Brain-Derived Neurotrophic Factor Silences GABA Synapses Onto Hypothalamic Neuroendocrine Cells Through a Postsynaptic Dynamin-Mediated Mechanism

Hewitt, Sarah; Bains, Jaideep S.

doi:10.1152/jn.01135.2005

Cited by 43 publications

(39 citation statements)

References 35 publications

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“…For example, BDNF rapidly down-regulates GABA receptor surface expression in cultured neurons from the hippocampus (Cheng and Yeh 2003) and cerebellum (Brunig et al 2001) and in hypothalamic slices (Hewitt and Bains 2006). BDNF has also been shown to decrease postsynaptic responses to applied GABA agonists.…”

Section: Discussionmentioning

confidence: 99%

“…BDNF has also been shown to decrease postsynaptic responses to applied GABA agonists. These effects were prevented by direct postsynaptic application of K252a (Cheng and Yeh 2003;Hewitt and Bains 2006;Tanaka et al 1997) or phospholipase C gamma (PLC␥) inhibitors (Mizoguchi et al 2003;Tanaka et al 1997), suggesting a postsynaptic trkB signaling requirement for these effects. In the present studies, we found no evidence for direct postsynaptic effects in layer 2/3 cortical pyramidal neurons, evidenced by the lack of effect of BDNF on mIPSC amplitude and the lack of effect on responses to locally applied GABA.…”

Section: Discussionmentioning

confidence: 99%

“…In cerebellar granule cells, BDNF decreases the amplitude and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively), suggesting both pre-and postsynaptic effects (Cheng and Yeh 2003). The effect of BDNF on IPSCs, however, was blocked by inclusion of the trkB inhibitor K252a to the postsynaptic cell (Cheng and Yeh 2003;Hewitt and Bains 2006;Tanaka et al 1997). Taken together, these results suggest that postsynaptic trkB receptors contribute to the initiation of many of the effects of BDNF at GABAergic synapses.…”

Section: Introductionmentioning

confidence: 88%

“…In the cortex, hippocampus, and cerebellum, trkB receptors are expressed not only in postsynaptic dendrites but also in GABAergic axon terminals (Drake et al 1999;Fryer et al 1996;Rico et al 2002). In the CA1 region of the hippocampus, BDNF reduces inhibitory transmission via both presynaptic (Frerking et al 1998) and postsynaptic mechanisms (Brunig et al 2001;Hewitt and Bains 2006;Mizoguchi et al 2003;Tanaka et al 1997). In cerebellar granule cells, BDNF decreases the amplitude and frequency of spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively), suggesting both pre-and postsynaptic effects (Cheng and Yeh 2003).…”

Section: Introductionmentioning

confidence: 99%

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BDNF Evokes Release of Endogenous Cannabinoids at Layer 2/3 Inhibitory Synapses in the Neocortex

Lemtiri‐Chlieh

Levine

2010

Journal of Neurophysiology

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. The neurotrophin brain-derived neurotrophic factor (BDNF) is a potent regulator of inhibitory synaptic transmission, although the locus of this effect and the underlying mechanisms are controversial. We explored a potential interaction between BDNF and endogenous cannabinoid (endocannabinoid) signaling because activation of type 1 cannabinoid (CB1) receptors potently regulates ␥-aminobutyric acid (GABA) release and both trkB tyrosine kinase receptors and CB1 receptors are highly expressed at synapses in neocortical layer 2/3. Here, we found that the effects of BDNF at inhibitory cortical synapses are mediated by the release of endocannabinoids acting retrogradely at presynaptic CB1 receptors. Specifically, acute application of BDNF rapidly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) via postsynaptic trkB receptor activation because intracellular delivery of the tyrosine kinase inhibitor K252a completely blocked the BDNF effect. Although triggered by postsynaptic trkB activation, BDNF exposure decreased presynaptic release probability, as evidenced by increases in the paired-pulse ratio and coefficient of variation of evoked responses. In addition, BDNF decreased the frequency but not the amplitude of action potential-independent miniature IPSCs and BDNF did not alter the postsynaptic response to locally applied GABA. These results suggest that BDNF induces the release of a retrograde messenger from the postsynaptic cell that regulates presynaptic neurotransmitter release. Consistent with a role for endocannabinoids as the retrograde signal, the effect of BDNF on IPSCs was blocked by CB1 receptor antagonists and was occluded by a cannabinoid receptor agonist. Furthermore, inhibiting endocannabinoid synthesis or transport also disrupted the BDNF effect, implicating postsynaptic endocannabinoid release triggered by BDNF.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

BDNF Evokes Release of Endogenous Cannabinoids at Layer 2/3 Inhibitory Synapses in the Neocortex

Lemtiri‐Chlieh

Levine

2010

Journal of Neurophysiology

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“…Similar effects (reduced immunoreactivity of β2/ 3 subunits) were observed with mouse cerebellar granule neurons (25), suggesting that GABA A -receptor endocytosis is enhanced in response to BDNF application at postsynaptic neurons. Furthermore, Hewitt and Bains reported that the BDNFactivated dynamin-mediated endocytosis of GABA A receptors was observed in the paraventricular nucleus of the hypothalamus parvocellular neurons (28). In contrast, it was reported that the BDNF-induced apparent reduction of GABAergic mIPSC in cultured hippocampal neurons may be predominantly due to reduced channel activity caused by the phosphorylation of the β3 subunit, not to the decreased number of receptors (26).…”

Section: Regulation Of Gaba a Receptor Endocytosismentioning

confidence: 99%

Regulation of GABAA-Receptor Surface Expression With Special Reference to the Involvement of GABARAP (GABAA Receptor-Associated Protein) and PRIP (Phospholipase C-Related, but Catalytically Inactive Protein)

et al. 2007

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Abstract. GABA A receptors are heteropentameric ligand-gated chloride channels composed of a variety of subunits, including α1 -6, β1 -3, γ1 -3, δ, ε, θ, and π, and play a key role in controlling inhibitory neuronal activity. Modification of the efficacy of the synaptic strength is produced by changes in both the number of neuronal surface receptors and pentameric molecular assembly, leading to differences of sensitivity to neurotransmitters and neuromimetic drugs. Therefore, it is important to understand the molecular mechanisms regulating the so-called "life cycle of GABA A receptors" including sequential pentameric assembly at the site synthesized, intracellular transport through the Golgi apparatus and the cytoplasm, insertion into the cell membrane, functional modulation at the cell surface, and finally internalization, followed by either recycling back to the surface membrane or lysosomal degradation. This review is focused on events related to the surface expression of the receptor containing the γ2 subunit and clathrin / AP2 complex-mediated phospho-regulated endocytosis of the receptor, with special reference to the function of novel GABA A receptor modulators, GABARAP (GABA A receptorassociated protein) and PRIP (phospholipase C-related, but catalytically inactive protein).

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Regulation of Excitation by GABAA Receptor Internalization

Leidenheimer

Results and Problems in Cell Differentiation

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Neuronal inhibition is of paramount importance in maintaining the delicate and dynamic balance between excitatory and inhibitory influences in the central nervous system. GABA (gamma-aminobutyric acid), the primary inhibitory neurotransmitter in brain, exerts its fast inhibitory effects through ubiquitously expressed GABA(A) receptors. Activation of these heteropentameric receptors by GABA results in the gating of an integral chloride channel leading to membrane hyperpolarization and neuronal inhibition. To participate in neurotransmission, the receptor must reside on the cell surface. The trafficking of nascent receptors to the cell surface involves posttranslational modification and the interaction of the receptor with proteins that reside within the secretory pathway. The subsequent insertion of the receptor into specialized regions of the plasma membrane is dictated by receptor composition and other factors that guide insertion at synaptic or perisynaptic/extrasynaptic sites, where phasic and tonic inhibition are mediated, respectively. Once at the cell surface, the receptor is laterally mobile and subject to both constitutive and regulated endocytosis. Following endocytosis the receptor undergoes either recycling to the plasma membrane or degradation. These dynamic processes profoundly affect the strength of GABAergic signaling, neuronal inhibition, and presumably synaptic plasticity. Heritable channelopathies that affect receptor trafficking have been recently recognized and compelling evidence exists that mechanisms underlying acquired epilepsy involve GABA(A) receptor internalization. Additionally, GABA(A) receptor endocytosis has been identified as an early event in the ischemic response that leads to excitotoxicity and cell death. This chapter summarizes what is known regarding the regulation of receptor trafficking and cell surface expression and its impact on nervous system function from both cell biology and disease perspectives.

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Brain-Derived Neurotrophic Factor Silences GABA Synapses Onto Hypothalamic Neuroendocrine Cells Through a Postsynaptic Dynamin-Mediated Mechanism

Cited by 43 publications

References 35 publications

BDNF Evokes Release of Endogenous Cannabinoids at Layer 2/3 Inhibitory Synapses in the Neocortex

BDNF Evokes Release of Endogenous Cannabinoids at Layer 2/3 Inhibitory Synapses in the Neocortex

Regulation of GABAA-Receptor Surface Expression With Special Reference to the Involvement of GABARAP (GABAA Receptor-Associated Protein) and PRIP (Phospholipase C-Related, but Catalytically Inactive Protein)

Regulation of Excitation by GABAA Receptor Internalization

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