PPT1 Deficiency-Induced GABA _AR Hyperpalmitoylation Impairs Synaptic Transmission and Memory Formation

Abstract

Background: Palmitoylation is a reversible and dynamic process involving addition of palmitic acid to cysteine residues of proteins. Studies have indicated that a variety of neuronal receptors, including glutamate receptors such as AMPAR, NMDAR, and GABA A R, are palmitoylated, which contributes to the dynamic modulation of synaptic strength in response to neuronal activity. However, little is known about the depalmitoylation of these receptors.Methods: A mouse model with a lost function mutation knock-in of palmitoyl protein thioesterase 1 (PPT1), an important enzyme for depalmitoylation, was employed to mimic human disease of infantile neuronal ceroid lipofuscinosis (INCLs). Immuno uorescent staining, Western blotting, biochemical assays, electrophysiological recording and behavioural tests were used to measure the effects of PPT1 de ciency.Results: We identi ed for the rst time that the GABA A Rα1 subunit rather than AMPAR is the substrate of PPT1. In PPT1-de cient mice, excessive palmitoylation and extended membrane location of GABA A R were detected. Simultaneously, spatial learning and memory de cits with dysregulation of neuronal network γ oscillation and impairment of long-term plasticity were shown in the mice at as early as 2month-old. Application of N-tert-butylhydroxylamine hydrochloride, a thioesterase mimetic, attenuated PPT1 mutation-induced GABA A R hyper-palmitoylation and its membrane accumulation with improved neuronal transmission and memory functions in the mice.Conclusions: These data provide new insights into the mechanisms of neuronal disorder caused by depalmitoylation de ciency and offer a clue for further intervention for INCLs and other neurodegenerative diseases.