Endocannabinoids are the endogenous agonists for the G-protein coupled, membrane-bound receptor that responds to the active ingredient in cannabis, A9-tetrahydrocannabinol. These small lipids are intercellular neural messengers with numerous behavioral roles in mammals. Endocannabinoid systems are also involved in the mechanisms of action of abused drugs. A leap forward in understanding the neurophysiology of endocannabinoids came with the discovery that some conventional neurotransmitters can mobilize endocannabinoids, thereby activating cannabinoid receptors on inhibitory nerve terminals. Activation of cannabinoid receptors inhibits GABA release. The group I metabotropic glutamate receptors (mGluRs) are especially effective in reducing GABAergic inhibitory responses. If maintained for a few minutes, the mGluR- initiated response reduction becomes permanent and constitutes a long-term depression of the inhibitory responses. Endocannabinoid-dependent, inhibitory long-term depression, eCB-iLTD, has already been implicated in resistance to extinction of fear-conditioned responses, and at the cellular level, in fostering long-term potentiation of excitatory synapses. The widespread distribution of endocannabinoids and their receptors in the brain enable endocannabinoids to influence neuronal information processing in profound ways, yet details of the cellular mechanisms of endocannabinoid production by mGluRs and eCB-iLTD are not understood. This proposal focuses on mGluR-activated endocannabinoid mobilization and eCB-iLTD in the hippocampus. A major hypothesis is that these responses are subject to a higher order control process, a form of metaplasticity, that adjusts (""""""""primes"""""""") the coupling between mGluRs and the cascade of reactions culminating in endocannabinoid release and eCB-iLTD induction.
The specific aims of the project are to test the hypotheses that: 1) enhancement of endocannabinoid responses is a form of metaplasticity;2) the enhancement is caused by a novel priming mechanism;3) priming occurs upstream of endocannabinoid synthesis;4) priming involves calcium-dependent biochemical pathways;and 5) that synaptically-induced iLTD is subject to priming. MGluRs, GABAergic synapses, and endocannabinoids are ubiquitous throughout the nervous system, where they have individually been implicated in a host of physiological and pathophysiological processes, including learning and memory, epilepsy, neuroprotection, and many others. The present project represents a focused effort to fill in critical gaps in our understanding of their interactions.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Sorensen, Roger
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University of Maryland Baltimore
Schools of Medicine
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Liang, Shu-Ling; Alger, Bradley E; McCarthy, Margaret M (2014) Developmental increase in hippocampal endocannabinoid mobilization: role of metabotropic glutamate receptor subtype 5 and phospholipase C. J Neurophysiol 112:2605-15
Nagode, Daniel A; Tang, Ai-Hui; Yang, Kun et al. (2014) Optogenetic identification of an intrinsic cholinergically driven inhibitory oscillator sensitive to cannabinoids and opioids in hippocampal CA1. J Physiol 592:103-23
Mattison, Hayley A; Bagal, Ashish A; Mohammadi, Michael et al. (2014) Evidence of calcium-permeable AMPA receptors in dendritic spines of CA1 pyramidal neurons. J Neurophysiol 112:263-75
Kim, Jimok; Tsien, Richard W; Alger, Bradley E (2012) An improved test for detecting multiplicative homeostatic synaptic scaling. PLoS One 7:e37364
Alger, Bradley E; Tang, Ai-Hui (2012) Do cannabinoids reduce brain power? Nat Neurosci 15:499-501
Wang, Meina; Hill, Matthew N; Zhang, Longhua et al. (2012) Acute restraint stress enhances hippocampal endocannabinoid function via glucocorticoid receptor activation. J Psychopharmacol 26:56-70
Alger, Bradley E (2012) Endocannabinoids at the synapse a decade after the dies mirabilis (29 March 2001): what we still do not know. J Physiol 590:2203-12
Tang, Ai-Hui; Karson, Miranda A; Nagode, Daniel A et al. (2011) Nerve terminal nicotinic acetylcholine receptors initiate quantal GABA release from perisomatic interneurons by activating axonal T-type (Cav3) Ca²? channels and Ca²? release from stores. J Neurosci 31:13546-61
Zhang, Longhua; Wang, Meina; Bisogno, Tiziana et al. (2011) Endocannabinoids generated by Ca2+ or by metabotropic glutamate receptors appear to arise from different pools of diacylglycerol lipase. PLoS One 6:e16305
Nagode, Daniel A; Tang, Ai-Hui; Karson, Miranda A et al. (2011) Optogenetic release of ACh induces rhythmic bursts of perisomatic IPSCs in hippocampus. PLoS One 6:e27691

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