The Neuroscientist

The neurotrophins (NTs) have recently been shown to elicit pronounced effects on quantal neurotransmitter release at both central and peripheral nervous system synapses. Due to their activity dependent release, as well as the subcellular localization of both protein and receptor, NTs are ideally suited to modify the strength of neuronal connections by “fine-tuning” synaptic activity through direct actions at presynaptic terminals. Here, using BDNF as a prototypical example, the authors provide an update of recent evidence demonstrating that NTs enhance quantal neurotransmitter release at synapses through presynaptic mechanisms. The authors further propose that a potential target for NT actions at presynaptic terminals is the mechanism by which terminals retrieve synaptic vesicles after exocytosis. Depending on the temporal demands placed on synapses during high-frequency synaptic transmission, synapses may use two alternative modes of synaptic vesicle retrieval, the conventional slow endosomal recycling or a faster rapid retrieval at the active zone, referred to as “kiss-and-run.” By modulating Ca²⁺ microdomains associated with voltage-gated Ca²⁺ channels at active zones, NTs may elicit a switch from the slow to the fast mode of endocytosis of vesicles at presynaptic terminals during high-frequency synaptic transmission, allowing more reliable information transfer and neuronal signaling in the central nervous system.

A basic characteristic of animal cells is the maintenance of a steep inwardly directed electrochemical gradient for sodium ions. In vertebrate neurons, this Na⁺ gradient energizes intracellular ion regulation and enables influx of Na⁺ during action potentials and excitatory postsynaptic currents. Several studies suggested that Na⁺ ions could also play a role in activity-dependent synaptic plasticity. This review focuses on recent studies that demonstrated the presence of substantial intracellular Na⁺ transients during action potential firing or excitatory synaptic transmission in postsynaptic dendrites and dendritic spines. The large amplitudes of these activity-induced Na⁺ transients suggest that this signal will significantly alter electrical and biochemical properties of spines and dendrites and might influence the properties of synaptic transmission.

Lysophosphatidic acid (LPA), a growth factor-like lysophospholipid, induces diverse cellular responses. The identification of the first LPA receptor gene, through studies of neuroproliferative regions within the embryonic cerebral cortex, has led to the classification of a family of at least eight lysophospholipid receptors with diverse roles in organismal development and function. A growing body of literature has identified roles for LPA signaling under physiological and pathological conditions, particularly within the developing nervous system. Here the authors review features of the LPA receptor family and cellular responses of nervous system-derived cells, and discuss developmental and pathological roles for LPA signaling in the nervous system.

Over the last two decades, glutamate has been established as the main excitatory neurotransmitter in the mammalian brain. Glutamate released from synapses activates ion channel-forming receptors at postsynaptic cells and consequently mediates fast postsynaptic potentials. These receptors are termed ionotropic glutamate receptors (iGluRs). The subsequent discovery of metabotropic glutamate receptors (mGluRs) revealed that glutamate can also mediate slow synaptic potentials, modulate ion channels, and directly couple to GTP binding proteins. In contrast to the iGluRs, the mGluRs possess seven transmembrane domains and a large intracellular C-terminus that involves interactions with a variety of other intracellular signaling systems. Eight functionally distinct mGluR subtypes are known to be localized to specific neuron types at presynaptic and/or postsynaptic membranes. Their physiological functions involve the generation of slow excitatory and inhibitory synaptic potentials, modulation of synaptic transmission, synaptic integration, and plasticity. The classical role of glutamate as a fast excitatory synaptic transmitter was largely extended by mGluRs acting as a neuromodulator and even as an activator of inhibitory mechanisms at certain synapses.

Cortical excitability reflects a balance between excitation and inhibition. Glutamate is the main excitatory and GABA the main inhibitory neurotransmitter in the mammalian cortex. Changes in glutamate and GABA metabolism may play important roles in the control of cortical excitability. Glutamate is the metabolic precursor of GABA, which can be recycled through the tricarboxylic acid cycle to synthesize glutamate. GABA synthesis is unique among neurotransmitters, having two separate isoforms of the rate-controlling enzyme, glutamic acid decarboxylase. The need for two separate genes on two chromosomes to control GABA synthesis is unexplained. Two metabolites of GABA are present in uniquely high concentrations in the human brain. Homocarnosine and pyrrolidinone have a major impact on GABA metabolism in the human brain. Both of these GABA metabolites have anticonvulsant properties and can have a major impact on cortical excitability.

Animals subjected to exercise display significant alterations in brain function and neurochemistry, reflecting the innate plasticity of the adult brain to environmental challenges. Following injury, the brain is sensitive to reorganization and regeneration, and thus may be primed for influence by external behavioral demand such as increased use of an injured forelimb. The focus of this review is on the effects of altered use of the impaired forelimb in unilateral rodent models of brain injury. Both the benefits of increased use and the detrimental effects of decreased use following injury will be discussed.

Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral proteases that are important in normal development, angiogenesis, wound repair, and a wide range of pathological processes. Growing evidence supports a key role of the MMPs in many neuroinflammatory conditions, including meningitis, encephalitis, brain tumors, cerebral ischemia, Guillain-Barré, and multiple sclerosis (MS). The MMPs attack the basal lamina macromolecules that line the blood vessels, opening the blood-brain barrier (BBB). They contribute to the remodeling of the blood vessels that causes hyalinosis and gliosis, and they attack myelin. During the acute inflammatory phase of MS, they are involved in the injury to the blood vessels and may be important in the disruption of the myelin sheath and axons. Normally under tight regulation, excessive proteolytic activity is detected in the blood and cerebrospinal fluid in patients with acute MS. Because they are induced in immunologic and nonimmunologic forms of demyelination, they act as a final common pathway to exert a “bystander” effect. Agents that block the action of the MMPs have been shown to reduce the damage to the BBB and lead to symptomatic improvement in several animal models of neuroinflammatory diseases, including experimental allergic encephalomyelitis. Such agents may eventually be useful in the control of excessive proteolysis that contributes to the pathology of MS and other neuroinflammatory conditions.