Role of cytoskeletal abnormalities in the neuropathology and pathophysiology of type I lissencephaly

Type I lissencephaly or agyria-pachygyria is a rare developmental disorder which results from a defect of neuronal migration. It is characterized by the absence of gyri and a thickening of the cerebral cortex and can be associated with other brain and visceral anomalies. Since the discovery of the first genetic cause (deletion of chromosome 17p13.3), six additional genes have been found to be responsible for agyria–pachygyria. In this review, we summarize the current knowledge concerning these genetic disorders including clinical, neuropathological and molecular results. Genetic alterations of LIS1, DCX, ARX, TUBA1A, VLDLR, RELN and more recently WDR62 genes cause migrational abnormalities along with more complex and subtle anomalies affecting cell proliferation and differentiation, i.e., neurite outgrowth, axonal pathfinding, axonal transport, connectivity and even myelination. The number and heterogeneity of clinical, neuropathological and radiological defects suggest that type I lissencephaly now includes several forms of cerebral malformations. In vitro experiments and mutant animal studies, along with neuropathological abnormalities in humans are of invaluable interest for the understanding of pathophysiological mechanisms, highlighting the central role of cytoskeletal dynamics required for a proper achievement of cell proliferation, neuronal migration and differentiation

Is neurogenesis relevant in depression and in the mechanism of antidepressant drug action? A critical review

ObjectivesMajor depression is a complex disorder that involves genetic, epigenetic and environmental factors in its aetiology. Recent research has suggested that hippocampal neurogenesis may play a role in antidepressant action. However, careful examination of the literature suggests that the complex biological and psychological changes associated with depression cannot be attributed to disturbance in hippocampal neurogenesis alone. While antidepressants may induce hippocampal neurogenesis in non-human primates, there is a paucity of evidence that such effects are sufficient for full therapeutic action in humans.MethodsThis review examines the literature on neurogenesis and discusses the stress-induced cortisol neurotoxicity and antidepressant-induced neurogenesis rescue model of depression. The disparity between a simple antidepressant-induced neurogenesis rescue model in the hippocampus and the complexity of clinical depression is analyzed through critical evaluation of recent research data.Results and conclusionsMajor depression is a complex brain disorder with multiple symptoms and disturbances reflecting dysfunction in more than one single brain area. Initial research suggesting a model of hippocampal degeneration as basis of depression, and reversal by antidepressants through neurogenesis seems to be over-simplified given the emergence of new data. Synaptogenesis and re-organization or re-integration of new neurons rather than simple addition of new neurons may underlie the role of antidepressant drugs in the reversal of some but not all symptoms in depression. The importance of the neurogenesis hypothesis of depression and antidepressant action lies in stimulating further research into the possible roles played by the new neurons and synapses generated