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Palmitoylation on NMDA receptor trafficking and function in corticostriatal co-culture from HD mouse model Wang, Liang


Huntington’s Disease (HD) is a neurodegenerative disorder in which the medium-sized spiny neurons (MSNs) of the striatum are earliest and most severely affected. Selective striatal degeneration in HD has been caused, in part, by altered N-methyl-D-aspartate receptor (NMDAR) activity. Our lab has found in the YAC128 transgenic mouse model of HD that GluN2B-containing NMDARs (2B-NMDARs) at extrasynaptic (Ex) sites are increased in striatum at an early stage; however, the mechanism underlying altered NMDAR trafficking in HD remains unknown. Palmitoylation at the C-terminus of 2B-NMDAR regulates its surface expression and synaptic targeting. Notably, a palmitoyl transferase (PAT) enzyme – ZDHHC17 (HIP14) – interacts with huntingtin, the protein mutated in HD. Pilot data in the lab suggests reduced 2B-NMDAR palmitoylation may contribute to increased Ex-NMDAR in striatal MSN from YAC128 HD mice. However, a potential role for HIP14 in regulating 2B-NMDAR trafficking has not been explored. On the other hand, suppression of acyl-protein thioesterases 1/2 (APT1/2), the depalmitoylation enzymes, by a small molecule inhibitor PalmB leads to increased protein palmitoylation level, which may affect NMDAR distribution. Here, we examined the effect of changing palmitoylation on NMDAR trafficking and function in YAC128 HD mice. Knockdown of endogenous HIP14 did not change 2B-NMDAR surface expression and total NMDAR current. The treatment of DMSO (vehicle) and PalmB reduced synaptic NMDAR current and increased Ex-NMDAR current, and the main difference was found in FVB/N (control) mouse. In contrast, after 4 hours of PalmB treatment, miniature excitatory postsynaptic current (mEPSC) frequency significantly increased at YAC128 but not FVB/N corticostriatal synapse. Investigation of palmitoylation on NMDAR activity is useful for clinical application.

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