Abstract
In the mature healthy mammalian neuronal networks, γ-aminobutyric acid (GABA) mediates synaptic inhibition by acting on GABAA and GABAB receptors (GABAAR, GABABR). In immature networks and during numerous pathological conditions the strength of GABAergic synaptic inhibition is much less pronounced. In these neurons the activation of GABAAR produces paradoxical depolarizing action that favors neuronal network excitation. The depolarizing action of GABAAR is a consequence of deregulated chloride ion homeostasis. In addition to depolarizing action of GABAAR, the GABABR mediated inhibition is also less efficient. One of the key molecules regulating the GABAergic synaptic transmission is the brain derived neurotrophic factor (BDNF). BDNF and its precursor proBDNF, can be released in an activity-dependent manner. Mature BDNF operates via its cognate receptors tropomyosin related kinase B (TrkB) whereas proBDNF binds the p75 neurotrophin receptor (p75NTR). In this review article, we discuss recent finding illuminating how mBDNF-TrkB and proBDNF-p75NTR signaling pathways regulate GABA related neurotransmission under physiological conditions and during epilepsy.
Highlights
A striking trait of early GABAergic transmission is that activation of γ-aminobutyric acid (GABAA) receptors (GABAARs) causes membrane depolarization and Ca2+ influx in immature neurons (Ben-Ari et al, 1989, 2007; Ganguly et al, 2001)
brain derived neurotrophic factor (BDNF) shapes the development of neuronal circuits, as well as the construction of inhibitory connections throughout life (Kovalchuk et al, 2004; Gubellini et al, 2005; Gottmann et al, 2009) and alterations in BDNF processing have been observed in diseases of the central nervous system (CNS), including schizophrenia, autism spectrum disorder (ASD) and epilepsy (Binder et al, 2001; Carlino et al, 2011; Garcia et al, 2012)
We focus on ionotropic GABAA or metabotropic GABAB receptors activation in triggering the postsynaptic release of BDNF, which in turn regulates the maturation of GABAergic synapses
Summary
A striking trait of early GABAergic transmission is that activation of γ-aminobutyric acid (GABAA) receptors (GABAARs) causes membrane depolarization and Ca2+ influx in immature neurons (Ben-Ari et al, 1989, 2007; Ganguly et al, 2001). During this critical period, depolarizing GABAAR activity plays a major role in neuronal network construction (Ben-Ari et al, 2007; Wang and Kriegstein, 2008; Sernagor et al, 2010). BDNF can be secreted either as a precursor (proBDNF) or a mature form (mBDNF; Nagappan et al, 2009; Yang et al, 2009)
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