GABA receptors in brain development, function, and injury

Abstract

This review presents a brief overview of the γ-aminobutyric acid (GABA) system in the developing and mature central nervous system (CNS) and its potential connections to pathologies of the CNS. γ-aminobutyric acid (GABA) is a major neurotransmitter expressed from the embryonic stage and throughout life. At an early developmental stage, GABA acts in an excitatory manner and is implicated in many processes of neurogenesis, including neuronal proliferation, migration, differentiation, and preliminary circuit-building, as well as the development of critical periods. In the mature CNS, GABA acts in an inhibitory manner, a switch mediated by chloride/cation transporter expression and summarized in this review. GABA also plays a role in the development of interstitial neurons of the white matter, as well as in oligodendrocyte development. Although the underlying cellular mechanisms are not yet well understood, we present current findings for the role of GABA in neurological diseases with characteristic white matter abnormalities, including anoxic-ischemic injury, periventricular leukomalacia, and schizophrenia. Development abnormalities of the GABAergic system appear particularly relevant in the etiology of schizophrenia. This review also covers the potential role of GABA in mature brain injury, namely transient ischemia, stroke, and traumatic brain injury/post-traumatic epilepsy.

Figure 1. GABA receptors in disease

a. Traumatic Brain Injury (TBI) and Stroke pathologies appear to involve increased tonic inhibition mediated by extrasynaptic GABA_A receptors (Clarkson et al. 2010; Mtchedlishvili et al. 2010). Increased tonic inhibition in TBI may contribute to subsequent functional impairment (Mtchedlishvili et al. 2010). Increased tonic inhibition impairs functional recovery following stroke; this increase may be a result of reduced function of GABA transporter 3/4 (GAT 3/4) mediated GABA reuptake (Clarkson et al. 2010). b. Increased GABA release enhances neuroprotective inhibitory transmission in large aspiny (LA) neurons (Li et al. 2009). This effect is most likely mediated by presynaptic GABA_A receptors, however the exact location of these receptors is not known. GAD expression increased following ischemia, which strongly suggests increased GABA synthesis. C. Endogenous GABA acts at GABA_B receptors to mediate neuroprotective effects following anoxia-ischemia in white matter (Fern et al. 1995). A possible target of the PKC second messenger system recruited is the Na⁺ /Ca²⁺ exchanger, which is reversed under anoxic conditions. Downregulation of the Na⁺ /Ca²⁺ exchanger may lead to neuroprotective effects (Fern et al. 1995). GABA_B receptors also act upon K⁺ and Ca²⁺ channels (see text). D. Gray matter abnormalities seen in schizophrenia include a decrease in GAD expression and decrease in presynaptic GABA release (Costa et al. 2001; Akbarian and Huang 2006). Reuptake of GABA via GABA transporter 1 (GAT1) is decreased (Yu et al. 2013). The ratio of NKCC1/KCC2 expression is increased in patients with schizophrenia, suggesting abnormal maturation, as normal maturation is accompanied by increased KCC2 expression and decreased NKCC1 expression (Hyde et al. 2011).