Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

Abstract

Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5’s enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

Regulation and function of the palmitoyl‐acyltransferase ZDHHC5

“…One found ZDHHC5 to be localised to the plasma membrane exclusively when palmitoylation of the C‐terminal tail was abolished [38] whereas the other found it to accumulate in cytosolic puncta [67]. Another recent study found that in neurons, the cell surface expression of ZDHHC5 C‐terminal palmitoylation mutant was significantly increased compared with wild‐type ZDHHC5 due to a decrease in ZDHHC5 turnover [68] supporting the former study [38]. A potential explanation of these conflicting results may be due to differences in the cell types used.…”

A sticky situation: regulation and function of protein palmitoylation with a spotlight on the axon and axon initial segment

“…Palmitoylation can alter the conformation of protein transmembrane domains or cytosolic regions, regulate proteinprotein interactions, and promote association with specific membrane microdomains (28)(29)(30)(31). In neurons, palmitoylation is best known to regulate synaptic expression and clustering of adhesion molecules, vesicle release machinery, signaling molecules, and neurotransmitter receptors, as well as their scaffolds and kinases (32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44) (reviewed in (1,20,(45)(46)(47)). Indeed, previous estimates suggest that 41% of all synaptic proteins are substrates for palmitoylation (17).…”