PPT1 Deficiency-Induced GABAAR 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 GABAAR, 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). Immunofluorescent staining, Western blotting, biochemical assays, electrophysiological recording and behavioural tests were used to measure the effects of PPT1 deficiency.Results: We identified for the first time that the GABAARα1 subunit rather than AMPAR is the substrate of PPT1. In PPT1-deficient mice, excessive palmitoylation and extended membrane location of GABAAR were detected. Simultaneously, spatial learning and memory deficits with dysregulation of neuronal network γ oscillation and impairment of long-term plasticity were shown in the mice at as early as 2-month-old. Application of N-tert-butylhydroxylamine hydrochloride, a thioesterase mimetic, attenuated PPT1 mutation-induced GABAAR 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 deficiency and offer a clue for further intervention for INCLs and other neurodegenerative diseases.