الفهرس 
BRAIN DEVELOPMENT AND EUROBIOLOGICAL REGULATION FACTORSOnly 14 pages are availabe for public view
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Abstract
Over the past several decades, significant advances have been made in our understanding of the basic stages and mechanisms of mammalian brain development. Studies elucidating the neurobiology of brain development span the levels of neural organization from the macro-anatomic, to the cellular, to the molecular. Together, this large body of work provides a picture of brain development as the product of a complex series of dynamic and adaptive processes operating within a highly constrained, genetically organized but constantly changing context. The view of brain development that has emerged from the developmental neurobiology literature presents both challenges and opportunities to psychiatrists seeking to understand the fundamental processes that underlie social and cognitive development, and the neural systems that mediate them.
The neurotrophins are the best understood trophic factors in the nervous system. Neurotrophins are initially synthesized as precursors or pro-neurotrophins that are cleaved to release the mature active proteins. The mature proteins form stable non-covalent dimers and are normally expressed at very low levels during development. Competition for trophic factors determines the number of surviving neurons during target innervation.
BDNF is found in neurons of the central nervous system. It’s expressed predominantly in hippocampus, cortex, and synapses of the basal forebrain. The synthesis of BDNF is subject to regulation by neuronal activity and specific transmitter systems. BDNF expression is also switched on in Schwann cells following peripheral nerve lesion. BDNF is expressed also in muscles and its expression is up-regulated in denervated muscles. BDNF is also produced in inflammatory processes by a wide range of hematopoietic cells including mast cells, macrophages, and T cells. In addition, airway epithelium constitutively expresses BDNF.
In fact, all neurotrophins, including BDNF, are synthesized as a pre-pro-neurotrophin precursor that undergo posttranslational modifications before giving rise to mature homodimeric protein. The pro-BDNF is produced in endoplasmic reticulum, which is accumulated in trans- Golgi network via Golgi apparatus. It has been suggested that pro-BDNF binds to sortilin in the Golgi, which facilitates the correct folding of the mature domain. The mature domain of BDNF binds to carboxypeptidase E, thereby sorting BDNF to the regulated secretary pathway.
Since BDNF supports the survival of sensory neurons, retinal ganglion cells, basal forebrain cholinergic neurons, and mesencephalic dopaminergic neurons in vitro, it may be of use in local treatment of nerve degeneration disorders such as Parkinson’s disease. The effects of BDNF on motor neurons raise the possibility that it may be useful in treating patients with motor neuropathies.
Current thinking, derived largely from genetic and behavioral studies, posits that the primary function of BDNF in the adult brain is to regulate synaptic transmission and plasticity, rather than cell survival. Hypotheses that BDNF may play a potential role in the pathophysiology of schizophrenia are based on the idea that BDNF is a key regulator of synaptic plasticity, and therefore various cognitive functions. Data from animal models of schizophrenia in which BDNF signaling is abnormally regulated lent initial support to these hypotheses. In humans, genetic studies have further supported a link between BDNF and schizophrenia as well as with brain dysfunction associated with the disorder.
Risperidone is one of the most widely used second-generation antipsychotic agents for treatment and maintenance therapy of schizophrenia and other related psychotic disorders. It has many clinical advantages over first-generation antipsychotic agents, such as a lower incidence of extrapyramidal symptoms, more frequent clinically significant improvement, a lower risk of relapse, and a favorable effect on both positive and negative symptoms. However, as with other antipsychotics, significant inter-individual differences in therapeutic response to risperidone in schizophrenia patients, both regarding therapeutic response and adverse effects, have also been reported. Genetic factors are commonly considered to be the main cause of these inter-individual differences.
Depression and suicidal behavior have recently been shown to be associated with disturbances in structural and synaptic plasticity. Brain-derived neurotrophic factor (BDNF) plays an important role in the maintenance and survival of neurons and in synaptic plasticity. Several lines of evidence suggest that BDNF is involved in depression, such that the expression of BDNF is decreased in depressed patients. In addition, antidepressants up-regulate the expression of BDNF. This has led to the proposal of the “neurotrophin hypothesis of depression”. Increasing evidence demonstrates that suicidal behavior is also associated with lower expression of BDNF, which may be independent from depression. Moreover, recent genetic studies also support a link of BDNF to depression/suicidal behavior. Not only BDNF, but abnormalities in its cognate receptor tropomycin receptor kinase B (TrkB) and its splice variant (TrkB.T1) have also been reported in depressed/suicidal patients. It has been suggested that epigenetic modulation of the BDNFand TrkBgenes may contribute to their altered expression and functioning. More recently, impairment in the functioning of pan75 neurotrophin receptor has been reported in suicide brain specimens. Pan75 neurotrophin receptor is a low-affinity neurotrophin receptor that, when expressed in conjunction with low availability of neurotropins, induces apoptosis. Overall, these studies suggest the possibility that BDNF and its mediated signaling may participate in the pathophysiology of depression and suicidal behavior.
The effects of antidepressants on the expression of the BDNF gene have been investigated extensively. In general, it hasbeen shown that when given to healthy rodents, severalclasses of antidepressants, including monoamine oxidaseinhibitors, selective serotonin reuptake inhibitors, tricyclicagents, noradrenaline reuptake inhibitors, and noradrenergicand specific serotonergic antidepressants, all increase expressionof BDNF in the brain.In addition, several otheragents known to have antidepressant properties also increaseexpression of BDNF in rodent brain. These agents includeα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acidand N-methyl-D-aspartate antagonists, electroconvulsiveshock, and trans-cranial magnetic stimulation.
Collectively, these data suggest that, in addition to serving as a potential biomarker for MDD and/or a therapeutic marker for the efficacy of antidepressant treatments, peripheral BDNF has behavioral and cellular effects that are similar to antidepressants. The precise mechanism(s) underlying the effects of peripheral BDNF remain to be determined but are likely to involve, in part, increased BDNF levels and TrkB signaling in the brain. These findings indicate that measures of serum BDNF can provide a novel window into brain structure and function that is relevant to the pathophysiology and treatment of mood disorders.