BDNF and NT-4, but not NT-3, promote development of inhibitory synapses in the absence of neuronal activity

Seil, Fredrick J.

doi:10.1016/s0006-8993(98)01304-3

Cited by 38 publications

(37 citation statements)

References 19 publications

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“…BDNF is trophic for GABA-containing interneurons, [15][16][17][18]60 and these neurons synapse directly on nearby large neurons that synthesize BDNF. Fairly consistent evidence exists for pathology in GABAcontaining interneurons in the brains of patients with schizophrenia, [61][62][63][64][65][66][67][68][69] and the reduction in BDNF may have consequences for this population of neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed trkB mRNA is found in both neuronal types in rodent brain and BDNF can influence the survival, neurite outgrowth and/or synapse formation of both glutamate [12][13][14] and GABA-containing neurons. [15][16][17][18] Since there is evidence for alterations in both excitatory and inhibitory neurons in cortex of subjects with schizophrenia (for reviews, see Blum and Mann 19 ; Goff and Coyle 20 ), we hypothesized that both large and/or small neurons may be compromised by this BDNF reduction and, in turn, may contain abnormal levels of trkB TK þ mRNA in the DLPFC of patients with schizophrenia as compared to controls. To begin to explore how BDNF mRNA levels and catalytic trkB receptor mRNA levels may relate, we tested if the levels of these measures correlated.…”

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confidence: 99%

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Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia

et al. 2005

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Patients with schizophrenia have reduced neurotrophin levels in their dorsolateral prefrontal cortex (DLPFC) compared to normal unaffected individuals. The tyrosine kinase-containing receptors, trkB and trkC, mediate the growth-promoting effects of neurotrophins and respond to changes in growth factor availability. We hypothesized that trkB and/or trkC expression would be altered in the DLPFC of patients with schizophrenia. We measured mRNA encoding the tyrosine kinase domain (TK þ )-containing form of trkB and measured pan trkC mRNA in schizophrenics (N ¼ 14) and controls (N ¼ 15) using in situ hybridization. TrkB and trkC mRNAs were detected in large and small neurons in multiple cortical layers of the human DLPFC. We found significantly diminished expression of trkB TK þ mRNA in large neurons in multiple cortical layers of patients as compared to controls, while small neurons also showed reductions in trkB TK þ mRNA that did not reach statistical significance. In normals, strong positive correlations were found between trkB TK þ mRNA levels and brain-derived neurotrophic factor (BDNF) mRNA levels among various neurons, while no correlation between BDNF and trkB TK þ was found in patients with schizophrenia. TrkC mRNA was also reduced in the DLPFC of schizophrenics in large neurons in layers II, III, V and VI and in small neurons in layer IV. Since neurons in the DLPFC integrate and communicate signals to various cortical and subcortical regions, these reductions in growth factor receptors may compromise the function and plasticity of the DLPFC in schizophrenia. Molecular Psychiatry (2005) 10, 637-650.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia

et al. 2005

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“…BDNF stimulates survival of both glutamate [5][6][7]92 and GABAergic neurons. [93][94][95][96][97] Reduced production of BDNF in the brain of patients with schizophrenia may have consequences for both neuronal populations. Indeed, we find that pyramidal neurons and nonpyramidal neurons throughout all layers of the adult human DLPFC contain the high-affinity tyrosine-containing receptor for BDNF, trkB TK þ 86 , and are therefore potentially sensitive to a reduction in BDNF.…”

Section: Potential Consequences Of Reduced Bdnfmentioning

confidence: 99%

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia

et al. 2003

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Anatomical and molecular abnormalities of excitatory neurons in the dorsolateral prefrontal cortex (DLPFC) are found in schizophrenia. We hypothesized that brain-derived neurotrophic factor (BDNF), a protein capable of increasing pyramidal neuron spine density and augmenting synaptic efficacy of glutamate, may be abnormally expressed in the DLPFC of patients with schizophrenia. Using an RNase protection assay and Western blotting, we detected a significant reduction in BDNF mRNA (mean = 23%) and protein (mean = 40%) in the DLPFC of patients with schizophrenia compared to normal individuals. At the cellular level, BDNF mRNA was expressed at varying intensities in pyramidal neurons throughout layers II, III, V, and VI of DLPFC. In patients with schizophrenia; neuronal BDNF expression was decreased in layers III, V and VI. Our study demonstrates a reduction in BDNF production and availability in the DLPFC of schizophrenics, and suggests that intrinsic cortical neurons, afferent neurons, and target neurons may receive less trophic support in this disorder.

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“…Recent studies have suggested a role for neurotrophins in the growth and refinement of neural connections, 43 dendritic arborization, 17 programmed cell death, 44 cortical lamination, 18,45 synaptogenesis, 46 and in activity-dependent synaptic plasticity. 47,48 Altered expression of NT3, NT4, trkB, and trkC as well as netrin 1 may have numerous potentially deleterious effects on cortical lamination during development. For example, an intriguing study demonstrated that administration of exogenous NT4 to organotypic cortical slice cultures results in dyslamination and neuronal heterotopia within cortical layers I to II.…”

Section: Altered Neurotrophin Expression and Aberrant Cytoarchitecturmentioning

confidence: 99%

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Kyin

Yang

Baybis

et al. 2001

The American Journal of Pathology

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Neurotrophins and their receptors modulate cerebral cortical development. Tubers in the tuberous sclerosis complex (TSC) are characterized histologically by disorganized cortical cytoarchitecture and thus, we hypothesized that expression of neurotrophin mRNAs and proteins might be altered in tubers. Using in situ transcription and mRNA amplification to probe cDNA arrays, we found that neurotrophin-3 (NT3) and trkB mRNA expression were reduced whereas neurotrophin-4 (NT4) and trkC mRNA expression were increased in whole tuber sections. Alterations in mRNA abundance were defined in single microdissected dysplastic neurons (DNs) and giant cells (GCs). NT3 mRNA expression was reduced in GCs and trkB mRNA expression was reduced in DNs. NT4 mRNA expression was increased in DNs and trkC mRNA expression was increased in both DNs and GCs. In three patients, TSC2 locus mutations were confirmed and the mean tuberin mRNA expression levels was reduced across all nine cases. Consistent with these observations, NT3 mRNA expression was reduced but trkC mRNA expression was increased in vitro in human NTera2 neurons ( Tubers in the tuberous sclerosis complex (TSC) are developmental abnormalities of cerebral cortical cytoarchitecture that are associated clinically with epilepsy. [1][2][3] Electrocorticography has shown that tubers are epileptogenic and seizures in TSC patients are often medically intractable despite anticonvulsant polytherapy. 4 -6 TSC is an autosomal-dominant disorder resulting from mutations in one of two genes, TSC1 or TSC2 7,8 although the mechanism by which mutations in either TSC gene leads to tuber formation is unknown. Disorganized cortical lamination and aberrant cellular morphology are important histological features of tubers. Large dysplastic neurons (DNs) and giant cells (GCs) are prominent cell types in tubers. 9 DNs and GCs share select morphological features including cytomegaly, the extension of aberrant processes often of unclear identity, ie, axons versus dendrites, and the expression of neural protein markers such as neurofilament and ␣-internexin. 1,9,10 The TSC2 knockout mouse 11 and the Eker rat strain 12 do not fully model human brain pathology in TSC, and thus, analysis of human tuber specimens provides the only direct avenue to study the mechanisms of tuber formation. One strategy to investigate the molecular pathogenesis of cytoarchitectural disorganization in tubers is to evaluate the expression of candidate genes and proteins in human tuber specimens that are relevant to cortical development. 10 Neurotrophins and their cognate receptors comprise a family of proteins that mediate proliferation, differentiation, migration, and process outgrowth during cortical development, 13,14 and thus, are ideal candidate molecules to investigate in tubers. Brainderived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) exert their effects on neurons by binding selectively to a family of neuronal cell membrane receptors, trks A to C. 13,14 NGF signals...

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BDNF and NT-4, but not NT-3, promote development of inhibitory synapses in the absence of neuronal activity

Cited by 38 publications

References 19 publications

Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia

Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

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