Investigating the Role of GABA in Neural Development and Disease Using Mice Lacking GAD67 or VGAT Genes

Abstract

Normal development and function of the central nervous system involves a balance between excitatory and inhibitory neurotransmission. Activity of both excitatory and inhibitory neurons is modulated by inhibitory signalling of the GABAergic and glycinergic systems. Mechanisms that regulate formation, maturation, refinement, and maintenance of inhibitory synapses are established in early life. Deviations from ideal excitatory and inhibitory balance, such as down-regulated inhibition, are linked with many neurological diseases, including epilepsy, schizophrenia, anxiety, and autism spectrum disorders. In the mammalian forebrain, GABA is the primary inhibitory neurotransmitter, binding to GABA receptors, opening chloride channels and hyperpolarizing the cell. We review the involvement of down-regulated inhibitory signalling in neurological disorders, possible mechanisms for disease progression, and targets for therapeutic intervention. We conclude that transgenic models of disrupted inhibitory signalling-in GAD67^+/- and VGAT^-/- mice-are useful for investigating the effects of down-regulated inhibitory signalling in a range of neurological diseases.

Keywords: GABA; GABA-receptors; GABAergic transmission; GAD65; GAD67; VGAT; glutamatergic transmission; neural development.

Figure 1

The mechanism of GABAergic neurotransmission. GABA is synthesised in the cytoplasm of the presynaptic terminal by GAD65 or GAD67 from glutamate supplied by adjacent glial cells via uptake of glutamine by the glutamine transporter and conversion to glutamate (1 to 4). GABA is then loaded into synaptic vesicles by VGAT (5) and released into the synaptic cleft via vesicle exocytosis (6). GABA can then bind to ionotropic GABA_A or GABA_C receptors (7), directly activating Cl⁻ flux across the postsynaptic membrane (8), or to metabotropic GABA_B receptors, indirectly activating Ca²⁺ or K⁺ ion channels via second messenger signalling (9). GABA is taken up from the synaptic cleft into glial cells via GAT 2/3 (10) for breakdown into glutamine (11) or into the presynaptic terminal via GAT-1 for recycling into synaptic vesicles (12).