Elucidation of molecular mechanisms of prenatal cannabinoid exposure: Identification of targets and therapies

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Project Abstract Cannabis is one of the most illicit drugs used during pregnancy, and with increased legalization, use during pregnancy is expected to rise. Clinical studies have shown prenatal cannabinoid exposure (PCE) results in residual cognitive deficits in offspring. Despite the rise in PCE, there is little understanding of a comprehensive mechanistic pathway responsible for learning and memory deficits associated with PCE. Our long-range goal is to understand how PCE affects cognition, and the goal of this proposal is to dissect the molecular mechanisms of memory and synaptic plasticity deficits associated with PCE. Our preliminary data demonstrate hippocampal-dependent memory impairments in PCE animals are concomitant with synaptic deficits in the form of decreased long-term potentiation (LTP) and enhanced long-term depression (LTD). Furthermore, we have demonstrated reductions in polysialylated-NCAM (PSA-NCAM), which is required for neurogenesis, neuronal pathfinding, and learning and memory. We have previously established that decreased PSA-NCAM can lead to deficits in LTP by modulating GluN2B-Ras-GRF1-p38 MAPK signaling pathway and altering the signaling balance of GluN2A- and GluN2B- containing NMDA receptors. Our preliminary data with PCE also indicates a decrease in GluN2A receptor expression and signaling with no change in GluN2B expression, indicating an imbalance in signaling. Based on our preliminary and published data, we hypothesize that PSA-NCAM mediated alterations in GluN2A- and GluN2B- signaling pathways are responsible for the altered synaptic plasticity and memory deficits resulting from PCE. The objective of this proposal is to dissect the molecular mechanisms by which PCE induces synaptic plasticity and cognitive deficits. We will use a multidisciplinary approach including behavioral, electrochemical, electrophysiological, cellular and molecular methodologies to test our hypotheses. We propose three interrelated but sequentially independent specific aims: (1) Investigate the molecular mechanisms of behavioral and synaptic plasticity deficits resulting from PCE, (2) Investigate how PSA-NCAM modifies synaptic transmission and plasticity by regulating NMDA receptor-mediated signaling in PCE animals, and (3) Determine the functional outcomes of application of a PSA mimetic & modulation of GluN2A- and GluN2B- containing NMDA receptors on PCE-induced synaptic plasticity and memory deficits. The data from our study not only points toward a specific mechanism responsible for PCE-related deficits but will also comprehensively assess the different roles played by synaptic molecules responsible for plasticity mechanisms closely associated with cognition.