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)

Levels of mRNA for c-fos, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), TrkB, and TrkC were studied using in situ hybridization in the rat brain at different reperfusion times after unilateral middle cerebral artery occlusion (MCAO). Short-term (15 min) MCAO, which does not cause neuronal death, induced elevated BDNF mRNA expression confined to ipsilateral frontal and cingulate cortices outside the ischemic area. With a longer duration of MCAO (2 h), which leads to cortical infarction, the increase was more marked and elevated BDNF mRNA levels were also detected bilaterally in dentate granule cells and CA1 and CA3 pyramidal neurons. Maximum expression was found after 2 h of reperfusion. At 24 h BDNF mRNA expression had returned to control values. In the ischemic core of the parietal cortex only scattered neurons were expressing high levels of BDNF mRNA after 15 min and 2 h of MCAO. Analysis of different BDNF transcripts showed that MCAO induced a marked increase of exon III mRNA but only small increases of exon I and II mRNAs in cortex and hippocampus. In contrast to BDNF mRNA, elevated expression of c-fos mRNA was observed in the entire ipsilateral cerebral cortex, including the ischemic core, after both 15 min and 2 h of MCAO. Two hours of MCAO also induced transient, bilateral increases of NGF and TrkB mRNA levels and a decrease of NT-3 mRNA expression, confined to dentate granule cells. The upregulation of BDNF mRNA expression in cortical neurons after MCAO is probably triggered by glutamate through a spreading depression-like mechanism. The lack of response of the BDNF gene in the ischemic core may be due to suppression of signal transduction or transcription factor synthesis caused by the ischemia. The observed pattern of gene expression after MCAO agrees well with a neuroprotective role of BDNF in cortical neurons. However, elevated levels of NGF and BDNF protein could also increase synaptic efficacy in the postischemic phase, which may promote epileptogenesis.
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PMID:Regulation of brain-derived neurotrophic factor gene expression after transient middle cerebral artery occlusion with and without brain damage. 758 36

Levels of mRNA for nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and the tyrosine kinase receptors trkB and trkC have been studied using in situ hybridization in the rat brain after topical application of KCl to the cortical surface (which induces spreading depression). Repeated episodes of spreading depression during 2 h caused a rapid and marked increase of BDNF mRNA levels in deep and, in particular, superficial cortical layers of the ipsilateral hemisphere (to 213 and 417% of control, respectively). Maximal levels were reached within 2 h after the cessation of spreading depression and at 24 h BDNF mRNA expression had returned to control values. Levels of BDNF mRNA were unaffected in the hippocampus, in areas outside the cerebral cortex and in the contralateral hemisphere. Furthermore, no change of the expression of mRNA for NGF, NT-3, trkC or the full length trkB receptor was detected at any time point. However, at 2 h after spreading depression there was an increased level (150% of control) in superficial cortical layers of mRNA hybridizing to an oligonucleotide probe detecting both truncated receptors lacking the tyrosine kinase domain and full length trkB receptors. Also one single episode of spreading depression gave rise to a significant increase of cortical BDNF mRNA levels (to 207% of control), which was attenuated (by 61%) after administration of the competitive NMDA receptor antagonist CGS 19755. The results provide evidence that mild brain insults associated with glutamate release and elevated intracellular calcium, such as spreading depression, also in the absence of seizure activity can lead to activation of the BDNF gene in cortical neurons.
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PMID:Rapid increase of BDNF mRNA levels in cortical neurons following spreading depression: regulation by glutamatergic mechanisms independent of seizure activity. 823 31

We tested the hypothesis that neurotrophin-3 (NT-3) in adult cats can rescue the central synapses made by muscle afferents from the effects of peripheral axotomy. The medial gastrocnemius (MG) muscle nerve in cats was axotomized and capped or axotomized and the distal end provided with either saline or NT-3 by mini-osmotic pump. Four to five weeks later monosynaptic excitatory postsynaptic potentials (EPSPs) elicited by electrical stimulation of the axotomized MG nerve were recorded in intact lateral gastrocnemius/soleus (LGS) motoneurons. The axotomized MG afferents without NT-3 treatment generated EPSPs averaging one-half of the amplitude of those generated by normal intact MG afferents. Axotomized MG afferents treated with NT-3 elicited EPSPs averaging 2.5 times normal amplitude and 5 times the amplitude of those from afferents axotomized but not treated. The very large EPSPs generated by NT-3-treated afferents remained as susceptible to depression during high-frequency stimulation (32 shocks at 167 Hz) as those elicited by untreated axotomized afferents. The arrival of the afferent volley of the cord dorsum potential and the onset of EPSPs were both delayed by axotomy of the group Ia afferents and were both restored by exposure to NT-3. This result suggests that the conduction velocity and thus the caliber of group Ia afferents are also controlled by NT-3. We conclude that the neurotrophin NT-3 has a continuing role in the maintenance of physiological function of muscle afferents in adult mammals.
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PMID:NT-3 increases amplitude of EPSPs produced by axotomized group Ia afferents. 911 68

The neurotrophins, nerve growth factor, brain-derived neurotrophic factor, neurotrophin-3 and neurotrophin-4/5, have--in addition to their known effects as neuronal survival factors--recently been found to modulate synaptic transmission in the rat hippocampus and neocortex. Using standard whole-cell patch-clamp recordings, we have now investigated the acute effects of brain-derived neurotrophic factor and neurotrophin-4/5 on unitary (i.e. single cell activated) glutamatergic synaptic connections in microcultures of postnatal rat hippocampal neurons. We show that, in approximately 30% of the cells, glutamatergic synaptic transmission is enhanced to 170 +/- 52% (neurotrophin-4/5, 100 ng/ml) and 143 +/- 35% (brain-derived neurotrophic factor, 100 ng/ml) of control values, respectively. The enhancement is abolished in the presence of the specific Trk tyrosine kinase inhibitor k252a (200 nM). Depending on the particular cell investigated, the enhancement consisted of transient and sustained components in varying quantities. A minority of neurons (10%) showed a depression of glutamatergic synaptic transmission to 64 +/- 14% (brain-derived neurotrophic factor) and 61 +/- 11% of control (neurotrophin-4/5). The enhancement of unitary glutamatergic synaptic transmission is mediated predominantly by presynaptic modifications, as is evident from (i) the concomitant decrease in paired-pulse facilitation, (ii) the concomitant increase in the variance of the evoked unitary synaptic currents and (iii) the enhanced miniature excitatory postsynaptic/autaptic current frequencies that could be observed in the absence of an effect on miniature excitatory postsynaptic/autaptic current amplitudes. Finally, we show that the successful enhancement of synaptic transmission by neurotrophin-4/5 critically depends on the degree of paired-pulse facilitation prior to the start of neurotrophin application, with autapses/synapses initially showing a higher degree of paired-pulse facilitation being enhanced more effectively. Taken together, these results suggest that the brain-derived neurotrophic factor- and neurotrophin-4/5-mediated enhancement of unitary glutamatergic synaptic transmission in hippocampal cultures results predominantly from a presynaptic modulation of transmitter release, and this modulation could participate in the neurotrophin-dependent modification of glutamatergic synaptic transmission in the hippocampus in situ.
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PMID:Modulation of unitary glutamatergic synapses by neurotrophin-4/5 or brain-derived neurotrophic factor in hippocampal microcultures: presynaptic enhancement depends on pre-established paired-pulse facilitation. 988 55

Exogenous delivery of the neurotrophic factors, brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3), promotes the function, sprouting and regrowth of 5-HT-containing neurones in the brains of adult rats. Similar infusions of BDNF into the dorsal raphe nucleus produce an antidepressant effect, as evaluated by several 'learned helplessness' paradigms. Environmental stressors such as immobilization induce depression and decrease BDNF mRNA. Antidepressants increase BDNF mRNA in the brain, via 5-HT2A and beta-adrenoceptor subtypes and prevent the stress-induced decreases in BDNF mRNA. In this article, Tony Altar discusses how existing treatments of depression might work by increasing endogenous brain levels of BDNF or NT-3, which in turn could promote monoamine-containing neurone growth and function. Drugs that selectively stimulate the production of neurotrophins could represent a new generation of antidepressants.
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PMID:Neurotrophins and depression. 1010 65

The aim of this study was to explore the role of endogenous neurotrophins for inhibitory synaptic transmission in the dentate gyrus of adult mice. Heterozygous knockout (+/-) mice or neurotrophin scavenging proteins were used to reduce the levels of endogenous brain-derived neurotrophic factor and neurotrophin-3. Patch-clamp recordings from dentate granule cells in brain slices showed that the frequency, but not the kinetics or amplitude, of miniature inhibitory postsynaptic currents was modulated in brain-derived neurotrophic factor +/- compared to wild-type (+/+) mice. Furthermore, paired-pulse depression of evoked inhibitory synaptic responses was increased in brain-derived neurotrophic factor +/- mice. Similar results were obtained in brain slices from brain-derived neurotrophic factor +/+ mice incubated with tyrosine receptor kinase B-immunoglobulin G, which scavenges endogenous brain-derived neurotrophic factor. The increased inhibitory synaptic activity in brain-derived neurotrophic factor +/- mice was accompanied by decreased excitability of the granule cells. No differences in the frequency, amplitude or kinetics of miniature inhibitory postsynaptic currents were seen between neurotrophin-3 +/- and +/+ mice. From these results we suggest that endogenous brain-derived neurotrophic factor, but not neurotrophin-3, has acute modulatory effects on synaptic inhibition onto dentate granule cells. The site of action seems to be located presynaptically, i.e. brain-derived neurotrophic factor regulates the properties of inhibitory interneurons, leading to increased excitability of dentate granule cells. We propose that through this mechanism, brain-derived neurotrophic factor can change the gating/filtering properties of the dentate gyrus for incoming information from the entorhinal cortex to hippocampus. This will have consequences for the recruitment of hippocampal neural circuitries both under physiological and pathological conditions, such as epileptogenesis.
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PMID:Increased synaptic inhibition in dentate gyrus of mice with reduced levels of endogenous brain-derived neurotrophic factor. 1111 2

In many areas of the nervous system, excitatory and inhibitory synapses are reconfigured during early development. We have previously described the anatomical refinement of an inhibitory projection from the medial nucleus of the trapezoid body to the lateral superior olive in the developing gerbil auditory brain stem. Furthermore, these inhibitory synapses display an age-dependent form of long-lasting depression when activated at a low rate, suggesting that this process could support inhibitory synaptic refinement. Since the inhibitory synapses release both glycine and GABA during maturation, we tested whether GABA(B) receptor signaling could initiate the decrease in synaptic strength. When whole cell recordings were made from lateral superior olive neurons in a brain slice preparation, the long-lasting depression of medial nucleus of the trapezoid body-evoked inhibitory potentials was eliminated by the GABA(B) receptor antagonist, SCH-50911. In addition, inhibitory potentials could be depressed by repeated exposure to the GABA(B) receptor agonist, baclofen. Since GABA(B) receptor signaling may not account entirely for inhibitory synaptic depression, we examined the influence of neurotrophin signaling pathways located in the developing superior olive. Bath application of brain-derived neurotrophic factor or neurotrophin-3 depressed evoked inhibitory potentials, and use-dependent depression was blocked by the tyrosine kinase antagonist, K-252a. We suggest that early expression of GABAergic and neurotrophin signaling mediates inhibitory synaptic plasticity, and this mechanism may support the anatomical refinement of inhibitory connections.
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PMID:GABA(B) and Trk receptor signaling mediates long-lasting inhibitory synaptic depression. 1143 32

Previous studies demonstrated that antidepressant treatment increases the expression of brain-derived neurotrophic factor (BDNF) in rat hippocampus. The present study was conducted to test the hypothesis that BDNF in the hippocampus produces an antidepressant effect in behavioral models of depression, the learned helplessness (LH) and forced swim test (FST) paradigms. A single bilateral infusion of BDNF into the dentate gyrus of hippocampus produced an antidepressant effect in both the LH and FST that was comparable in magnitude with repeated systemic administration of a chemical antidepressant. These effects were observed as early as 3 d after a single infusion of BDNF and lasted for at least 10 d. Similar effects were observed with neurotrophin-3 (NT-3) but not nerve growth factor. Infusions of BDNF and NT-3 did not influence locomotor activity or passive avoidance. The results provide further support for the hypothesis that BDNF contributes to the therapeutic action of antidepressant treatment.
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PMID:Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. 1194 26

Neurotrophic factors yield neuroprotection by mechanisms that may be related to their effects as inhibitors of apoptosis as well as their effects on ion channels. The effect of ciliary neurotrophic factor (CNTF) on high-threshold voltage-activated Ca channels in cultured fetal mouse brain cortical neurones was investigated. Addition of CNTF into serum-free growth medium resulted in delayed reduction of the Ca2+ currents. The currents decreased to 50% after 4 h and stabilized at this level during incubation with CNTF for 48 h. Following removal of CNTF the inhibition was completely reversed after 18 h. CNTF reduced the current of all pharmacological subtypes of Ca channels as shown by use of selective blockers of L, N, and P/Q type Ca channels (nifedipine, omega-conotoxin MVIIA, omega-agatoxin IVA). The Ca channel depression was mediated via the CNTF receptor, because enzymatic cleavage of the alpha-subunit glycerophosphatidylinositol anchor of the receptor eliminated the response. The CNTF effect was not elicited through pertussis toxin-sensitive G proteins. Other neurotrophic factors like neurotrophin-3 and insulin-like growth factor-I had no effect on the Ca2+ currents. These results may have important implications for the possible functions of CNTF in the nervous system, such as altered synaptic activity, neuronal excitability and susceptibility to brain ischaemia.
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PMID:CNTF inhibits high voltage activated Ca2+ currents in fetal mouse cortical neurones. 1215 74

Nerve growth factor was the first identified protein with anti-apoptotic activity on neurons. This prototypic neurotrophic factor, together with the three structurally and functionally related growth factors brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4/5 (NT4/5), forms the neurotrophin protein family. Target T cells for neurotrophins include many neurons affected by neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and peripheral polyneuropathies. In addition, the neurotrophins act on neurons affected by other neurological and psychiatric pathologies including ischemia, epilepsy, depression and eating disorders. Work with cell cultures and animal models provided solid support for the hypothesis that neurotrophins prevent neuronal death. While no evidence exists that a lack of neurotrophins underlies the etiology of any neurodegenerative disease, these studies have spurred on hopes that neurotrophins might be useful symptomatic-therapeutic agents. However first clinical trials led to variable results and severe side effects were observed. For future therapeutic use of the neurotrophins it is therefore crucial to expand our knowledge about their physiological functions as well as their pharmacokinetic properties. A major challenge is to develop methods for their application in effective doses and in a precisely timed and localized fashion.
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PMID:Neurotrophins. 1257 26


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