α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

Abstract

In the brain, AMPA-type glutamate receptors are major postsynaptic receptors at excitatory synapses that mediate fast neurotransmission and synaptic plasticity. α/β-Hydrolase domain-containing 6 (ABHD6), a monoacylglycerol lipase, was previously found to be a component of AMPA receptor macromolecular complexes, but its physiological significance in the function of AMPA receptors (AMPARs) has remained unclear. The present study shows that overexpression of ABHD6 in neurons drastically reduced excitatory neurotransmission mediated by AMPA but not by NMDA receptors at excitatory synapses. Inactivation of ABHD6 expression in neurons by either CRISPR/Cas9 or shRNA knockdown methods significantly increased excitatory neurotransmission at excitatory synapses. Interestingly, overexpression of ABHD6 reduced glutamate-induced currents and the surface expression of GluA1 in HEK293T cells expressing GluA1 and stargazin, suggesting a direct functional interaction between these two proteins. The C-terminal tail of GluA1 was required for the binding between of ABHD6 and GluA1. Mutagenesis analysis revealed a GFCLIPQ sequence in the GluA1 C terminus that was essential for the inhibitory effect of ABHD6. The hydrolase activity of ABHD6 was not required for the effects of ABHD6 on AMPAR function in either neurons or transfected HEK293T cells. Thus, these findings reveal a novel and unexpected mechanism governing AMPAR trafficking at synapses through ABHD6.ABHD6 | AMPA receptor | synapses | receptor trafficking

Cutting Edge: Dysregulated Endocannabinoid-Rheostat for Plasmacytoid Dendritic Cell Activation in a Systemic Lupus Endophenotype

“…Systemic immunomodulatory role of cannabinoid receptor signaling is widely reported, and a link with autoreactive inflammation is also suggested (11). Apart from modulation of endocannabinoids, the substrate of ABHD6, function of this enzyme is also reported in various other physiological contexts, namely receptor recycling in the CNS (12), insulin secretion by pancreatic b cells (13), and lipolysis in metabolic tissues (14). Accordingly, deregulation of this enzyme has been implicated in various clinical contexts of CNS disorders and metabolic disorders (13)(14)(15), but any pathogenetic role of ABHD6 in immunological disorders remains unidentified.…”

Identification of Protein Tyrosine Phosphatase Receptor Type O (PTPRO) as a Synaptic Adhesion Molecule that Promotes Synapse Formation

“…Similarly, the deletion of NL1 reduces the NMDA/AMPA receptor ratio in hippocampal CA3-CA1 synapses (Chubykin et al, 2007). Although NL1/2/3 triple-KO mice exhibit a postnatal lethal phenotype and impaired synaptic transmission at the GABAergic/glycinergic and glutamatergic synapses, the number of synapses is normal in the brain of NL1/2/3 triple-KO mice, suggesting that NLs are not essential for initiating synapse formation (Varoqueaux et al, 2006). Moreover, SynCAM1-KO mice exhibit a modest (10 Ϯ 3%) decrease in the number of excitatory synapses, but not inhibitory synapses, in the hippocampal CA1 stratum radiatum (Robbins et al, 2010).…”

CRISPR/Cas9 system-mediated impairment of synaptobrevin/VAMP function in postmitotic hippocampal neurons

“…This group injected the target region with two separate viruses, one carrying the Cas9 gene, and one carrying the guide RNA and recorded firing rate, a postsynaptic phenotype, from transfected cells and neighboring control cells. More recently, Wei et al used calcium phosphate to sparsely transfect cultured hippocampal neurons and KO α/β-Hydrolase domain-containing 6 (ABHD6) (Wei et al, 2016). Again, they recorded from transfected cells or un-transfected controls and measured postsynaptic cell autonomous phenotypes.…”