Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Changes in neurotrophic factor expression in the brain are part of the stress response. Decreased BDNF may contribute to hippocampal damage that occurs during chronic stress or aging. Stress-induced increases in NT-3 may be important for neural plasticity and adaptation or sensitization to repeated stress. Stress-induced changes in neurotrophic factors may be particularly relevant to the cognitive changes that occur in recurrent depression, aging, and posttraumatic stress disorder.
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PMID:Effects of stress on neurotrophic factor expression in the rat brain. 859 2

The influence of serotonin (5-HT) on neuronal function is mediated by regulation of receptor-coupled intracellular signal transduction pathways, and the therapeutic action of 5-HT selective reuptake inhibitors (SSRIs), as well as other types of antidepressants, most likely involves regulation of these intracellular pathways. The cyclic adenosine monophosphate (cAMP) second messenger system is one pathway that could be involved in antidepressant action. Chronic administration of antidepressants, including SSRIs, up-regulates the cAMP pathway at several levels, including increased expression of the cAMP response element binding protein (CREB). Among the multiple target genes that could be regulated by CREB and that could be involved in antidepressant actions and the pathophysiology of depression in brain-derived neurotrophic factor (BDNF). Stress decreases the expression of BDNF, and reduce levels of this neurotrophic factor could contribute to the atrophy and decreased function of stress-vulnerable hippocampal neurons. In contrast, antidepressant treatment increases the expression of BDNF in hippocampus, and could thereby reverse the stress-induced atrophy of neurons or protect these neurons from further damage. Up-regulation of the cAMP and BDNF systems has resulted in a novel model for the mechanism of action of antidepressants and new targets for the development of therapeutic agents.
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PMID:Novel therapeutic approaches beyond the serotonin receptor. 975 54

According to modern views of the cerebellum in motor control, each cerebellar functional unit, or microzone, learns how to execute predictive and coordinative control, based on long-term depression of the granule cell-Purkinje cell synapses. In the present paper, in light of recent experimental and theoretical studies on synaptic elimination and cerebellar motor learning, a model of the formation of cerebellar microzones by climbing fiber synaptic elimination is proposed. It is shown that competition for an activity-dependent supply of neurotrophic factor can reproduce the spatio-temporal characteristics of climbing fiber synaptic elimination. It is further shown that when this elimination is accurate, motor coordination can be acquired in an arm reaching task. In view of the results of the present study, several predictions are proposed.
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PMID:A model of activity-dependent formation of cerebellar microzones. 979 30

Stress, which can precipitate and exacerbate depression, causes atrophy and in severe cases death of hippocampal neurons. Atrophy of the hippocampus has also been observed in patients suffering from recurrent major depression. The present study examines the influence of electroconvulsive seizures, one of the most effective treatments for depression, on the morphology and survival of hippocampal neurons. The results demonstrate that chronic administration of electroconvulsive seizures induces sprouting of the granule cell mossy fiber pathway in the hippocampus. This sprouting is dependent on repeated administration of electroconvulsive seizures, reaches a maximum 12 days after the last treatment and is long lasting (i.e. up to six months). Electroconvulsive seizure-induced sprouting occurs in the absence of neuronal loss, indicating that sprouting is not a compensatory response to cell death. This is different from the sprouting induced by kindling or excitotoxin treatment, which induce cell death along with recurrent seizures. Electroconvulsive seizure-induced sprouting is significantly diminished in brain-derived neurotrophic factor heterozygote knockout mice, indicating that this neurotrophic factor contributes to mossy fiber sprouting. However, infusion of brain-derived neurotrophic factor into the hippocampus does not induce sprouting of the mossy fiber pathway. The results demonstrate that chronic administration of electroconvulsive seizures induces mossy fiber sprouting and suggest that increased expression of brain-derived neurotrophic factor is necessary, but not sufficient for the induction of this sprouting. Although the functional consequences remain unclear, sprouting of the mossy fiber pathway would appear to oppose the actions of stress and could thereby contribute to the therapeutic actions of electroconvulsive seizure therapy.
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PMID:Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. 1005 Dec 25

Long-term desensitization of AMPA receptors (LTDA) is a core mechanism of long-term depression, a model of motor learning in the cerebellum. In this study we investigated the expression of neurotrophic factor genes after induction of LTDA in cultured cerebellar slices. LTDA was induced by application of quisqualate and monitored as a population response with a wedge recording technique. The levels of mRNA were quantified by reverse transcription followed by polymerase chain reaction. Quisqualate, at a dose and duration that reliably induced LTDA, elicited a significant and specific increase in BDNF mRNA with a peak at four hours after the application. By cell fractionation, the major source of BDNF mRNA increase was found to be in granule cells. In addition, a small but significant increase of transcripts with specific exon usage was observed in a Purkinje cell fraction. These results indicate that BDNF may be coinduced with LTDA and suggest that the slow and sustained increase of BDNF mRNA might play a role in later phases of synaptic plasticity in the cerebellum.
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PMID:A stimulus paradigm inducing long-term desensitization of AMPA receptors evokes a specific increase in BDNF mRNA in cerebellar slices. 1046

As part of a safety and tolerability study, a 65-year-old man with Parkinson's disease (PD) received monthly intracerebroventricular injections of glial-derived neurotrophic factor (GDNF). His parkinsonism continued to worsen following intracerebroventricular GDNF treatment. Side effects included nausea, loss of appetite, tingling, L'hermitte's sign, intermittent hallucinations, depression, and inappropriate sexual conduct. There was no evidence of significant regeneration of nigrostriatal neurons or intraparenchymal diffusion of the intracerebroventricular GDNF to relevant brain regions. Alternative GDNF delivery systems should be explored.
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PMID:Clinicopathological findings following intraventricular glial-derived neurotrophic factor treatment in a patient with Parkinson's disease. 1048 76

1. The authors have recently reported a new protocol for inducing long-term depression through activation of GABAA receptors in the hippocampal slices. This long-term depression is reversed by bicuculline and potentiated by neurosteroids such as alphaxalone. It was also shown that glutamate receptor activity is not involved in the induction of this novel type of long-term depression. Brain derived neurotrophic factor is a member of the neurotrophins family widely expressed in the central nervous system. There is increasing evidence that indicate an important role for brain-derived neurotrophic factor in synaptic plasticity. It has been reported that brain-derived neurotrophic factor level is downregulated by GABA system. The present study investigated a possible relation between muscimol-induced long-term depression and brain-derived neurotrophic factor level. 2. Extracellular recordings were made in the CA1 pyramidal cell layer of rat hippocampal slices following orthodromic stimulation of Schaffer collateral fibers in stratum radiatum. 3. It was observed that brain-derived neurotrophic factor at concentration that did not have any effect itself on the population spike, prevents the induction of long-term depression by muscimol. In addition to this, K-252a an inhibitor of Trk type kinase blocked the prevention of muscimol-induced LTD by brain-derived neurotrophic factor. 4. The results suggest that there is an interaction between muscimol-induced long-term depression and brain-derived neurotrophic factor and may explain the post receptor mechanism of muscimol-induced long-term depression through a bilateral relation between GABAA activity and brain-derived neurotrophic factor.
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PMID:Prevention of muscimol-induced long-term depression by brain-derived neurotrophic factor. 1058 43

Electroconvulsive therapy, which is used to treat refractory major depression in humans increases seizure threshold and decreases seizure duration. Moreover, the expression of brain derived neurotrophic factor induced by electroshocks (ECS) might protect hippocampal cells from death in patients suffering from depression. As temporal lobe epilepsy is linked to neuronal damage in the hippocampus, we tested the effect of repeated ECS on subsequent status epilepticus (SE) induced by lithium-pilocarpine and leading to cell death and temporal epilepsy in the rat. Eleven maximal ECS were applied via ear-clips to adult rats. The last one was applied 2 days before the induction of SE by lithium-pilocarpine. The rats were electroencephalographically recorded to study the SE characteristics. The rats treated with ECS before pilocarpine (ECS-pilo) developed partial limbic (score 2) and propagated seizures (score 5) with a longer latency than the rats that underwent SE alone (sham-pilo). Despite this delay in the initiation and propagation of the seizures, the same number of ECS- and sham-pilo rats developed SE with a similar characteristic pattern. The expression of c-Fos protein was down-regulated by repeated ECS in the amygdala and the cortex. In ECS-pilo rats, c-Fos expression was decreased in the piriform and entorhinal cortex and increased in the hilus of the dentate gyrus. Neuronal damage was identical in the forebrain areas of both groups, while it was worsened by ECS treatment in the substantia nigra pars reticulata, entorhinal and perirhinal cortices compared to sham-pilo rats. Finally, while 11 out of the 12 sham-pilo rats developed spontaneous recurrent seizures after a silent period of 40+/-27 days, only two out of the 10 ECS-pilo rats became epileptic, but after a prolonged latency of 106 and 151 days. One ECS-pilo rat developed electrographic infraclinical seizures and seven did not exhibit any seizures. Thus, the extensive neuronal damage occurring in the entorhinal and perirhinal cortices of the ECS-pilo rats seems to prevent the establishment of the hyperexcitable epileptic circuit.
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PMID:Electroshocks delay seizures and subsequent epileptogenesis but do not prevent neuronal damage in the lithium-pilocarpine model of epilepsy. 1099 2

Recent evidence suggests hippocampal and possibly cortical atrophy is associated with major depression. Chronic electroconvulsive seizures (ECS) induce brain-derived neurotrophic factor (BDNF) expression and sprouting of the mossy fiber pathway in the hippocampus, effects that may be related to electroconvulsive therapy's (ECT) mechanism of action. The objective of this study was to investigate the role of NMDA (N-methyl-D-aspartate) receptor in mediating the ECS-induced mossy fiber sprouting and BDNF expression. Timm histochemistry and in situ hybridization methodologies were used to determine the effect of pretreatment with ketamine, an NMDA antagonist, on ECS-induced sprouting and BDNF expression. The results demonstrate the ability of ketamine pretreatment to attenuate ECS-induced sprouting in the dentate gyrus and BDNF expression in the medial prefrontal cortex and the dentate gyrus. In addition, we found a significant decrease in seizure duration with ketamine pretreatment. These data suggest that NMDA receptor activation contributes to both the regulation of neurotrophic factor expression and the morphological changes associated with seizure activity. However, other effects resulting from shortened seizure duration and seizure intensity cannot be excluded. These findings are of increasing interest, as they relate to the use of ECT in the treatment of depression, and the specific anesthetic agents that are used.
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PMID:ECS-Induced mossy fiber sprouting and BDNF expression are attenuated by ketamine pretreatment. 1128 11

Evidence suggests that brain-derived neurotrophic factor (BDNF) may be important in the pathophysiology of depression, in addition to its role as a neurotrophic factor for sensory neurons. The authors conducted a series of experiments examining the behavioral profile of BDNF heterozygous knockout and wild-type mice. The heterozygous and wild-type mice did not differ on measures of activity, exploration, or hedonic sensitivity, or in the forced swim test. When assessed in the learned helplessness paradigm, heterozygous mice were slower to escape after training than were wild-type mice (p = .02). This effect may be accounted for by the fact that these mice demonstrate a reduced sensitivity to centrally mediated pain, apparent on the hot plate and Formalin injection tests of nociception. Overall, heterozygous mice were not more likely to display anxious or depressive-like behaviors and, consequently, may not constitute a murine model of genetic vulnerability to mood and anxiety disorders.
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PMID:Performance of heterozygous brain-derived neurotrophic factor knockout mice on behavioral analogues of anxiety, nociception, and depression. 1158 27


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