Several decades of research continue to show that activity-dependent changes in synaptic efficacy are critical to experience-dependent modification of neural function. The mechanisms underlying these changes are more diverse than previously expected. Recently, a new type of use-dependent synaptic plasticity that requires retrograde signaling by endogenous cannabinoids (endocannabinoids) has been identified in several brain structures. Endocannabinoids are produced """"""""on-demand"""""""" from neurons, cross the synaptic cleft, and by activating presynaptic cannabinoid receptors, suppress transmitter release in a transient or long-term manner. The mechanisms and physiological consequences of endocannabinoid-mediated synaptic plasticity are not fully understood. The experiments proposed here are designed to investigate the molecular mechanisms downstream of cannabinoid receptor activation, induction rules under more physiological conditions, and functional impact of eCB-mediated synaptic plasticity. To address these issues, we will focus on the hippocampus in vitro where we have found that endocannabinoids mediate long-term depression at inhibitory synapses. We will also extend our studies of eCB-plasticity to the dentate gyrus and prefrontal cortex, two brain areas where eCBs are thought to play a role in the etiology of epilepsy and schizophrenia, respectively. By modulating synaptic transmission, endocannabinoids participate in a wide range of brain function including cognition, motor control, aversive and feeding behaviors, pain perception and reward. Dysregulation of endocannabinoid signaling has been implicated in several neurological and psychiatric conditions. A better understanding of endocannabinoid-mediated plasticity is crucial not only a more realistic representation of neural function but also to identify how marijuana abuse may affect the brain, and ultimately, to develop novel therapeutic strategies targeting the endocannabinoid system.

Public Health Relevance

Endocannabinoids have emerged as key regulators of basic neural functions by mediating activity-dependent synaptic plasticity. Drugs that target these molecules and their receptors could be extremely useful for the development of new treatments for a variety of neurological and psychiatric disorders. Research on the endocannabinoid system not only helps in gaining a greater understanding of how marijuana acts in the brain and why it is abused, but it also provides new clues about how the brain works.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Sorensen, Roger
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Albert Einstein College of Medicine
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Weng, Feng-Ju; Garcia, Rodrigo I; Lutzu, Stefano et al. (2018) Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation. Neuron 97:1137-1152.e5
Monday, Hannah R; Younts, Thomas J; Castillo, Pablo E (2018) Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease. Annu Rev Neurosci 41:299-322
Nandi, Sayan; Alviña, Karina; Lituma, Pablo J et al. (2018) Neurotrophin and FGF Signaling Adapter Proteins, FRS2 and FRS3, Regulate Dentate Granule Cell Maturation and Excitatory Synaptogenesis. Neuroscience 369:192-201
Monday, Hannah R; Castillo, Pablo E (2017) Closing the gap: long-term presynaptic plasticity in brain function and disease. Curr Opin Neurobiol 45:106-112
Hashimotodani, Yuki; Nasrallah, Kaoutsar; Jensen, Kyle R et al. (2017) LTP at Hilar Mossy Cell-Dentate Granule Cell Synapses Modulates Dentate Gyrus Output by Increasing Excitation/Inhibition Balance. Neuron 95:928-943.e3
Dore, Kim; Stein, Ivar S; Brock, Jennifer A et al. (2017) Unconventional NMDA Receptor Signaling. J Neurosci 37:10800-10807
Araque, Alfonso; Castillo, Pablo E; Manzoni, Olivier J et al. (2017) Synaptic functions of endocannabinoid signaling in health and disease. Neuropharmacology 124:13-24
Harony-Nicolas, Hala; Kay, Maya; Hoffmann, Johann du et al. (2017) Oxytocin improves behavioral and electrophysiological deficits in a novel Shank3-deficient rat. Elife 6:
Batista, Gervasio; Monday, Hannah R (2016) Visualizing Local Protein Synthesis and Its Modulation by FMRP and Visual Experience. J Neurosci 36:11834-11836
Oh, Won Chan; Lutzu, Stefano; Castillo, Pablo E et al. (2016) De novo synaptogenesis induced by GABA in the developing mouse cortex. Science 353:1037-1040

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