Gamma-Aminobutyric acid (GABA) is the neurotransmitter at most inhibitory synapses in the vertebrate forebrain. The GABA(A) receptor is a ligand- gated anion channel composed of multiple receptor subunits. Alterations in GABAergic transmission have been implicated as a possible etiologic factor in some forms of epilepsy, and developmental changes in expression of GABA(A) receptor subunits may play an important role in both normal development and certain developmental neurological disorders such as age- related epilepsies. The GABA(A) receptor is the site of action of phenobarbital and benzodiazepines, two of the most commonly used anticonvulsants during infancy and early childhood. Little is known of processes regulating developmental expression of the GABA(A) receptor under normal conditions, and the effects of pathophysiological states such as seizures and anticonvulsant treatment on developmental expression of GABA(A) receptors have not been studied. A novel approach is proposed for addressing these questions by combining an in vitro system of forebrain neuronal development with the technique of single cell mRNA amplification which permits simultaneous molecular, electrophysiological, and morphological characterization of individual developing neurons. To evaluate potential mechanisms involved in developmental regulation of GABA(A) receptor subunit gene expression it is proposed: 1. To examine the developmental expression of the GABA(A) individual forebrain neurons differentiating in vitro and in vivo. 2. To examine the role of synapse formation and neuronal activity in the regulation of GABA(A) receptor subunit expression during development. 3. To determine the effects of seizure activity and treatment with anticonvulsant medications on the pattern of developmental expression of GABA(A) receptor subunit mRNAs utilizing an in vitro seizure model. It is anticipated that these studies will provide insight into mechanisms regulating developmental expression of the GABA(A) receptor both during normal neurodevelopment and in developmental neurological disorders such as the pediatric epilepsies.
|Brooks-Kayal, A R; Shumate, M D; Jin, H et al. (1998) Selective changes in single cell GABA(A) receptor subunit expression and function in temporal lobe epilepsy. Nat Med 4:1166-72|