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 My unpublished studies have demonstrated a mechanistic link between Akt and DGLa, and show that disruption of 2-AG signaling leads to deficits in social interaction and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.

Public Health Relevance

The classical symptoms of autism spectrum disorder (ASD) are improper social function, compulsive/repetitive behavior and communication deficiencies. Current treatment options are limited due to a lack of basic knowledge about how these behaviors are normally controlled by the brain, and due to the lack of effective therapeutic targets. This study will use cutting edge technology to learn more about how endocannabinoids control behaviors ASD relevant behaviors, which may lead to new treatments of ASD and related psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01MH107765-01
Application #
8948711
Study Section
Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
Program Officer
Rosemond, Erica K
Project Start
2015-07-07
Project End
2019-04-30
Budget Start
2015-07-07
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
$143,751
Indirect Cost
$10,648
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Shonesy, Brian C; Parrish, Walker P; Haddad, Hala K et al. (2018) Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Biol Psychiatry 84:304-315
Marks, Christian R; Shonesy, Brian C; Wang, Xiaohan et al. (2018) Activated CaMKII? Binds to the mGlu5 Metabotropic Glutamate Receptor and Modulates Calcium Mobilization. Mol Pharmacol 94:1352-1362
Harris, Nicholas A; Isaac, Austin T; Günther, Anne et al. (2018) Dorsal BNST ?2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors. J Neurosci 38:8922-8942
Bluett, Rebecca J; Báldi, Rita; Haymer, Andre et al. (2017) Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Nat Commun 8:14782
Stephenson, Jason R; Wang, Xiaohan; Perfitt, Tyler L et al. (2017) A Novel Human CAMK2A Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors. J Neurosci 37:2216-2233
Patel, Sachin; Shonesy, Brian C; Bluett, Rebecca J et al. (2016) The Anxiolytic Actions of 2-Arachidonoylglycerol: Converging Evidence From Two Recent Genetic Endocannabinoid Deficiency Models. Biol Psychiatry 79:e78-e79
Baucum 2nd, Anthony J; Shonesy, Brian C; Rose, Kristie L et al. (2015) Quantitative proteomics analysis of CaMKII phosphorylation and the CaMKII interactome in the mouse forebrain. ACS Chem Neurosci 6:615-31