Abstract
BackgroundPalmitoylation, the addition of palmitate to proteins by palmitoyl acyltransferases (PATs), is an important regulator of synaptic protein localization and function. Many palmitoylated proteins and PATs have been implicated in neuropsychiatric diseases, including Huntington disease, schizophrenia, amyotrophic lateral sclerosis, Alzheimer disease, and X-linked intellectual disability. HIP14/DHHC17 is the most conserved PAT that palmitoylates many synaptic proteins. Hip14 hypomorphic mice have behavioral and synaptic deficits. However, the phenotype is developmental; thus, a model of post-developmental loss of Hip14 was generated to examine the role of HIP14 in synaptic function in the adult.ResultsTen weeks after Hip14 deletion (iHip14 Δ/Δ), mice die suddenly from rapidly progressive paralysis. Prior to death the mice exhibit motor deficits, increased escape response during tests of anxiety, anhedonia, a symptom indicative of depressive-like behavior, and striatal synaptic deficits, including reduced probability of transmitter release and increased amplitude but decreased frequency of spontaneous post-synaptic currents. The mice also have increased brain weight due to microgliosis and astrogliosis in the cortex.ConclusionsBehavioral changes and electrophysiological measures suggest striatal dysfunction in iHip14 Δ/Δ mice, and increased cortical volume due to astrogliosis and microgliosis suggests a novel role for HIP14 in glia. These data suggest that HIP14 is essential for maintenance of life and neuronal integrity in the adult mouse.Electronic supplementary materialThe online version of this article (doi:10.1186/s12915-016-0333-7) contains supplementary material, which is available to authorized users.
Highlights
Palmitoylation, the addition of palmitate to proteins by palmitoyl acyltransferases (PATs), is an important regulator of synaptic protein localization and function
Hip14 deletion was induced in Hip14 “floxed” mice (Hip14F)/F;Cre + mice at 6 weeks of age by TM treatment to allow mice a month to recover from TM toxicity prior to any behavior testing performed at 3 months of age [19]
Hip14 mRNA and protein levels were assessed at 10 days after the last injection and 6 weeks post-induction to assess deletion efficiency compared to Hip14F/F;Cre– TM control mice
Summary
Palmitoylation, the addition of palmitate to proteins by palmitoyl acyltransferases (PATs), is an important regulator of synaptic protein localization and function. Conclusions: Behavioral changes and electrophysiological measures suggest striatal dysfunction in iHip14Δ/Δ mice, and increased cortical volume due to astrogliosis and microgliosis suggests a novel role for HIP14 in glia. These data suggest that HIP14 is essential for maintenance of life and neuronal integrity in the adult mouse. Palmitoylation is the reversible addition of long chain fatty acids, typically palmitate, to proteins at cysteine residues [3, 4] It is mediated by DHHC-domain containing palmitoyl acyltransferases (PATs) that palmitoylate proteins at cysteine residues via a thioester bond [5, 6]. Palmitoylation regulates the synaptic insertion/removal of α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptor (AMPAR)
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