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The therapeutic potential of mGlu3 modulation in MeCP2-related disorders

Award Number: F32MH111124
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2018

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The therapeutic potential of mGlu3 modulation in MeCP2-related disorders - Project Summary Precise levels of the gene regulator Methyl CpG Binding Protein 2 (MeCP2) are known to be a key determinant for proper neurological development and function. The importance of balanced levels of MeCP2 is highlighted by the fact that a loss of MECP2 results in an Autism Spectrum Disorder known as Rett Syndrome; in contrast, duplication of MECP2 leads to a disorder known as MECP2 Duplication syndrome. While Rett Syndrome is an extensively well studied disease area, the molecular etiology of MECP2 Duplication Syndrome remains far less understood. This genetic neurodevelopmental disorder has a wide symptomology including stereotypy, hypotonia, severe cognitive impairments, seizures, and autism. Importantly, both of these disorders critically lack effective therapeutic treatment. Therefore, this research proposal has been designed to develop the candidate’s technical research skills that are necessary to conduct independent neuropharmacology research, while having a positive impact on the field of glutamate systems biology and neurological disorders. In rodent models of MECP2 Duplication Syndrome in which MeCP2 is overexpressed, increases in glutamatergic synapse formation in hippocampal neurons occur, as well as impairments in hippocampal synaptic plasticity and cognitive functions in mice. Interestingly, the metabotropic glutamate receptor 3 (mGlu3) has been shown to be involved in regulating synaptic plasticity and cognitive behaviors in mice, and furthermore, mGlu3 expression has been shown to correlate with MeCP2 expression levels in the brain. Therefore, an upregulation of mGlu3 may contribute to neurological impairments seen in MECP2 Duplication rodent models as well as patients. In support of this theory, we present preliminary data indicating significant increases in mGlu3 protein expression in the hippocampus of mice overexpressing MeCP2 as well as impairment in a form of synaptic plasticity known as long-term depression. It is hypothesized that MeCP2-overexpression causes increases in mGlu3 expression and function, which contribute to synaptic plasticity impairments and cognitive deficits observed in learning and memory paradigms. This will be directly tested by measuring mGlu3-induced second messenger signaling as well as mGlu3-mediated synaptic plasticity and cognitive phenotypes in an animal model of MECP2 Duplication syndrome. Taken together, these studies will elucidate new basic biology and physiology of mGlu3, while also identifying the therapeutic potential of mGlu3 modulation for MeCP2-related disorders.


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: 2021 ( Subtotal = -$1,113 )
2021	2017	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Mental Health Research Grants	000	2	12/29/2020	NON-COMPETING CONTINUATION	-$1,113
														Subtotal = -$1,113

Issue Date FY: 2017 ( Subtotal = $58,466 )
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	001	2	6/8/2017	NON-COMPETING CONTINUATION	$57,066
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Mental Health Research Grants	000	1	1/19/2017	SUPPLEMENT FOR EXPANSION	$1,400
														Subtotal = $58,466

Issue Date FY: 2016 ( Subtotal = $54,294 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	001	1	6/14/2016	NEW	$0
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Mental Health Research Grants	000	1	6/14/2016	NEW	$54,294
														Subtotal = $54,294

Grand Total All Awards = $111,647

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The therapeutic potential of mGlu3 modulation in MeCP2-related disorders

Award Number: F32MH111124

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2018

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