A Local Reduction in Cortical GABAergic Synapses after a Loss of Endogenous Brain-Derived Neurotrophic Factor, as Revealed by Single-Cell Gene Knock-Out Method

Kohara, Keigo; Yasuda, Hiroki; Huang, Yan; Adachi, Naoki; Sohya, Kazuhiro; Tsumoto, Tadaharu

doi:10.1523/jneurosci.1943-07.2007

Cited by 124 publications

(113 citation statements)

References 62 publications

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“…Previous results have demonstrated that knockeddown BDNF expression in cultured cortical neurons decreases the number of GABAergic synapses, resulting in reduced mIPSC frequency (29). Overexpression of the BDNF gene, as well as chronic treatment with BDNF, promotes maturation of GABAergic innervations in the hippocampus (17).…”

Section: Discussionmentioning

confidence: 99%

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

Shinoda

Sadakata

Nakao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Calcium-dependent activator protein for secretion 2 (CAPS2) is a dense-core vesicle-associated protein that is involved in the secretion of BDNF. BDNF has a pivotal role in neuronal survival and development, including the development of inhibitory neurons and their circuits. However, how CAPS2 affects BDNF secretion and its biological significance in inhibitory neurons are largely unknown. Here we reveal the role of CAPS2 in the regulated secretion of BDNF and show the effect of CAPS2 on the development of hippocampal GABAergic systems. We show that CAPS2 is colocalized with BDNF, both synaptically and extrasynaptically in axons of hippocampal neurons. Overexpression of exogenous CAPS2 in hippocampal neurons of CAPS2-KO mice enhanced depolarization-induced BDNF exocytosis events in terms of kinetics, frequency, and amplitude. We also show that in the CAPS2-KO hippocampus, BDNF secretion is reduced, and GABAergic systems are impaired, including a decreased number of GABAergic neurons and their synapses, a decreased number of synaptic vesicles in inhibitory synapses, and a reduced frequency and amplitude of miniature inhibitory postsynaptic currents. Conversely, excitatory neurons in the CAPS2-KO hippocampus were largely unaffected with respect to field excitatory postsynaptic potentials, miniature excitatory postsynaptic currents, and synapse number and morphology. Moreover, CAPS2-KO mice exhibited several GABA system-associated deficits, including reduced late-phase long-term potentiation at CA3-CA1 synapses, decreased hippocampal theta oscillation frequency, and increased anxiety-like behavior. Collectively, these results suggest that CAPS2 promotes activity-dependent BDNF secretion during the postnatal period that is critical for the development of hippocampal GABAergic networks.dense-core vesicles | brain-derived neurotrophic factor | GABAergic synapse

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Section: Discussionmentioning

confidence: 99%

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

Shinoda

Sadakata

Nakao

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Although BDNF-TrkB signaling is known to regulate synaptic formation and transmission tone between glutamatergic principal neurons and interneurons (1)(2)(3)(4)11), its specific role in network function remains unclear. Using the TrkB-PV −/− mice, in which the trkB gene has been specifically deleted in PV+ interneurons, we show that BDNFTrkB signaling in PV+ interneurons is critical for the gamma band rhythmic activity in the hippocampal network.…”

Section: Discussionmentioning

confidence: 99%

“…Among cortical interneurons, PV+ interneurons express trkB abundantly (6). This anatomical organization of the BDNF signaling components and the known importance of feedback and feedforward communication between principal cells and interneurons (7)(8)(9)(10)(11) suggest a potential role for TrkB signaling in modulating neuronal network function.…”

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confidence: 88%

TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus

Zheng

An²,

Yang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Although brain-derived neurotrophic factor (BDNF) is known to regulate circuit development and synaptic plasticity, its exact role in neuronal network activity remains elusive. Using mutant mice (TrkB-PV −/− ) in which the gene for the BDNF receptor, tyrosine kinase B receptor (trkB), has been specifically deleted in parvalbuminexpressing, fast-spiking GABAergic (PV+) interneurons, we show that TrkB is structurally and functionally important for the integrity of the hippocampal network. The amplitude of glutamatergic inputs to PV+ interneurons and the frequency of GABAergic inputs to excitatory pyramidal cells were reduced in the TrkB-PV −/− mice. Functionally, rhythmic network activity in the gamma-frequency band (30-80 Hz) was significantly decreased in hippocampal area CA1. This decrease was caused by a desynchronization and overall reduction in frequency of action potentials generated in PV+ interneurons of TrkB-PV −/− mice. Our results show that the integration of PV+ interneurons into the hippocampal microcircuit is impaired in TrkB-PV −/− mice, resulting in decreased rhythmic network activity in the gamma-frequency band.gamma oscillations | synaptic transmission | Cre recombinase | dendrite | slice T yrosine kinase B receptor (TrkB), the cognate receptor for brain-derived neurotrophic factor (BDNF) and neurotrophin-4, mediates key signaling events that control many aspects of neuronal development and function (1-4), including the maturation of parvalbumin-positive (PV+) interneurons in the hippocampal microcircuit. BDNF is preferentially synthesized in, and secreted from glutamatergic neurons, whereas trkB is expressed in both glutamatergic and γ-aminobutyric acid (GABA)-ergic neurons in hippocampus (5). Among cortical interneurons, PV+ interneurons express trkB abundantly (6). This anatomical organization of the BDNF signaling components and the known importance of feedback and feedforward communication between principal cells and interneurons (7-11) suggest a potential role for TrkB signaling in modulating neuronal network function.Rhythmic activity in cortical networks is important for the formation of neuronal assemblies (12)(13)(14). Of particular interest is rhythmic network activity in the gamma-frequency band (30-80 Hz, gamma oscillations) (15-17). Gamma oscillations are a result of the synchronized electrical activity of the neurons within a network and are thought to be important for temporal encoding, binding of sensory features, and memory storage and retrieval (18)(19)(20)(21)(22). Moreover, gamma oscillations are altered in several brain disorders, such as Alzheimer's disease (23-25), schizophrenia (24, 26-31), and epilepsy (24,32,33). Gamma oscillations are exquisitely susceptible to modulation of the cellular and synaptic mechanisms underlying the rhythmic activity. Fast-spiking PV+ interneurons are the main recipient of recurrent glutamatergic innervations in the hippocampal circuitry, and their role in gamma-frequency synchronization in cortical and hippocampal networks is well-establish...

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“…Evoked LFPs are dominated by excitatory synaptic transmission, but contain the combination of excitatory and inhibitory post-synaptic potentials. As chronic changes in BDNF signaling have been shown to positively correlate with the amount of perisomatic inhibition 6,25 by parvalbumin-expressing interneurons we also determined whether the TrkB.T1-EGFP transgenic animals showed changes in inhibitory inputs using immunohistochemistry. We examined the parvalbumin-positive boutons around pyramidal cell bodies, which provide the major source of inhibition in the cortex.…”

Section: Synaptic Efficacy Is Reduced By Overexpression Of Trkbt1mentioning

confidence: 99%

“…The reduction in excitatory transmission was thus larger than the response losses alone suggested. Chronic reduction of 9 postsynaptic release of BDNF is known to reduce perisomatic inhibition 25 . If this is mediated by a postsynaptic effect on inhibitory synapses, a similar mechanism could be at work in the transgenic mice.…”

Section: Normalization Model Reliably Matches Experimental Datamentioning

confidence: 99%

Contrast gain control and cortical TrkB signaling shape visual acuity

Heimel¹,

Saiepour²,

Chakravarthy³

et al. 2010

Nat Neurosci

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2The limits of visual acuity and contrast sensitivity are set by the eye, but what we perceive is determined by the visual cortex 1 . In healthy, mature people and animals, the visual acuities of the retina and the cortex are well-matched 2 , but this match is neither automatic nor unbreakable. Differences between cortical and retinal acuity are most apparent during development, when cortical acuity continues to rise after retinal development is completed 3 , and during aging, when behavioral acuity falls even without obvious changes in the eye or the thalamus 4 . Differences also occur as a result of cortical injury or erroneous development. This is the case with amblyopia, the most prevalent (2-4%) visual impairment in young people. Amblyopia is a reduced psychophysical acuity in one or both eyes. It is believed to be caused by deficient processing in the visual cortex 5 , but the mechanisms underlying the dissociations of retinal and cortical acuity in amblyopia and in the healthy aging and developing brain are unclear. Interestingly, there is a good match between changes in the cortical expression level of brain-derived neurotrophic factor (BDNF) and changes in visual acuity.During development, acuity and BDNF levels rise 6 , while both slowly decrease with age 4,7 . This relationship between BDNF and acuity also holds for experimentally induced amblyopia. BDNF mRNA and protein levels 8,9 and acuity 10 in the primary visual cortex (V1) responding to a monocularly deprived eye are all below normal. In amblyopic rats receiving environmental enrichment 11 or antidepressant treatment 12 , increased BDNF expression in the cortex was seen in parallel to the restoration of visual acuity. Moreover, transgenic mice overexpressing BDNF in the forebrain show a faster rise of cortical acuity 6 even when reared in darkness 13 . Although there is a wealth of data on the involvement of BDNF and its main receptor TrkB in neuronal development 14 , synaptic efficacy 15 , -morphology 16 and -plasticity 17,18 , it has remained unknown how BDNF promotes visual acuity at the coding level and whether BDNF signaling plays a role in acuity in the mature cortex. For these reasons we studied visual acuity in adult transgenic mice where, after normal development is completed, cortical TrkB/BDNF signaling is impaired. We found a loss of acuity, caused by a reduction in apparent contrast. Using a combination of experiments and modeling, we show the involvement of cortical gain control in the selective loss of responses to visual stimuli with high spatial frequencies and the maintenance of responses to low spatial frequencies. RESULTS Genetic inhibition of TrkB signaling in the adult cortexTo investigate the role of TrkB signaling in cortical acuity in the mature animal we overexpressed a dominant negative TrkB.T1-EGFP fusion protein 19 in a large proportion of pyramidal cells after the maturation of cortical acuity. This was achieved by crossing mice carrying a Cre-dependent TrkB.T1-EGFP-transgene under the control of the Thy-1 promoter ...

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A Local Reduction in Cortical GABAergic Synapses after a Loss of Endogenous Brain-Derived Neurotrophic Factor, as Revealed by Single-Cell Gene Knock-Out Method

Cited by 124 publications

References 62 publications

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

Calcium-dependent activator protein for secretion 2 (CAPS2) promotes BDNF secretion and is critical for the development of GABAergic interneuron network

TrkB signaling in parvalbumin-positive interneurons is critical for gamma-band network synchronization in hippocampus

Contrast gain control and cortical TrkB signaling shape visual acuity

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