Pro-Brain-Derived Neurotrophic Factor Inhibits GABAergic Neurotransmission by Activating Endocytosis and Repression of GABA_AReceptors

Abstract

GABA is the canonical inhibitory neurotransmitter in the CNS. This inhibitory action is largely mediated by GABA type A receptors (GABA A Rs). Among the many factors controlling GABAergic transmission, brain-derived neurotrophic factor (BDNF) appears to play a major role in regulating synaptic inhibition. Recent findings have demonstrated that BDNF can be released as a precursor (proBDNF). Although the role of mature BDNF on GABAergic synaptogenesis and maintenance has been well studied, an important question still unanswered is whether secreted proBDNF might affect GABAergic neurotransmission. Here, we have used 14 d in vitro primary culture of hippocampal neurons and ex vivo preparations from rats to study the function of proBDNF in regulation of GABA A R trafficking and activity. We demonstrate that proBDNF impairs GABAergic transmission by the activation of two distinct pathways: (1) a RhoA-Rock-PTEN pathway that decreases the phosphorylation levels of GABA A R, thus affecting receptor function and triggering endocytosis and degradation of internalized receptors, and (2) a JAK-STAT-ICER pathway leading to the repression of GABA A Rs synthesis. These effects lead to the diminution of GABAergic synapses and are correlated with a decrease in GABAergic synaptic currents. These results revealed new functions for proBDNF-p75 neurotrophin receptor signaling pathway in the control of the efficacy of GABAergic synaptic activity by regulating the trafficking and synthesis of GABA A Rs at inhibitory synapses.

Inhibition of RhoA reduces propofol-mediated growth cone collapse, axonal transport impairment, loss of synaptic connectivity, and behavioural deficits

“…Anaesthetised, electrically 'silenced', or both neurones exhibit increased proBDNF signalling relative to mature BDNF (mBDNF) signalling. 11e13,82 ProBDNF binds to the p75 NTR receptor to activate RhoA, 83,84 while mBDNF binds to the TrkB receptor to activate Rac1/Cdc42. 85,86 It is conceivable that propofol-induced p75 NTR, signalling leads to increased RhoA activation with a concomitant decrease in mBDNF activation of TrkB and Rac1/ Cdc42 signalling, altering the 'yin and yang' of Rho GTPase signalling that is pivotal during development.…”

Exogenous progesterone exacerbates running response of adolescent female mice to repeated food restriction stress by changing α4-GABAA receptor activity of hippocampal pyramidal cells

“…proBDNF is known to have effects that are antagonistic to those of BDNF (Lu, Pang, & Woo, 2005). BDNF enhances and proBDNF represses synthesis and activity of synaptic GABA A R (Riffault et al, 2014). Thus, it is conceivable that an increase in proBDNF without increased BDNF to balance it might result in a decreased expression of α4 subunits as seen in the P4-injected vulnerable animals.…”

SORT1 Mutation Resulting in Sortilin Deficiency and p75NTR Upregulation in a Family With Essential Tremor

“…Since the expression of p75 NTR , which binds to sortilin to mediate neuronal cell death ( Nykjaer et al., 2004 ) and modulates cholinergic transmission ( Yang et al., 2002 ), was also found significantly elevated in mutant cells when compared with wild-type ( Figure 4(a) ), one may commend that under pathological conditions dysregulation of sortilin may upregulate p75 NTR expression levels. Considering that p75 NTR is not only upregulated in pathological conditions ( Nykjaer et al., 2005 ) but also in impaired GABAergic transmission ( Riffault et al., 2014 ), the sortilin deficiency caused by the p.G171A mutation might also be responsible for defects in neurotransmission, resulting in both the development of tremor and high p75 NTR expression.…”