indications that FGFs play a role in schizophrenia and mood disorders (Terwisscha van Scheltinga and others 2009; Turner and others 2006; Turner and others 2012). At the DNA level, single nucleotide polymorphisms (SNPs) near FGFR1 were strongly associated with schizophrenia in a genome-wide association study (Shi and others 2011). Second, an SNP located 85 kb from the nearest gene, FGFR2, was the only significant finding after several rounds of replication in a linkage fine mapping study on schizophrenia (O’Donovan and others 2009). A neighboring SNP was significantly associated with bipolar disorder (Wang and others 2012). In FGF2, an SNP associated with reduced FGF2 expression was associated with reduced treatment response in depressed patients (Kato and others 2009). Furthermore, the disruption of neuronal PAS domain protein 3 (NPAS3) was reported to co-segregate with illness in a small family with schizophrenia (Kamnasaran and others 2003). Npas3 knock-out mice show an 80% reduction in Fgfr1 mRNA (Pieper and others 2005) and express behavioral and physiological abnormalities similar to Fgfr1 mutant mice, including reduced novel object recognition and prepulse inhibition (Brunskill and others 2005).

At the mRNA expression level, decreased FGFR2 in the hippocampus and cingulate cortex and slightly raised FGFR1 in the hippocampus were found in postmortem brains of schizophrenia patients (Gaughran and others 2006; Katsel and others 2005). In depressed patients, FGFR1 mRNA was raised and FGF2 expression decreased independent of medication use (Gaughran and others 2006). In addition, the level of FGF2 protein in serum was increased in medicated schizophrenia patients and in nonmedicated patients with high negative symptoms (Hashimoto and others 2003).

Thus, associations have been found across the psychosis–mood disorder spectrum. Genetic variants in FGFs could increase the vulnerability for psychiatric disorders in general rather than causing a specific symptom.

Environmental Risk Factors

Two important risk factors for psychiatric disease, which are also related to FGFs, are obstetric complications and stress (Cannon and others 2002; Khashan and others 2008). The impact of environmental insults may be greater in FGF-deficient conditions. For example, it was shown that Fgf2 knock-out (Fgf2−/−) mice suffered much higher rates of cell death than wild type mice after 6-OHDA lesioning, a model for Parkinson’s disease (Timmer and others 2007). After ischemia, Fgf2−/− mice show an increased infarct volume and reduced neurogenesis compared with wild type mice (Zechel and others 2010). Unfortunately, the impact of perinatal hypoxia or stress on adult behavior has not been investigated in Fgf deficient mice.

What is clear, however, is that acute restrain stress induces an up-regulation of hippocampal FGF2 protein and mRNA in adult rats (Molteni and others 2001). In contrast, chronic stress reduced Fgf2 mRNA in the prefrontal cortex (Molteni and others 2001), whereas repeated social defeat reduced Fgf2 and Fgfr1 mRNA in the hippocampus in adult rats (Turner and others 2008a). The increase in Fgf2 in the prefrontal cortex and hippocampus after stress was particularly high after escapable stress compared with uncontrollable stress (Bland and others 2007). The authors, therefore, suggest that FGF2 might be involved in emotional regulation during stressful experiences. Prenatal stress affects Fgf2 expression in both short and long terms. Prenatal exposure to corticosterone produces a significant reduction in Fgf2 mRNA levels in the hippocampus of male rats (Molteni and others 2001). In adult rats that had been exposed to prenatal stress, the baseline Fgf2 levels were decreased in the prefrontal cortex and increased in the entorhinal cortex and striatum, while the Fgf2 response to a new stressful event was significantly altered as well (Fumagalli and others 2005).

Similarly, perinatal hypoxia showed long-term effects on Fgf2 expression. Perinatal anoxia leads to lifelong reductions in baseline Fgf2 mRNA in the ventral tegmental area and an enhancement of the Fgf2 response to stress (Flores and Stewart 2000; Riva and others 2005). Perinatal hypoxia causes an apparent loss of cortical neurons. In wild type mice, the numbers of excitatory neurons were recovered after 1 month, whereas the number of inhibitory interneurons remained decreased (Fagel and others 2009). In mice lacking Fgfr1, however, the deficits in excitatory neurons were persistent and the deficits in interneurons worse compared with wild type mice. So the FGF system seems to be required for recovery from hypoxia, while hypoxia itself may result in disturbances in FGFs.

The long-term decreases in baseline Fgf2 levels are thought to increase vulnerability to psychopathology. Baseline hippocampal Fgf2 mRNA expression correlated with anxiety (Eren-Kocak and others 2011), and Fgf2 administration reduces anxiety behaviors and depression-like behaviors in rodents; see also the Treatment section (Perez and others 2009; Turner and others 2008a; Turner and others 2011). In humans, a FGF2 SNP is associated with reduced treatment response in depressed patients (Kato and others 2009).

The effects of increased Fgf2 shortly after perinatal stress are less evident. Given the neuroprotective properties of FGF2, it was first hypothesized that this increase in Fgf2 is a mechanism to compensate for possible subsequent tissue damage (Molteni and others 2001). The requirement of Fgfr1 for recovery of hypoxia has been shown (Fagel and others 2009). However, it was recently reported that a single subcutaneous injection of FGF2 on postnatal day 2 resulted in long-term adverse effects (Turner and others 2009). Cocaine sensitization was increased, dopamine D2 receptor expression in the nucleus accumbens increased, and Fgf2 expression in the ventral tegmental area decreased (Clinton and others 2012). These effects may be a result of a disturbed balance between proliferation and differentiation, because FGF2 administration was shown to increase proliferation and delay differentiation of dopamine precursor cells (Grothe and Timmer 2007; Timmer and others 2007).

Although adverse events lead to long-term decreases in Fgf2, stimulating environments were shown to increase Fgf2 levels. For example, Fgf2 mRNA was up-regulated in an enriched environment, in the offspring of mothers who showed higher levels of pup licking and grooming (i.e., increased maternal care) and after physical activity (Dono 2003; Fumagalli and others 2005; Perez and others 2009; Turner and others 2008a).

FGFR1

Next, we will review and discuss the effects of changes in FGFR1, FGFR2, FGF2, and FGF17 on behavior and neurobiology. A summary of the findings can be found in Table 1 (behavior) and Table 2 (neurobiology).

Table 1.

Summary of Findings on Disease Associations and Behavior

	FGFR1	FGFR2	FGF2	FGF17
Genetic association with disease	Schizophrenia (Gaughran and others 2006; Katsel and others 2005; Shi and others 2011)	Schizophrenia, bipolar disorder (Gaughran and others 2006; Katsel and others 2005; O’Donovan and others 2009; Wang and others 2012)	Schizophrenia, SSRI response (Gaughran and others 2006; Kato and others 2009)	Not specifically assessed
Environment	NA	NA	Lifelong changes in Fgf2 expression after perinatal hypoxia or stress. Injury, stress, and seizures increase Fgf2 (Frank 2007; Fumagalli and others 2005; Ganat 2002; Riva and others 2005)	Normal (Scearce-Levie and others 2008)
Sensitivity to drugs	Increased (dnFGFR1) and normal (rgFGFR1) response to amphetamine. Phenotype rescued by histamine H3 receptor agonist (Fgfr1a−/− fish) (Muller Smith and others 2008; Norton and others 2011; Shin and others 2004)	NA	Increased response to dopaminergic and GABAergic drugs (Fadda and others 2007; Korada and others 2002)	NA
Neurotransmitters	Increased extracellular dopamine; serotonergic hyperinnervation in midbrain. Levels of GABA, serotonin, and dopamine transporter were normal (Klejbor and others 2006; Klejbor and others 2009; Muller Smith and others 2008; Shin and others 2004)	NA	Increased dopaminergic neurons. Dopamine increases FGF2 release. FGF2 affects dopamine sensitivity (Grothe and Timmer 2007; Ratzka and others 2012; Reuss and others 2003)	NA
Locomotor	Increased activity (rgFGFR1, thFGFR1, dnFGFR1), head bobbing after 6 weeks of age (dnFGFR1) and exploration of novel open field (Fgfr1a−/− fish) (Klejbor and others 2006; Muller Smith and others 2008; Norton and others 2011; Shin and others 2004)	Increased activity in novelty (Fgfr2 disrupted in OL) (Kaga and others 2006)	Increased activity (Fadda and others 2007)	NA
Cognition	Reduced memory retention (bFGFR1) (Zhao and others 2007)	Reduced spatial and object memory (Stevens and others 2012)	NA	Normal (Scearce-Levie and others 2008)
PPI	Reduced PPI, normalized after antipsychotic (thFGFR1) (Klejbor and others 2006)	NA	NA	Normal (Scearce-Levie and others 2008)
Social	Less social interaction (thFGFR1), increased aggression (FGFR1a−/− fish) (Klejbor and others 2009; Norton and others 2011)	NA	NA	Inability to compare and respond to novel social information. Less vocalization of pups (Scearce-Levie and others 2007)
Anxiety	Normal (thFGFR1) (Klejbor and others 2009)	NA	Increased anxiety after Fgf2 knockdown, normal in Fgf2−/− (Eren-Kocak and others 2011; Fadda and others 2007)	Normal (Scearce-Levie and others 2008)
Depressive behaviors	NA	NA	Less depressive behavior after FGF2 administration (Elsayed and others 2012; Turner and others 2008a)	NA

For precise description and references, see the text. Depressive behaviors were tested with the sucrose consumption test and forced swim test. SSRI = serotonin reuptake inhibitor; PPI = prepulse inhibition; OL = oligodendrocytes; NA= not assessed. Fgfr1 mutant mice are indicated by abbreviations with Fgfr1 deficiency induced in: radial glial cells (rgFGFR1), tyrosine hydroxylase (TH) expressing (dopaminergic) neurons (thFGFR1 mice), whole brain (bFGFR1), or in the telencephalon during development (dnFGFR1).

Table 2.

Summary of Neurobiological Findings

	FGFR1	FGFR2	FGF2	FGF17
Brain size	Reduced brain volume, frontal and temporal most (dnFGFR1, Fgfr1a−/− zebrafish), less dopamine neurons (thFGFR1) (Norton and others 2011; Klejbor and others 2006; Shin and others 2004)	Reduced brain volume, medial prefrontal most (Stevens and others 2010a)	Reduced cortex, normal hippocampus and striatum (Ortega and others 1998; Raballo and others 2000)	Reduced dorsal frontal cortex and cerebellum, reduced projections to striatum and midbrain (Cholfin and Rubenstein 2007)
Neurites	Decreased neurite outgrowth (Klejbor and others 2006; Shin and others 2004)	NA	Reduced spine length; affects excitatory synapses (Li and others 2002; Zechel and others 2006)	NA
Excitatory/inhibitory neurons	Normal glut+, reduced PV+ neurons, correlated with hyperactivity (rgFGFR1). Reduced glut+ and normal PV+ neurons (dnFGFR1) (Muller Smith and others 2008; Shin and others 2004; Smith and others 2010)	Reduction of PV+ neurons in hippocampus, correlated with spatial memory. Secondary reduced PV+ neurons in BST and septum (Stevens and others 2012)	Reduced glut+, normal GABA+ neurons in cortex, reduced glut+ fibers to striatum (Fadda and others 2007; Korada and others 2002; Ortega and others 1998)	NA
White matter	Astrocytes impaired of supporting PV+ neurons (rgFGFR1) (Muller Smith and others 2008)	Normal OL and myelin (FGFR2 disrupted in OL) (Kaga and others 2006)	FGF2 can activate glia cells. Increased gliogenesis after FGF2 administration in prefrontal cortex, is possible mechanism of antidepressive effects (Elsayed and others 2012; Reuss and others 2003)	NA
Adult neurogenesis	NA	Reduced DCX+ cells, correlated with object memory (Stevens and others 2012)	Increased neurogenesis and DG volume after FGF2 injection (Zechel and others 2010)	NA
LTP	Disrupted (Zhao and others 2007)	NA	Disrupted (Zechel and others 2006)	NA

For precise description and references, see text. Finding concern FGF mutant mice, unless otherwise stated. glut = glutamate; PV = parvalbumin; BST = bed nucleus of stria terminalis; OL = oligodendrocytes; DCX = doublecortin; LTP = long-term potentiation; DG = dentate gyrus; NA = not assessed. Fgfr1 mutant mice are indicated by abbreviations with Fgfr1 deficiency induced in: radial glial cells (rgFGFR1), tyrosine hydroxylase (TH) expressing (dopaminergic) neurons (thFGFR1 mice), whole brain (bFGFR1), or in the telencephalon during development (dnFGFR1).

FGFR1 in Behavior

Because full Fgfr1 knockout mice have severe skull malformations and die embryonically, mutant constructs have been made with loss of functional Fgfr1 restricted to specific cells or brain regions. For example, Fgfr1 expression was abolished in radial glial cells by a Cre recombinase-induced deletion of Fgfr1^flox alleles (the mice are here abbreviated as rgFGFR1 mice) (Ohkubo and others 2004). Radial glial cells are the primary progenitors of neurons in the dorsal telencephalon, and this procedure results in near complete absence of Fgfr1 in the embryonal telencephalon after embryonic day 13.5, while maintaining expression in other regions. Others have inserted of a dominant negative Fgfr1 gene under a tyrosine hydroxylase (TH) promoter in mice (thFGFR1 mice) (Klejbor and others 2006). As TH is the rate-limiting enzyme in dopamine synthesis, this results in absence of Fgfr1 expression in dopaminergic neurons but normal expression in other regions, including the cortex and striatum. Furthermore, a line of conditional knock-out mice was generated with loss of Fgfr1 restricted to the whole brain (bFGFR1 mice) (Zhao and others 2007). Last, in the dnFGFR1 mice, the expression of Fgfrs in the telencephalon was reduced by a dominant negative Fgfr1 under an Otx1 promoter (Shin and others 2004). This reduces the expression of not only Fgfr1 but all Fgfrs during early development.

For these Fgfr1 models, an increase in locomotor activity is the most replicated finding, with reports in the rdFGFR1, thFGFR1, and dnFGFR1 mice. Besides hyperactivity, dnFGFR1 mice showed occasional head bobbing and turned compulsively in one direction (Shin and others 2004). These abnormalities were absent at birth and developed at around 6 weeks of age (equivalent to adolescence). As disturbances in most neurotransmitter systems and several brain regions can give rise to hyperactive behavior, it is yet unclear what causes this behavior in the Fgfr1 mutant mice. Perhaps, the alterations in dopaminergic, serotonergic, and histaminergic functioning described hereafter are part of the pathology leading to the observed hyperactivity.

First, alterations were reported in the dopaminergic system. The thFGFR1 mutant mice displayed deficits in prepulse inhibition (PPI) (Klejbor and others 2006). In PPI, the startle response evoked by a stimulus (usually a sound) is attenuated by a weak stimulus prior to the stimulus (a prepulse). Deficits in PPI are also found in schizophrenia patients, correlate with symptom severity, and can arise from a hyperdopaminergic state in the striatum (Klejbor and others 2006). In these mice, the deficits could be normalized after treatment with flupentixol, an antipsychotic with dopamine D2 antagonistic actions. In addition, a functional hyperactivity of the dopamine system was shown by an increased sensitivity to amphetamine (a dopamine agonist) in dnFGFR1 mice (Shin and others 2004). Reductions in Fgfrs other Fgfr1 might have contributed to this effect. In contrast, rdFGFR1 mice showed unaltered responses to cocaine, amphetamine, and dopamine D1 or D2 agonists (Muller Smith and others 2008).

Second, a different study on thFGFR1 mice showed that besides deficits in PPI, these mice engage less in social interaction (Klejbor and others 2009). This could be corrected by treatment with the specific 5-HT2A receptor antagonist M100907 and with quetiapine (an atypical antipsychotic with 5HT affinity) (Klejbor and others 2009). This effect is specific, as locomotor activity and anxiety measures were unchanged. Similar to the hyperactivity, the behavioral and neurochemical abnormalities were not present at birth but developed after puberty (Klejbor and others 2009). This suggests that, whereas Fgfr1 deficiency is restricted to catecholaminergic neurons, the disturbed development affects other neurotransmitter systems as well, including the serotonergic system.

Third, behavioral deficits specifically related to histamine were reported in fgfr1 mutant zebrafish. Zebrafish have two separate fgfr1 genes, and absence of one of these is not lethal due to compensatory mechanisms. fgfr1a−/− zebrafish show an increased boldness, as measured by the time needed to reach the most distant point in a novel open field (Norton and others 2011). In addition, these fish showed increased mirror-induced aggression. Both behaviors were specifically related to reduced histamine throughout the brain and not to changes in other neurotransmitters. The concentration of histamine-N-methyltransferase (HMNT), a histamine degrading enzyme, was increased and the phenotype could be rescued by administration of an HNMT inhibitor or the histamine receptor 3 agonist imetit (Norton and others 2011). Fluoxetine (a serotonin reuptake inhibitor [SSRI]) or galantamine (acetylcholine antagonist) reduced agression in wild type and fgfr1a−/− zebrafish to the same extend.

These observations can be related to the previous findings in several ways. Histamine H3 receptors were found to form heterodimers with dopamine D2 receptors, and imetit can inhibit the locomotor activation induced by D1 or D2 receptor agonists (Ferrada and others 2008). Perhaps imetit was effective in the fgfr1a−/− zebrafish because its striatal dopamine levels were relatively increased. Moreover, because the tuberomammillary nucleus, the only region of the brain with histaminergic neurons, receives glutaminergic input from the prefrontal cortex, the changes in histamine could be secondary to disturbed prefrontal cortex development (see FGFR1 in neurobiology) (Brown and others 2001).

Other neurotransmitter systems and processes may be affected as well. For example, dnFGFR1 mice showed a stronger and shorter response to guanfacine, an α2 adrenal receptor agonist (Shin and others 2004). The bFGFR1 mice displayed a memory deficit specific to the retention of the learned spatial information in the Morris water maze task (Zhao and others 2007), which is related to adult neurogenesis (see FGFR1 in neurobiology).

In summary, Fgfr1 deficiency has been associated with locomotor hyperactivity, deficits in prepulse inhibition, and disturbed cognitive and social behavior. Depressive and compulsive behaviors have not been tested in these mice, so a role in other psychopathology is not excluded. In the next section, we will describe how these behavioral abnormalities relate to neurobiological findings in Fgfr1 mutant mice, for example, to reductions in interneurons.

FGFR1 in Neurobiology

Similar to schizophrenia patients, dnFGFR1 mice show reductions in total brain size, with most prominent reductions in frontal and temporal regions (Haijma and others 2012; Shin and others 2004).

Excitatory glutamatergic neurons and inhibitory interneurons seem to be affected differently, which could lead to an imbalance between excitation and inhibition. Such a disturbed excitation/inhibition balance has been suggested to play a role in schizophrenia and autism pathology (Marin 2012). In rdFGFR1 mice fewer parvalbumine positive (PV+) interneurons were found in the cerebral cortex of young adults, whereas glutamatergic neuron numbers were unaltered (Muller Smith and others 2008). The reduction in interneurons correlated with the amount of locomotor hyperactivity, suggesting that the hyperactivity is mediated by reduced inhibitory activity in the cortex. Similarly, the numbers of PV+ and somatostatin+ interneurons were reduced in adult rgFGFR1 mice (Ohkubo and others 2004). This may be the result of postnatal loss, as these numbers were normal at birth. Astrocytes isolated from these mutants were impaired in supporting interneuron development in vitro, suggesting that the loss is caused by glia dysfunction (Smith and others 2010). In contrast to previous findings, the dnFGFR1 mouse showed fewer pyramidal neurons and normal numbers of GABAergic and PV+ neurons (Shin and others 2004). The expression of all Fgfrs in these mice was reduced during development only, indicating that the survival-promoting role of Fgfrs for PV+ neurons increases postnatally.

Furthermore, loss of Fgfr1 specific to dopaminergic neurons of the midbrain was shown to have secondary effects on the serotonergic system. After blocking of Fgfr1 signaling in the ventral tegmental area and substantia nigra (by using thFGFR1 mice), cell size and density were decreased in these regions specifically (Klejbor and others 2006). Despite the loss of dopaminergic neurons, extracellular dopamine levels in the striatum were increased. In addition, serotonergic innervation to these dopaminergic regions was increased (Klejbor and others 2009). During brain development there is competition between serotonin and dopamine for brain target sites. A complex interaction of dopamine and serotonin in the prefrontal cortex during development may explain the effects of serotonergic drugs on social behavior.

Moreover, the bFGFR1 mice with memory impairments also displayed deficits in adult neurogenesis and long-term potentiation (LTP) in the hippocampus (Zhao and others 2007). In addition, Fgfr1 deficiency was shown to decrease dendritic outgrowth in vitro (Klejbor and others 2006) and in vivo (Shin and others 2004).

An integrated overview of the findings on FGFR1 can be found in Figure 1. In Fgfr1 mutant mice, locomotor hyperactivity, deficits in prepulse inhibition, and disturbed cognitive and social behavior are associated with abnormalities in dopamine, serotonin, and histamine neurotransmitter systems. Together this resembles a schizophrenia-like phenotype. FGFR1 has widespread actions and deficiency of this growth factor receptor results in global reductions in neuronal density. Deficiency in Fgfr1 may lead to a cascade of abnormalities, starting with postnatal increasingly disturbed glia functioning. This reduces the number of GABAergic PV+ neurons, which is, in turn, associated with locomotor hyperactivity. PV+ interneurons mediate the activity of the glutamatergic cortical projects to dopaminergic areas (Carlsson and others 2001), whereas reduced development of dopaminergic neurons results in deficits in prepulse inhibition. Because of competition between projecting neurons for target brain sites, this secondarily affects other neurotransmitter systems. Dysfunction in the serotonin system was associated with reduced social interaction in these mice. In addition, memory is disturbed, possibly related to reduced adult neurogenesis.

Figure 1.

Consequences of FGFR1 deficiency. Evidence from several studies is combined to generate hypotheses about brain circuits that are affected by FGFR1. Dark green arrow = excitatory, glutamatergic projection; light green arrow = inhibitory, GABAergic projection; purple arrow = dopaminergic projection; blue arrow = histaminergic transmission. DA = dopamine; 5-HT = serotonin; glu = glutamate; SN = substantia nigra; VTA = ventral tegmental area; Tubero mam n. = tuberomammilary nucleus; PV = parvalbumin; PPI = prepulse inhibition; > = possible causal relationship.

FGFR2

FGFR2 in Behavior

Mice with abolished Fgfr2 expression in radial glia cells displayed impairments in memory at adulthood (Stevens and others 2012). These mice showed significantly slower learning in an 8-day Morris water maze test and performed worse on the probe trial on the ninth day of this test. In an object recognition test on three consecutive days, Fgfr2 mutant mice also performed worse.

When Fgfr2 expression was specifically abolished in oligodendrocytes, 38% of the mice showed a pronounced hyperactivity after mild environmental stimulation, such as moving the cage or exposure to a novel open field (Kaga and others 2006). This behavior developed after 2 weeks of age and could be normalized by dopamine D1 or D2 antagonists, suggesting a postnatal defect in dopaminergic signaling, similar to some findings in Fgfr1 mutant mice. Other behavioral tests were not reported for these mice.

FGFR2 in Neurobiology

When Fgfr2 signaling was abolished in radial glial cells, cortical volume was generally reduced (Stevens and others 2010a). The reduction was strongest in the medial prefrontal cortex and was due to fewer cortical excitatory pyramidal neurons. This correlated with reduced subcortical inhibitory (PV+) neuron numbers in the cortical projection regions (septum and bed nuclei of the stria terminalis).

In addition, in the hippocampus, volume and number of PV+ neurons were reduced and adult neurogenesis was decreased (Stevens and others 2012). Interestingly, these abnormalities were related to specific memory deficits. The number of PV+ neurons correlated with long-term spatial reference memory, whereas reduced differentiating (doublecortin+) neurons correlated with object recognition. Differentiation and object recognition were reduced even when Fgfr2 deficiency started in adulthood, whereas the deficits in interneurons and spatial memory were only seen after Fgfr2 reductions in early development. This suggests FGFR2 is involved in two distinct processes related to hippocampal function and memory.

Fgfr2 is abundantly expressed in oligodendrocytes and stimulates outgrowth and myelination in vitro (Kaga and others 2006). Surprisingly, abolishing Fgfr2 expression in oligodendrocytes did not lead to any observable defects in these cells or myelination in vivo. Although their hyperactive behaviors were responsive to dopamine receptor antagonists (described above), there were no indications of reduced dopamine and glutamatergic neuron numbers. This suggests a functional rather than structural deficit in the dopamine system. The authors propose that the hyperactive phenotype is caused by abnormal axon–oligodendrocyte interactions in dopaminergic neurons. The findings are summarized in Figure 2.

Figure 2.

Consequences of FGFR2 deficiency. Evidence from several studies is combined to formulate hypotheses about brain circuits that are affected by FGFR2. Dark green arrow = excitatory, glutamatergic projection; light green arrow = inhibitory, GABAergic projection. DA = dopamine; glu = glutamate; PV = parvalbumin; PFC = prefrontal cortex; BST = bed nucleus of stria terminalis; OL = oligodendrocyte.

FGF2

FGF2 in Behavior

In mice, Fgf2 expression was fully abolished by replacing the first exon of the Fgf2 gene with an Hprt minigene (Zhou and others 1998). These Fgf2−/− mice showed locomotor hyperactivity in the open field, as well as an increased locomotor response to dopaminergic drugs (cocaine, amphetamine, and apomorphine) (Fadda and others 2007). Sleeping time following administration of GABA receptor agonist sodium pentobarbital was increased (Korada and others 2002). Together, this indicates disturbances in the dopamine and GABA neurotransmitter systems.

In rats, knockdown of Fgf2 expression resulted in increased anxiety behavior in an elevated plus maze (Eren-Kocak and others 2011). There was a strong, positive correlation between the Fgf2 concentration in the hippocampus and the time spent in open arms (i.e., less anxiety). Rats bred for high anxiety behavior showed low expression of Fgf2 mRNA in the hippocampus (Perez and others 2009; Turner and others 2012). Interestingly, environmental enrichment increased Fgf2 levels and reduced anxiety in these rats. In contrast, Fgf2−/− mice displayed normal anxiety behavior in the open field (Fadda and others 2007).

Administration of FGF2 can reduce depressive-like behaviors (see Treatment). The effect of loss of FGF2 on depressive behaviors has not been investigated. So, together these studies suggest that FGF2 is related to locomotor activity, anxiety levels, and depressive behaviors.

FGF2 in Neurobiology

Fgf2−/− mice showed a 10% reduction in cerebral cortex size and decreased neuron density (Raballo and others 2000). In the cortex, Fgf2 seems to affect excitatory pyramidal neurons more than inhibitory neurons, in contrast to Fgfr1. Several studies found reductions in pyramidal neurons, most prominent in the deep layers of the frontal cortex (Korada and others 2002; Ortega and others 1998; Raballo and others 2000). A specific class of neurons arising from the dorsal pseudostratified ventricular epithelium appears to be affected (Raballo and others 2000). GABAergic interneurons were relatively spared (Korada and others 2002; Raballo and others 2000), although one study found reductions in PV+ neurons as well (Ortega and others 1998). In addition, increased numbers of ectopic PV+ neurons were reported in Fgf2 deficient mice (Dono and others 1998), indicating a possible migration defect.

Neuron numbers in the hippocampus, striatum, and cerebellum were normal (Ortega and others 1998). Several studies suggest that hippocampal neurons are sensitive to the effects of FGF2, however. FGF2 administration increased adult neurogenesis in the hippocampus and dentate gyrus volume in wild type rodents in standard conditions and following ischemia, whereas after Fgf2 deficiency the opposite was observed: increased infarct volume and reduced neurogenesis after ischemia (Zechel and others 2010). Together this suggests that FGF2 is pharmacologically effective but not physiologically required for neurogenesis in the hippocampus under normal conditions. Perhaps the lack of FGF2 on its own can be compensated for, but after stress this compensation may be insufficient (Grothe and Timmer 2007).

It is also possible that FGF2 affects neuron morphology and function rather than neuron number in the hippocampus under normal conditions. Fgf2 may be required for correct synapse formation, as spine length was reduced in Fgf2−/− mice and LTP disrupted (Zechel and others 2006). Conversely, FGF2 administration increases the formation of excitatory synapses in vitro, by activating MAPK signaling (Li and others 2002). In addition, ectopic administration of FGF2 resulted in aberrant targeting of axons in Xenopus (Yamaguchi 2001).

FGF2 also has specific effects on dopaminergic neurons. It increases proliferation and delays differentiation of dopamine precursor cells, protects dopaminergic neurons from neurotoxin-induced cell death, and increases survival of transplanted dopaminergic neurons (Grothe and Timmer 2007; Timmer and others 2007). Remarkably, in Fgf2−/− mice the number of dopaminergic neurons in the substantia nigra was 35% increased from late embryonic development onwards (Ratzka and others 2012). Although no compensatory up-regulation of other Fgf ligands was observed, activation of downstream signaling pathways was normal. Perhaps alternative ligands or co-receptors, such as NCAM or heparan sulfate proteoglycans (see Introduction), are (over)compensating for the lack of FGF2 (Ratzka and others 2011). An increase in the nuclear isoform of FGFR1 may also explain the finding, as nuclear FGFR1 is known to increase TH expression (the rate-limiting enzyme in dopamine synthesis) (Ratzka and others 2012). Moreover, it was hypothesized that abnormalities in the dopaminergic system ultimately originate from a dysfunction in glutamatergic inputs from the prefrontal cortex to GABAergic cells in the striatum (Fadda and others 2007). Accordingly, fewer cortical glutamatergic fibers were found to innervate the striatum (Fadda and others 2007).

In addition to the neuronal effects, FGF2 can activate oligodendrocytes, astrocytes, and microglia (Reuss and von Bohlen und Halbach 2003). FGF2 increases proliferation and blocks terminal differentiation of precursor oligodendrocytes, whereas in mature oligodendrocytes it stimulates outgrowth and inhibits the expression of myelin-related genes (Bansal 2002). The early effects of FGF2 on proliferation are FGFR3 mediated, whereas the later effects on outgrowth are FGFR2 mediated, as the oligodendrocytes change in FGFR expression during maturation (Fortin and others 2005).

The findings on FGF2 are summarized in Figure 3. With FGFR1 as its main receptor, some of the abnormalities in Fgf2−/− mice overlap with Fgfr1 mutant mice. Both affect global brain structures, gliogenesis, and genetic deletion of either of these genes leads to locomotor hyperactivity. In contrast, the effect on dopaminergic neurons was opposite: a decrease for Fgfr1, but an increase for Fgf2. Because different behavioral tests were used for the Fgfr1 and Fgf2 mice (cognitive and social behaviors for Fgfr1 and anxiety behaviors for Fgf2), overlap in behaviors other than locomotion was not shown.

Figure 3.

Schematic model of FGF2 functioning. Evidence from several studies is combined to generate hypotheses about brain circuits that are affected by FGF2. Dark green arrow = excitatory, glutamatergic projection; light green arrow = inhibitory, GABAergic projection; purple arrow = dopaminergic projection. DA = dopamine; glu = glutamate; SN = substantia nigra; VTA = ventral tegmental area; > = possible causal relationship.

FGF17

FGF17 in Behavior

Fgf17−/− mice display a specific deficit in social behavior: less interest in a novel female after habituation to the first female. The authors suggest that these mice have an inability to compare and respond to novel social information (Scearce-Levie and others 2008). In addition, pups showed reduced ultrasonic vocalizations when separated from the dam at postnatal day 8. Male to female aggression, novelty suppressed feeding, anxiety behavior, locomotion, and PPI were normal.

FGF17 in Neurobiology

In Fgf17−/− mice volume reductions were specific to the dorsal frontal cortex and cerebellum (Cholfin and Rubenstein 2007). In addition, the projections from the cortex to the striatum and ventral midbrain were reduced, which may have contributed to the observed social deficits in these mice. The dorsal frontal cortex is involved in working memory, attention, and social valuation and is important in schizophrenia and autism (Courchesne and others 2011; Volk and Lewis 2010). A schematic representation of the findings is displayed in Figure 4.

Figure 4.

Schematic model of FGF17 functioning. Evidence from several studies is combined to formulate hypotheses about brain circuits that are affected by FGF17. Dark green arrow = all projections from this region.

Treatment

The neuroprotective properties of FGF2 instigated investigations on possible therapeutic effects. Whereas increases in FGF2 in early life may disturb developmental processes, as described in Environmental Risk Factors, administration of FGF2 at adult age has been proven beneficial. Perhaps FGF2 functions in more specific and subtle processes at this age. The examples of beneficial effects of FGF2 administration in animal models include reduced anxiety behavior in rats that are prone to anxiety (Perez and others 2009), reduced depression-like behavior in the forced swim test (Turner and others 2008b), and a reduction in depression-like behavior induced by chronic unpredictable stress in the sucrose consumption test (Elsayed and others 2012). In a mouse model of Alzheimer’s disease, increasing gene expression of FGF2 through viral infection significantly restored spatial learning, even after onset of the symptoms (Kiyota and others 2011). FGF2 facilitated recovery of perinatal cortical injury, whether it was given before or after injury (Comeau and others 2007).

Interestingly, the positive effects of FGF2 on behavior coincide with effects on neurogenesis and gliogenesis. The reduction in anxiety was accompanied by an increase in survival of adult born neurons and glia in the hippocampus (Perez and others 2009). In the Alzheimer’s model too, neurogenesis was increased after inducing Fgf2 levels (Kiyota and others 2011). FGF2 infusion into the prefrontal cortex, but not into the striatum, restored the reduced gliogenesis induced by chronic unpredictable stress (Elsayed and others 2012). This produced antidepressant actions in the novelty suppressed feeding and forced swim tests (Elsayed and others 2012). Furthermore, this study showed that the antidepressants fluoxetine and imipramine partially require FGF2/FGFR signaling for their behavioral as well as gliogenic actions. An independent study showed that FGF2 was able to reverse the depressive behaviors induced by olfactory bulbectomy, as well as ameliorate its effects on hippocampal adult neurogenesis (Jarosik and others 2011). Moreover, endogenous FGF2 was necessary for the behavioral effects of amitryptiline.

Studies like these suggest that some of the conventional psychiatric treatments may exert their effect by influencing FGF functioning. Antidepressant and antipsychotic medication can increase neurogenesis, and several of these drugs were reported to increase FGF expression (Eisch and Petrik 2012; Terwisscha van Scheltinga and others 2009). Although they increase neurotransmitter levels within minutes to hours, their therapeutic effects may take weeks to develop, with a lag time similar to that necessary for neuronal maturation (Eisch and Petrik 2012).

In humans, treatments targeting the FGF family are being explored for a wide range of disorders, as reviewed by Beenken and Mohammadi (2009). FGFR inhibition is trialed for treatment of malignancy, and paracrine FGFs have a potential in angiogenesis, cytoprotection, and tissue repair. Regarding psychiatric disease, there is one study in children with mental retardation caused by perinatal hypoxia (Aguilar and others 1993). A large developmental and cognitive improvement (+10 IQ points) was reported after treatment with intramuscular injections of FGF2, compared with placebo-treated children. FGF2 was generally well tolerated, did not cause toxic or allergic reactions, and is easily administrated as it crosses the blood-brain barrier. Unfortunately, administration of FGF2 led to higher mortality rates in two clinical trials with acute stroke patients, because of a dose-dependent hypotension (Wu 2005). The dosage used was substantially higher than in the treated children (125 µg/kg vs. 0.4 µg/kg).

Thus, although treatment with FGF2 or other drugs influencing the FGF system is promising for psychiatric disorders, more research is needed to investigate its efficacy in specific disorders, as well as the dosages and age groups in which it can safely be applied. Peripheral side effects might be reduced by applying FGF2 intranasally. This was proven a successful way to deliver FGF2 to the brain without affecting blood pressure (Ma and others 2008). Another option is to design agents that specifically bind to a dimer of two receptors, in order to increase specificity of the drug action. FGFR1 forms a heterodimer with adenosine A_2A receptors and together these receptors oppose the actions of dopamine D₂ receptors, located on the same cells (Flajolet and others 2008). In addition, FGFR1 has recently been shown to form heterodimers with the 5-HT1A (serotonin) receptor in the hippocampus and raphe nucleus (Borroto-Escuela and others 2012). Activation of this dimer may be important for the antidepressant and neurotrophic effects of serotonin. Developing agents that specifically target the FGFR1 heterodimers could be a completely novel strategy to influence the dopamine system in schizophrenia patients.

Summary of the Findings

To unravel the pathophysiology of psychiatric disorders, studies are focusing on molecular pathways on which genetic and environmental risk factors converge. Growth factor functioning could be such a convergent pathway. Genetic variants in FGFR1, FGFR2, and FGF2 are associated with schizophrenia and depressive disorder. Moreover, early life disturbances, such as hypoxia or social stress, may lead to lifelong reductions in Fgf2 expression. Several FGFs and FGFRs are involved in regulation of neuronal growth and patterning during development and in neurogenesis and gliogenesis, axon outgrowth, myelinogenesis, and tissue repair into adulthood. Disturbances of the FGF system can therefore have a major impact, especially during critical phases of brain development.

All described mutant Fgf mice show a reduction in brain volume. This is likely due to decreased proliferation and earlier differentiation rather than increased apoptosis or cell death (Reuss and von Bohlen und Halbach 2003). Other common features include effects on axon growth, synapse formation, and long-term potentiation.

In Fgfr1 and Fgf2 mutant mice, neurons of the prefrontal cortex are particularly affected, which results in less innervation of the striatum. Together with “unsupportive astrocytes” this may impair the number and functionality of GABAergic interneurons and dopaminergic neurons. In concert, these subtle but widespread abnormalities may explain the schizophrenia-like symptoms, including locomotor hyperactivity, impaired prepulse inhibition, reduced working memory, altered responsiveness to drugs, and depressive-like behaviors. FGF2 is involved in gliogenesis, which may be part of its antidepressive properties.

More localized brain regions are affected by FGFR2 (hippocampus and medial prefrontal cortex) and FGF17 (dorsal frontal cortex). However, absence of these proteins leads to disturbances not restricted to these regions and may also initiate a cascade of events. For example, reductions in cortical neuron numbers resulted in dysfunctional subcortical projections in Fgfr2 and Fgf17 mutant mice models. This affected the development of other brain regions, such as the bed nucleus of stria terminalis and septum in Fgfr2 mutant mice. These models show how the development of the different brain regions is highly interrelated. What starts as subtle disturbances in a specific cell type or region results secondarily in widespread abnormalities. The Fgfr2 and Fgf17 mutant mouse models display aberrant cognitive and complex social behaviors, respectively.

Future Research and Concluding Remarks

Interestingly, the observed deficits after disruption of FGF2/FGFR1 signaling resemble those seen in schizophrenia patients. Phenotypic overlap at the behavioral as well as biological level give this model reasonable face validity. For example, disturbances in working memory, prepulse inhibition, locomotor activity, and responsiveness to drugs were reported for schizophrenia patients as well as Fgfr1 mutant mice (MacDonald and Schulz 2009; Minassian and others 2010). On a biological level, overlapping features include reduced brain volumes, especially in frontal and temporal regions (Haijma and others 2012), and predominant alterations in PV+ interneurons (Marin 2012). In Fgfr1 mutant mice, the interneuron deficit was related to astrocyte dysfunction. Abnormalities in glia cells and white matter play an important role in schizophrenia (Bernstein and others 2009). However, relatively little is known about the role of astrocytes in schizophrenia and this would be interesting to follow up.

In addition, several other questions may be addressed in future research. Abnormal glia cell functions seem to be central in the abnormalities in Fgfr1, Fgfr2, and Fgf2 deficient mice. It is unknown which glial cell types are affected most, how these cells respond to loss or gain of FGF(R)s, and how this in turn influences glia–neuron interactions. These findings can be compared with the abnormalities in these cell types in schizophrenia patients. Second, depressive behaviors have not been investigated in Fgfr1 deficient mice, social behaviors not in Fgfr2 deficient mice, and cognitive and social behaviors not in Fgf2−/− mice. It is likely that these genes are involved in those behaviors, based on similarities between the genes and the brain circuits that they are involved in. Third, based on its effects on social behavior, it would be very interesting to investigate the association of genetic variations in FGF17 with schizophrenia or autism in humans.

The effects of FGFs and their receptors can be compared with those of other neurotrophic factors or candidate genes for psychiatric disorders. The behavioral and neuro-anatomical dysfunctions observed in Fgfr1 and Fgf2 deficient mice resemble those that were observed in models using disruption in schizophrenia 1 (Disc1), Nrg1, and Bdnf (Brandon and Sawa 2011; Favalli and others 2012; Shamir and others 2012). These genes have been associated with schizophrenia and mood disorders and have functions in neurogenesis, migration, and synapse formation during development and in adulthood. Perhaps the functions of these growth factors converge to influence similar brain circuitry.

To conclude, several members of the FGF gene family are associated with psychopathology in human and animal studies. They are not only important in brain development but also modulate the impact of environmental stressors on the brain. Studies in animal models with genetic variations in FGFs or FGFRs will provide an important basis for understanding the neurobiological mechanisms underlying aberrant behavior. Moreover, administration of FGF2 or other agents targeting the FGF system is a promising new treatment option for neuropsychiatric disorders.

Footnotes

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by a Veni grant from Zorg Onderzoek Nederland, Medische Wetenschappen (ZON-MW, the Dutch Organization for Health Research and Development) to SB (Project No. 91686137).

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