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Regulation of Signaling by mGluR5

Award Number: R01MH062646
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/15/2001
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Regulation of Signaling by mGluR5 - PROJECT SUMMARY We and others have shown that stimulation or potentiation of metabotropic glutamate receptor 5 (mGlu5) reverses cognitive deficits in rodent models relevant for schizophrenia and other neurological disorders. We have also made the discovery that co-activation of another mGlu receptor subtype, termed mGlu3, dramatically potentiates mGlu5 signaling in the hippocampus as well as in in vitro culture systems. We demonstrate here that co-activation of mGlu3 and mGlu5 induces hippocampal long-term potentiation (LTP) and potentiates induction of LTP by afferent stimulation. Furthermore, mGlu3 activation enhances hippocampal-dependent learning in an mGlu5-dependent manner. Using mice in which mGlu3 or mGlu5 can be deleted in a cell-type specific pattern, we have also found that loss of either receptor from hippocampal pyramidal cells eliminates the ability of mGlu3 agonists to enhance long-term potentiation or improve performance in a hippocampal-dependent cognitive task. These findings provide a mechanistic bridge to genome-wide association studies (GWAS) and other human genetic studies showing associations between polymorphisms in the GRM3 gene and impaired cognitive function in schizophrenia patients. Additional co-expression studies suggest that this specific mGlu3/mGlu5 cross-talk may also occur in other brain regions that are critical for cognitive deficits in schizophrenia, such as the prefrontal cortex (PFC). For example, mGlu5 also regulates PFC-dependent cognitive function and our preliminary data suggest that activation of mGlu5 induces a novel form of LTP at excitatory synapses from the amygdala projections onto a specific population of inhibitory interneurons that express somatostatin (SST-INs). Mechanistically, these may reverse reductions in PFC inhibitory transmission that are associated with cognitive and negative symptoms of schizophrenia. Both mGlu3 and mGlu5 are expressed in SST-INs, and both have been implicated in forms of memory that depend on activation of SST-INs. We have also found evidence for specific signaling interactions between mGlu3 and mGlu5 in SST-INs. Based on these results, we postulate that mGlu3 and mGlu5 interact to induce LTP in PFC SST-INs. Furthermore, we hypothesize that either mGlu5 PAMs or mGlu3 agonists will enhance forms of cognition that require activation of SST-INs in the PFC, and that this response will be increased upon co-activation of these receptors. Using mGlu3 and mGlu5 subtype-selective modulators, mice lacking each receptor in a cell-type specific pattern, as well as chemogenetic, optogenetic, and a Drugs Acutely Restricted by Tethering (DART) approach to modulate activity of specific neuronal populations, we will test the hypothesis that mGlu3 activation enhances multiple other forms of cognitive function that are regulated by mGlu5 potentiation. Finally, we will determine if this mGlu3/5 interaction is intact after juvenile exposure of rodents to phencyclidine, which induces cognitive deficits that may be relevant for 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: 2025 ( Subtotal = $601,066 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	25	7/8/2025	NON-COMPETING CONTINUATION	$601,066
														Subtotal = $601,066

Issue Date FY: 2024 ( Subtotal = $601,065 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	24	6/27/2024	NON-COMPETING CONTINUATION	$601,065
														Subtotal = $601,065

Issue Date FY: 2023 ( Subtotal = $601,065 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	003	23	6/21/2023	NON-COMPETING CONTINUATION	$601,065
2023	2022	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	002	22	6/14/2023	COMPETING CONTINUATION	$23,965
2023	2022	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	22	1/5/2023	COMPETING CONTINUATION	$0
2023	2020	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	001	21	6/14/2023	NON-COMPETING CONTINUATION	-$23,965
														Subtotal = $601,065

Issue Date FY: 2022 ( Subtotal = $601,065 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	22	9/15/2022	COMPETING CONTINUATION	$601,065
														Subtotal = $601,065

Issue Date FY: 2020 ( Subtotal = $488,700 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	21	4/24/2020	NON-COMPETING CONTINUATION	$488,700
														Subtotal = $488,700

Issue Date FY: 2019 ( Subtotal = $488,700 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	20	4/19/2019	NON-COMPETING CONTINUATION	$488,700
														Subtotal = $488,700

Issue Date FY: 2018 ( Subtotal = $488,700 )
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Mental Health Research Grants	000	19	4/26/2018	NON-COMPETING CONTINUATION	$488,700
														Subtotal = $488,700

Issue Date FY: 2017 ( Subtotal = $488,700 )
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	003	18	8/11/2017	NON-COMPETING CONTINUATION	$48,870
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	002	18	4/15/2017	NON-COMPETING CONTINUATION	$439,830
2017	2016	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	001	17	12/12/2016	COMPETING CONTINUATION	$180,507
2017	2015	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	000	16	12/12/2016	NON-COMPETING CONTINUATION	-$180,507
														Subtotal = $488,700

Issue Date FY: 2016 ( Subtotal = $543,000 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	17	6/17/2016	COMPETING CONTINUATION	$543,000
2016	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	16	6/15/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $543,000

Issue Date FY: 2015 ( Subtotal = $437,426 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	16	1/15/2015	NON-COMPETING CONTINUATION	$437,426
														Subtotal = $437,426

Issue Date FY: 2014 ( Subtotal = $437,426 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	15	1/21/2014	NON-COMPETING CONTINUATION	$393,683
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	15	5/7/2014	NON-COMPETING CONTINUATION	$43,743
														Subtotal = $437,426

Issue Date FY: 2013 ( Subtotal = $419,929 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	14	1/17/2013	NON-COMPETING CONTINUATION	$393,683
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	14	6/10/2013	NON-COMPETING CONTINUATION	$26,246
														Subtotal = $419,929

Issue Date FY: 2012 ( Subtotal = $437,426 )
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	13	9/25/2012	NON-COMPETING CONTINUATION	$2,120
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	13	1/25/2012	NON-COMPETING CONTINUATION	$435,306
														Subtotal = $437,426

Issue Date FY: 2011 ( Subtotal = $435,064 )
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	12	1/24/2011	COMPETING CONTINUATION	$435,064
														Subtotal = $435,064

Issue Date FY: 2010 ( Subtotal = $316,729 )
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	11	1/28/2010	NON-COMPETING CONTINUATION	$316,729
														Subtotal = $316,729

Issue Date FY: 2009 ( Subtotal = $394,229 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	002	10	9/17/2009	SUPPLEMENT FOR EXPANSION	$77,500
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	10	3/12/2009	NON-COMPETING CONTINUATION	$285,056
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	10	7/13/2009	NON-COMPETING CONTINUATION	$31,673
														Subtotal = $394,229

Issue Date FY: 2008 ( Subtotal = $316,729 )
2008	2008	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	9	2/13/2008	NON-COMPETING CONTINUATION	$316,729
														Subtotal = $316,729

Issue Date FY: 2007 ( Subtotal = $316,299 )
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	8	2/13/2007	NON-COMPETING CONTINUATION	$316,299
														Subtotal = $316,299

Issue Date FY: 2006 ( Subtotal = $324,240 )
2006	2006	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	7	1/30/2006	COMPETING CONTINUATION	$324,240
														Subtotal = $324,240

Grand Total All Awards = $10,299,495

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Regulation of Signaling by mGluR5

Award Number: R01MH062646

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/15/2001

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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