Loss of Depalmitoylation Disrupts Homeostatic Plasticity of AMPARs in a Mouse Model of Infantile Neuronal Ceroid Lipofuscinosis

Protein palmitoylation is the only reversible post-translational lipid modification. Palmitoylation is held in delicate balance by depalmitoylation to precisely regulate protein turnover. While over 20 palmitoylation enzymes are known, depalmitoylation is conducted by fewer enzymes. Of particular interest is the lack of the depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1) that causes the devastating pediatric neurodegenerative condition infantile neuronal ceroid lipofuscinosis (CLN1). While most of the research on Ppt1 function has centered on its role in the lysosome, recent findings demonstrated that many Ppt1 substrates are synaptic proteins, including the AMPA receptor (AMPAR) subunit GluA1. Still, the impact of Ppt1-mediated depalmitoylation on synaptic transmission and plasticity remains elusive. Thus, the goal of the present study was to use the Ppt1(-/-) mouse model (both sexes) to determine whether Ppt1 regulates AMPAR-mediated synaptic transmission and plasticity, which are crucial for the maintenance of homeostatic adaptations in cortical circuits. Here, we found that basal excitatory transmission in the Ppt1(-/-) visual cortex is developmentally regulated and that chemogenetic silencing of the Ppt1(-/-) visual cortex excessively enhanced the synaptic expression of GluA1. Furthermore, triggering homeostatic plasticity in Ppt1(-/-) primary neurons caused an exaggerated incorporation of GluA1-containing, calcium-permeable AMPARs, which correlated with increased GluA1 palmitoylation. Finally, Ca2+ imaging in awake Ppt1(-/-) mice showed visual cortical neurons favor a state of synchronous firing. Collectively, our results elucidate a crucial role for Ppt1 in AMPAR trafficking and show that impeded proteostasis of palmitoylated synaptic proteins drives maladaptive homeostatic plasticity and abnormal recruitment of cortical activity in CLN1.