The hippocampus is the brain region mediating learning and memory. Hippocampal dysfunction disorders, which include Alzheimer's disease and epilepsy, are a significant health problem disrupting life and costing millions of dollars. Recently, endocannabinoids (eCBs) were suggested as candidates to treat Alzheimer's disease for beneficial effects on the evolution of the disease and alleviating symptoms. In addition, eCBs are an excellent target for antiepileptogenesis because eCB receptors are often presynaptic and decrease excitatory transmitter release thus mitigating excitatory seizure activity. The cellular process of hippocampal learning and memory is synaptic plasticity. Synaptic plasticity or changes in synaptic activity occur in response to afferent input from our senses, allowing for us to respond and adapt to changes and experiences in our environment. Currently, several important pathways were demonstrated to play a role in modulating plasticity, including eCBs and eCB receptors. The primary eCB receptor in the brain is cannabinoid receptor 1 (CB1). This receptor for example impairs memory by decreasing plasticity when activated by THC, the active component in marijuana. While many have studied the effect of CB1 on synaptic plasticity, there are other eCB pathways/receptors involved in plasticity not accounted for by CB1. These accounts were described as being from a 'non-CB1'or unidentified CB3 receptor because CB1 (nor CB2) was involved. However, this 'non-CB1'receptor (possibly one or more receptors) has not been correlated to a particular receptor type. In order to fully understand how a 'non-CB1'receptor is influencing hippocampal plasticity and thus learning and memory, we must first identify what this receptor is. One excellent candidate for this receptor is the yet to e classified orphan G protein receptor, GPR55, because it is expressed in the brain and is functionally active. Importantly, GPR55 binds eCBs such as anandamide. The main goal of this research proposal is to investigate GPR55 and related receptors as putative hippocampal eCB receptors that modulate hippocampal plasticity, and thus memory formation. We will first use quantitative real-time PCR and immunocytochemistry to examine cellular expression of hippocampal GPR55 mRNA and protein. Then using whole cell and field electrophysiology we will examine the involvement of GPR55 in modulation of excitatory synaptic transmission and altering hippocampal synaptic plasticity, namely long-term potentiation. The broad long-term goals of this project are to better understand the role eCBs, especially novel eCB receptors, play in modulating hippocampal function and plasticity with a view towards alleviating some of the complications associated with pathologic states in the hippocampus including Alzheimer's disease and epilepsy.

Public Health Relevance

Alzheimer's and epilepsy are disease states that occur in the hippocampus, the brain region involved in learning and memory, which is mediated by synaptic plasticity, critical for memory. Endocannabinoids modulate hippocampal synaptic plasticity and therefore memory as well as epilepsy, however, many endocannabinoid pathways exist in the hippocampus have not been identified. Our goal is to investigate a novel receptor we believe to be involved in endocannabinoid- mediated modulation of synaptic plasticity with a view towards applying what we learn towards alleviating deficits in disease states such as Alzheimer's and epilepsy.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Academic Research Enhancement Awards (AREA) (R15)
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Special Emphasis Panel (ZRG1-MDCN-E (96))
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Stewart, Randall R
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Brigham Young University
Schools of Arts and Sciences
United States
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