PPT1 Deficiency-Induced GABAAR Hyperpalmitoylation Impairs Synaptic Transmission and Memory Formation

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. In this study, we adopted PPT1-deficient mice, an animal model that closely mimics human disease of infantile neuronal ceroid lipofuscinosis (INCLs), by knocking in a CLN1 c.451C > T nonsense mutation. We identified for the first time that the GABAARα1 subunit rather than AMPAR is the substrate of PPT1. In PPT1-deficient mice, we found the excessive palmitoylation and extended membrane location of GABAAR. Miniature inhibitory postsynaptic current (mIPSC) recorded from CA1 pyramidal neurons of PPT1-KI mice was also enhanced without disturbance of excitatory neuronal transmission. Spatial learning and memory deficits with enhancement of γ oscillation while attenuation of phase coupling was 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 hyperpalmitoylation and its membrane accumulation with improved neuronal transmission and memory functions in the mice. 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.