Protein Trafficking Regulating the Formation of GABAergic Synapses

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Project Summary Neural inhibition by ?-aminobutyric acid (GABA) is vitally important for normal brain function as is evident from deficits in GABAergic transmission associated with a wide range of devastating neurological and psychiatric disorders including epilepsy, anxiety, mood disorders, mental retardation, and many others. Deficits in GABAergic transmission are commonly associated with deficits in expression, cellular distribution, or functional properties of GABA-A receptors. Here we focus on palmitoylation as a critically important mechanism that controls the trafficking of GABA-A receptors and the synaptic cell adhesion molecule neuroligin, which both are critically important for GABAergic inhibitory synaptic transmission. Our preliminary experiments show that the gamma2 subunit of GABA-A receptors and neuroligin 2 (NL2) are in vitro palmitoylated selectively by the same struturally related palmitoyltransferases, GODZ and SERZ-beta (also known as zDHHC3 and 7). Palmitoylation by these enzymes in postsynaptic neurons contributes to normal trafficking of GABA-A receptors, normal GABAergic innervation and normal function of GABAergic synapses. Moreover, accumulation of NL2 at synapses requires postsynaptic gamma2 subunit containing GABA-A receptors. Together, these preliminary findings lead us to propose the central hypothesis that GODZ/SERZ-¿-mediated palmitoylation and functional cooperativity between NL2 and GABA-A receptors play important roles in formation and postsynaptic differentiation of GABAergic inhibitory synapses. To further test this hypothesis we will i) test the function of GODD/SERZ-¿ in palmitoylation and trafficking of GABA-A receptors, ii) test the function of GODD/SERZ-¿ in palmitoylation and trafficking of NL2, and iii) analyze cooperativity between ?2 subunit-containing GABA-A receptors and NL2 in the formation of GABAergic synapses. Together these experiments will provide a thorough understanding of a mechanism that contributes to faithful apposition of GABAA receptors across form GABAergic terminals and thereby contributes to assembly and differentiation of GABAergic inhibitory synapses.