Endocannabinoids (eCBs) act at presynaptic type 1 cannabinoid receptors (CB1Rs) to depress neurotransmitter release, resulting in either short- or long-term depression of synaptic transmission. Unlike traditional neurotransmitters, release of eCBs is controlled by `on-demand' synthesis. Altered eCB signaling has been implicated and intensely studied in multiple psychiatric disorders, including schizophrenia, anxiety, OCD, addiction and depression. Converging evidence also suggests a link between eCBs and autism spectrum disorders (ASDs), heterogeneous neurodevelopmental disorders defined by impairments in social behavior, communication and restrictive/repetitive behaviors. Although the neurobiology of ASD is poorly understood, studies in both humans and ASD animal models suggest a commonality of defective excitatory synaptic function. In particular, genetic variations in synaptic scaffolding proteins (SAPAP2, Shank3, Homer1 and PSD-95) are associated with ASD. Postsynaptic synthesis of the most abundant eCB, 2-arachidonoylglycerol (2-AG), by diacylglycerol lipase-a (DGLa) is triggered by Ca2+ influx and/or activation of group 1 metabotropic glutamate receptors (mGluR1/5). My postdoctoral work showed that DGLa is part of a multi-protein complex that also contains CaMKII and ASD-linked synaptic scaffolding proteins (SAPAP2, Shank3, Homer1 and PSD-95) in the striatum. I went on to show that CaMKII restrains synaptic 2-AG synthesis by phosphorylating and inhibiting DGLa. It is well known that Homer proteins also form complexes with mGluR5 and Akt, a multifunctional Ser/Thr kinase. Moreover, impairments in mGluR5 and Akt signaling have been associated with ASDs, and mGluR5 stimulation activates both Akt and DGLa. My unpublished studies have demonstrated a mechanistic link between Akt and DGLa, and show that disruption of 2-AG signaling leads to deficits in social interaction and repetitive behaviors. Thus, the proposed studies will further elucidate the mechanism by which Akt regulates 2-AG signaling and will test the overall hypothesis that striatal 2-AG signaling regulates social and repetitive behavioral domains. This will be accomplished through biochemical, electrophysiological and behavioral approaches in combination with conditional and viral mediated mouse transgenics. Completion of the proposed studies and training is crucial for my successful transition to an independent career and will generate multiple opportunities for future independent funding of projects exploring how these mechanisms are involved in brain disorders such as ASD.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
