Abstract
PAK1 inhibitors are known to markedly improve social and cognitive function in several animal models of brain disorders, including autism, but the underlying mechanisms remain elusive. We show here that disruption of PAK1 in mice suppresses inhibitory neurotransmission through an increase in tonic, but not phasic, secretion of endocannabinoids (eCB). Consistently, we found elevated levels of anandamide (AEA), but not 2-arachidonoylglycerol (2-AG) following PAK1 disruption. This increased tonic AEA signaling is mediated by reduced cyclooxygenase-2 (COX-2), and COX-2 inhibitors recapitulate the effect of PAK1 deletion on GABAergic transmission in a CB1 receptor-dependent manner. These results establish a novel signaling process whereby PAK1 upregulates COX-2, reduces AEA and restricts tonic eCB-mediated processes. Because PAK1 and eCB are both critically involved in many other organ systems in addition to the brain, our findings may provide a unified mechanism by which PAK1 regulates these systems and their dysfunctions including cancers, inflammations and allergies.
Highlights
It is generally accepted that normal brain function is dependent upon a balance of excitation and inhibition and that altered E/I ratios are associated with, and thought to cause, a wide range of neurological and mental disorders, including autism and schizophrenia (Eichler and Meier, 2008; Kehrer et al, 2008; Marın, 2012; Yizhar et al, 2011)
Since all the animal models of brain disorders that are functionally rescued by manipulations of PAK1 share a common deficit in E/I balance (Braat and Kooy, 2015; Dolan et al, 2013; Eichler and Meier, 2008; Gao and Penzes, 2015; Hayashi et al, 2007; Kehrer et al, 2008; Lewis et al, 2005; Marın, 2012; Molosh et al, 2014; Yizhar et al, 2011), we examined whether disrupting PAK1 would affect the E/I ratio by performing whole cell patch-clamp recordings in CA1 pyramidal neurons of hippocampal slices acutely prepared from PAK1 KO mice and their WT littermates (Figure 1a)
To exclude the possibility that the KO mice may have suffered developmental compensations that could contribute to the reduced eIPSC, we tested the effect of the group1 p21-activated kinases (PAKs) inhibitor IPA3 (10 mM) (Rudolph et al, 2013)
Summary
It is generally accepted that normal brain function is dependent upon a balance of excitation and inhibition (i.e. balanced E/I ratio) and that altered E/I ratios are associated with, and thought to cause, a wide range of neurological and mental disorders, including autism and schizophrenia (Eichler and Meier, 2008; Kehrer et al, 2008; Marın, 2012; Yizhar et al, 2011). Subjected to multiple regulations, GABA transmission is strongly inhibited by endocannabinoids (eCBs), a group of neuromodulatory lipids known to affect a wide range of physiological processes and medical conditions (Katona and Freund, 2012; Morena et al, 2016; Piomelli, 2003). ECBs are produced and secreted from postsynaptic neurons and activate presynaptic cannabinoid 1 (CB1) receptors to reduce the release of a multitude of neurotransmitters, including GABA (Katona and Freund, 2012; Morena et al, 2016; Piomelli, 2003).
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