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Role of Phospholipase D in M1 Allosteric Modulation of Synaptic Plasticity: Implications for the Treatment of Schizophrenia

Award Number: F31MH114368
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Role of Phospholipase D in M1 Allosteric Modulation of Synaptic Plasticity: Implications for the Treatment of Schizophrenia - Project Summary Agents that activate muscarinic acetylcholine receptors (mAChRs) have exciting potential as novel treatments for the negative symptoms and cognitive disturbances in patients suffering from schizophrenia. Previous mAChR agonists failed in clinical development due to a lack of selectivity for individual mAChR subtypes and adverse effects associated with activation of peripheral mAChRs. We have now discovered and characterized highly selective positive allosteric modulators (PAMs) for individual mAChR subtypes and found that selective PAMs for the M1 mAChR have robust cognition-enhancing effects and may have actions that predict reduction in negative symptoms. Of specific interest was the finding that M1 PAMs enhance a form of M1-dependent long-term depression, termed mLTD, at the hippocampo-prefrontal cortex (PFC) synapse. Impaired LTD at this synapse is disrupted in rodent models of schizophrenia and is thought to correlate with deficits in hippocampo-PFC communication observed in schizophrenia patients. It was assumed that M1 PAMs act through potentiation of canonical Gaq signaling, which leads to the activation of phospholipase C (PLC) and that activation of PLC is a key mechanism by which M1 activation induces multiple CNS effects. However, our lab and others have shown that M1 activation can also lead to activation of phospholipase D (PLD), independent of PLC activation. While most M1 PAMs potentiate coupling of M1 to both PLC and PLD, we reported the discovery of a novel M1 PAM that displays stimulus bias and thereby potentiates M1 coupling to PLC activation, while having no effect on PLD activity. I now present exciting data using novel highly selective PLD inhibitors suggesting that activation of PLD is required for induction of mLTD in the PFC. Whether potentiation of M1 coupling to PLD is required for M1 PAM-induced reversal of synaptic plasticity and behavioral deficits in a rodent model of cortical dysfunction in schizophrenia remains unknown. Completion of this research proposal will elucidate new basic biology and signaling downstream of the M1 mAChR while also providing key insight into the therapeutic potential of allosteric modulation of M1 as a potential treatment for the cognitive and negative symptoms observed in patients with schizophrenia.


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: 2022 ( Subtotal = -$1,642 )
2022	2019	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	001	3	4/22/2022	NON-COMPETING CONTINUATION	-$1,642
2022	2018	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	2	4/22/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = -$1,642

Issue Date FY: 2021 ( Subtotal = -$16,576 )
2021	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	3	3/22/2021	NON-COMPETING CONTINUATION	-$16,576
														Subtotal = -$16,576

Issue Date FY: 2019 ( Subtotal = $29,698 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	001	3	7/26/2019	NON-COMPETING CONTINUATION	$682
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	3	7/4/2019	NON-COMPETING CONTINUATION	$29,016
														Subtotal = $29,698

Issue Date FY: 2018 ( Subtotal = $29,206 )
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	2	7/24/2018	NON-COMPETING CONTINUATION	$29,206
														Subtotal = $29,206

Issue Date FY: 2017 ( Subtotal = $28,726 )
2017	2017	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	1	7/13/2017	NEW	$28,726
2017	2017	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	001	1	7/13/2017	NEW	$0
														Subtotal = $28,726

Grand Total All Awards = $69,412

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Role of Phospholipase D in M1 Allosteric Modulation of Synaptic Plasticity: Implications for the Treatment of Schizophrenia

Award Number: F31MH114368

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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