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

Award Number: R01DA046723
ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $295,850 )
2024	2024	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD NW	KENNESAW	GA	30144	COBB	USA	Drug Use and Addiction Research Programs	001	5	5/10/2024	NON-COMPETING CONTINUATION	$295,850
2024	2023	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD NW	KENNESAW	GA	30144	COBB	USA	Drug Use and Addiction Research Programs	003	4	6/3/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$84,204
2024	2023	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD NW	KENNESAW	GA	30144	COBB	USA	Drug Use and Addiction Research Programs	000	4	5/9/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2022	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	002	3	6/3/2024	NON-COMPETING CONTINUATION	-$84,204
														Subtotal = $295,850

Issue Date FY: 2023 ( Subtotal = $306,850 )
2023	2023	KENNESAW STATE UNIVERSITY	1000 CHASTAIN RD	KENNESAW	GA	30144	COBB	USA	Drug Use and Addiction Research Programs	001	4	8/7/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$306,850
2023	2022	AUBURN UNIVERSITY	321-A INGRAM HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	000	3	8/4/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $306,850

Issue Date FY: 2022 ( Subtotal = $308,350 )
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	004	3	7/12/2022	SUPPLEMENT FOR EXPANSION	-$47,879
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	001	3	2/18/2022	SUPPLEMENT FOR EXPANSION	$43,091
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	000	3	2/17/2022	NON-COMPETING CONTINUATION	$320,606
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	003	3	3/25/2022	SUPPLEMENT FOR EXPANSION	$4,788
2022	2022	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	002	3	3/25/2022	NON-COMPETING CONTINUATION	$35,623
2022	2021	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	005	2	7/13/2022	SUPPLEMENT FOR EXPANSION	-$47,879
														Subtotal = $308,350

Issue Date FY: 2021 ( Subtotal = $338,550 )
2021	2021	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	001	2	7/29/2021	SUPPLEMENT FOR EXPANSION	$47,879
2021	2021	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	000	2	2/5/2021	NON-COMPETING CONTINUATION	$290,671
														Subtotal = $338,550

Issue Date FY: 2020 ( Subtotal = $352,843 )
2020	2020	AUBURN UNIVERSITY	107 SAMFORD HALL	AUBURN	AL	36849	LEE	USA	Drug Use and Addiction Research Programs	000	1	4/7/2020	NEW	$352,843
														Subtotal = $352,843

Grand Total All Awards = $1,602,443

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

Award Number: R01DA046723

ORGANIZATION: NATIONAL INSTITUTE ON DRUG ABUSE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/15/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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