Functional role of ambient GABA in refining neuronal circuits early in postnatal development

Abstract

Early in development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. GABA exerts its action via synaptic and extrasynaptic GABAA receptors mediating phasic and tonic inhibition, respectively. Here, recent data on the contribution of “ambient” GABA to the refinement of neuronal circuits in the immature brain have been reviewed. In particular, we focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons. The transient increase in intracellular calcium following the depolarizing action of GABA leads to inhibition of DNA synthesis and cell proliferation. Tonic GABA exerts also a chemotropic action on cell migration. Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses.

New insights in the systemic and molecular underpinnings of general anesthetic actions mediated by γ-aminobutyric acid A receptors

“…[9,12,39] Furthermore, drugs that enhance the function of α2- but not α1-subunits should be useful for providing antihyperalgesia against inflammatory and neuropathic pain. [18] It is also important to consider that the expression pattern of GABA A receptor subtypes in the brain and spinal cord is altered by therapeutically relevant factors including drug usage[40], inflammation[41], injury[31], disease[42,43], age[44,45] and pregnancy (Figure 2)[46]. These novel findings are strengthening the need for individualized anesthesia care.…”

Controversies in preterm brain injury

“…In the immature brain, GABA may have even broader effects because it is initially a trophic factor controlling cellular proliferation and migration (Cellot and Cherubini 2013). This multiplicity of roles makes the use of these drugs in preterm infants particularly worrisome.…”

Maternal immune activation alters glutamic acid decarboxylase-67 expression in the brains of adult rat offspring

“…Imbalance between excitatory glutamate and inhibitory GABA function has been implicated in the pathophysiology of schizophrenia (Roberts, 1972; Huguenard and Prince, 1992; Hashimoto et al, 2003; Lewis et al, 2005; Woo et al, 2008; Chiang et al, 2012; Nakazawa et al, 2012). GABAergic systems are also critical in proper brain development and, therefore, a point of convergence and target in the study of schizophrenia (Wassef et al, 2003; Cellot and Cherubini, 2013; Schmidt and Mirnics, 2015). Modulation of GABA transmission in the brain is often monitored via glutamate decarboxylase isoform 67 kDa (GAD 67 ), the rate-limiting enzyme in GABA synthesis.…”