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

• DOI: 10.1523/jneurosci.1113-23.2023
• Publication Date: 2023-10-26T17:50:11Z
• Authors: Kevin P. Koster; Eden Flores-Barrera; Emilce Artur de l...; Adriana Caballero; Kuei Y. Tseng; Akira Yoshii
• Keywords: Palmitoylation

Protein palmitoylation is the only reversible post-translational lipid modification. Palmitoylation held in delicate balance by depalmitoylation to precisely regulate protein turnover. While over 20 enzymes are known, conducted fewer enzymes. Of particular interest lack of depalmitoylating enzyme palmitoyl-protein thioesterase 1 (PPT1) that causes devastating pediatric neurodegenerative condition infantile neuronal ceroid lipofuscinosis (CLN1). most research on Ppt1 function has centered its role lysosome, recent findings demonstrated many substrates synaptic proteins, including AMPA receptor (AMPAR) subunit GluA1. Still, impact Ppt1-mediated transmission and plasticity remains elusive. Thus, goal present study was use −/− mouse model (both sexes) determine whether regulates AMPAR-mediated plasticity, which crucial for maintenance homeostatic adaptations cortical circuits. Here, we found basal excitatory visual cortex developmentally regulated chemogenetic silencing excessively enhanced expression Furthermore, triggering primary neurons caused an exaggerated incorporation GluA1-containing, calcium-permeable AMPARs, correlated with increased GluA1 palmitoylation. Finally, Ca 2+ imaging awake mice showed favor a state synchronous firing. Collectively, our results elucidate AMPAR trafficking show impeded proteostasis palmitoylated proteins drives maladaptive abnormal recruitment activity CLN1. SIGNIFICANCE STATEMENT Neuronal communication orchestrated movement receptors from membrane. modification, process must be balanced depalmitoylation. The significance evidenced discovery mutation (Ppt1) severe neurodegeneration. In this study, equilibrium provided critical (AMPAR)-mediated associated This finding complements explosion emphasizing necessity