The Neuroscientist

Even though phosphorylation of phosphatidylinositols by phosphoinositide 3-kinase has an important and pervasive role in the nervous system, little is known about the phosphatases that reverse this reaction. Recently, such a phosphatase, PTEN, was cloned as a tumor suppressor for gliomas. We now know that PTEN is a tumor suppressor for many tumor types and is a phosphatidylinositol phosphatase specific for the 3-position of the inositol ring. PTEN is expressed in most, if not all, neurons and is localized in the nucleus and cytoplasm. PTEN is not evident in neural processes or synapses. PTEN is induced during neuronal differentiation and is required for survival of differentiating neuronal cells. In summary, PTEN is a regulatory molecule with multiple functions at multiple subcellular sites. Further studies are required to determine which downstream pathways are regulated by PTEN, by which mechanisms PTEN activity is regulated, which stimuli regulate PTEN activity, and why a molecule that inhibits several survival pathways is induced during neurogenesis.

It is perhaps presumptuous to talk about the molecular basis of a subjective sensation such as pain, but defined conformational changes in membrane proteins, controlled by a family of extra- and intracellular messenger molecules, are known to underlie the activation of sensory nerve terminals and the process of synaptic neurotransmission, which are necessary for pain perception. Furthermore, a subset of neurotransmission processes has a permissive, and possibly exclusive, role in pain perception. Clearly, the experience of pain in the clinical sense with all its affective components of unpleasantness and suffering cannot yet be fully understood in molecular terms, but the process of nociception, whereby the signal generated as a result of tissue damaging or potentially damaging peripheral stimuli reaches and evokes neuronal activity in the central nervous system, is becoming better characterized. Recent advances in neurobiology have given us insights that are already helping improve understanding of the events that lead to a patient experiencing pain and, it is hoped, will also lead to more successful treatment strategies.

Dopamine projections from the midbrain to the striatum and frontal cortex are involved in behavioral reactions controlled by rewards, as inferred from deficits in parkinsonism, schizophrenia, and drug addiction. Recent experiments have shown that dopamine neurons are not directly modulated in relation to movements. Rather, they appear to code the rewarding aspects of environmental stimuli. They show short, phasic increases of activity following primary food and liquid rewards (“unconditioned stimuli”) and conditioned, reward-predicting stimuli of visual, auditory, and somatosensory modalities. They also display smaller activation-depression sequences after stimuli resembling rewards and after novel or particularly intense stimuli. Rewards are only reported as far as they occur differently than predicted. According to learning theories, a “prediction error” message may constitute a powerful teaching signal for behavior and learning. The phasic reward message is different from the more tonic enabling function of dopamine that is deficient in Parkinson’s disease, indicating that dopamine neurons subserve different functions at different time scales. Neurons in other brain structures, such as the striatum, orbitofrontal cortex, and amygdala, code the quality, quantity, and preference of rewards. The dopamine reward prediction error signal may cooperate with these reward perception signals during the learning and performance of behavioral reactions to motivating environmental stimuli.

The identification of numerous genes involved in the development of the cerebral cortex has led to an increased interest in the early stages of corticogenesis, when the first postmitotic neurons migrate into the cortical plate to form the foundation of the adult cortex. However, the cellular substrate of gene expression in early human cortical development is widely unknown. This article analyzes the complex sequence of events in the differentiation of the preplate, the predecessor of the neocortex, and discusses the possible origin and migratory routes of the neuronal populations involved in the transition from preplate to cortical plate. The neuronal classes present in embryonic and early fetal stages are redefined in terms of their relationship with the Reelin-Dab1 signaling pathway whose integrity is essential for successful migration into the cortex. A timetable of developmental steps is provided, and the peculiarities of the preplate derivatives in the human brain, marginal zone, and subplate are discussed. The results presented here may contribute to a deeper understanding of the pathogenesis of migration disorders.

The thalamus has long been thought to convey subcortical information to the cortex. Indeed, models of basal ganglia function attribute the primary role for the thalamus to a simple relay of information processed in the basal ganglia to the cortex. The thalamic nuclear groups that are associated primarily with this function are the ventral anterior and ventral lateral nuclei and the mediodorsal thalamic nucleus. However, recent studies have shown that the corticothalamic projection is important for the dynamics of the thalamo-cortical processing. Furthermore, the relay nuclei that carry basal ganglia output to the cortex have recently been shown to project back to the basal ganglia directly. These two recent developments indicate a more dynamic role for the thalamus in basal ganglia information processing than a passive relay.

There is a devastating loss of function when substantial numbers of axons are interrupted by injury to the spinal cord. This loss may be eventually reversed by providing bridging prostheses that will enable axons to regrow across the injury site and enter the spinal cord beyond. This review addresses the bridging strategies that are being developed in a number of spinal cord lesion models: complete and partial transection and cavities arising from contusion. Bridges containing peripheral nerve, Schwann cells, olfactory ensheathing glia, fetal tissue, stem cells/neuronal precursor cells, and macrophages are being evaluated as is the administration of neurotrophic factors, administered by infusion or secreted by genetically engineered cells. Biomaterials may be an important factor in developing successful strategies. Due to the complexity of the sequelae following spinal cord injury, no one strategy will be effective. The compelling question today is: What combinations of the strategies discussed, or new ones, along with an initial neuroprotective treatment, will substantially improve outcome after spinal cord injury?

Mesial temporal lobe epilepsy is the most common form of human epilepsy, and its pathophysiological substrate is usually hippocampal sclerosis, the most common epileptogenic lesion encountered in patients with epilepsy. The disabling seizures associated with mesial temporal lobe epilepsy are typically resistant to antiepileptic drugs but can be abolished in most patients by surgical treatment. Anteromesial temporal resection, therefore, is the most common surgical procedure performed to treat epilepsy, and stereo-tactically implanted intracerebral electrodes are required in some patients to localize the epileptogenic region. This clinical setting provides a large number of patients for invasive in vivo research with microelectrode and microdialysis techniques and in vitro research following surgical resection on a single epileptic disorder. Consequently, much has now been learned about the fundamental neuronal mechanisms underlying the epileptogenic properties of the human hippocampus in mesial temporal lobe epilepsy. Parallel reiterative studies in patients and animal models of this disorder indicate that enhanced inhibition, in addition to enhanced excitation, underlies the appearance of hypersynchronous neuronal discharges responsible for generating spontaneous seizures. Recent studies have elucidated what may be unique electrophysiological markers of epileptogenicity, which could have valuable diagnostic utility. Although basic research on mesial temporal lobe epilepsy may ultimately suggest novel approaches to treatment and prevention, attention must also be given to maximizing the application of available effective treatments. In particular, the safety and efficacy of surgical therapy has greatly improved in recent years, yet this alternative treatment remains seriously underutilized worldwide. An appropriate increase in referral of patients with this surgically remediable syndrome to epilepsy centers will not only relieve a great many patients of their disabling seizures and reduce the burden of epilepsy but will also provide increased opportunities for invasive research that could ultimately result in even more effective therapies or cures.