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PSD-95 deficiency alters glutamatergic synapses during development in the prefrontal cortex

Award Number: K00MH124182
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/28/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2024

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PSD-95 deficiency alters glutamatergic synapses during development in the prefrontal cortex - Project Summary/Abstract Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein located at the dendritic spines of excitatory synapses and is involved in the recruitment, trafficking, and stabilization of N-methyl-D- aspartic acid receptors (NMDAR’s) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPAR's) to the postsynaptic membrane during synaptic maturation. Previous studies have shown that within the hippocampus, PSD-95 deficiency causes “silent synapse” formation that may be associated with the pathology observed in the neurological disorders of schizophrenia (SCZ) and autism. However, the effects of PSD-95 deficiency within the prefrontal cortex (PFC), a brain region with delayed maturation, have yet to be investigated. The PFC, located anterior of the frontal lobe, is responsible for cognition, working memory, emotional control, and sociability. It is also highly associated with neurodevelopmental disorders, especially schizophrenia. We hypothesize that PSD-95 deficiency will disrupt synaptic maturation in an age-dependent manner due to an increase in NMDAR/AMPAR-glutamatergic transmission that leads to impairments in PFC development and function. In this study we use a PSD-95-/- mouse to model PSD-95 deficiency and investigate NMDA and AMPA-receptor properties within the medial prefrontal cortex (mPFC). We explore protein expression levels of NMDAR and AMPAR-subunits and other relevant scaffolding proteins. Additionally, we examine NMDAR/AMPAR-transmission to characterize silent synapses, and accordingly, we will examine working memory function and social interaction to measure social novelty and exploration. Furthermore, based on our preliminary finding of increased NMDA/AMPA ratio in corticocortical afferents, we will examine the major inputs of the mPFC − the mediodorsal thalamus (MD), which is responsible for the development and function of the mPFC via reciprocal connections mediated by glutamatergic transmission. We further hypothesize that PSD-95 deficiency will impair thalamocortical projections via disrupted glutamatergic transmission, resulting in afferent-specific changes in synaptic function and neurodevelopmental deficits of the mPFC that lead to physiological and behavioral dysfunctions. We will inject an adeno-associated virus (AAV) vector expressing channelrhodopsin-2 (ChR2) within the MD and use optogenetics to specifically activate MD inputs to mPFC to record excitatory postsynaptic currents. Together, this data will provide a greater understanding of how PSD-95 affects the glutamate receptor composition and transmission as it relates to mPFC development and function.


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 = $0 )
2024	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	7/16/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $68,580 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	6	3/30/2023	NON-COMPETING CONTINUATION	$68,580
														Subtotal = $68,580

Issue Date FY: 2022 ( Subtotal = $68,580 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	3/22/2022	NON-COMPETING CONTINUATION	$68,580
														Subtotal = $68,580

Issue Date FY: 2021 ( Subtotal = $68,580 )
2021	2021	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	3/31/2021	NON-COMPETING CONTINUATION	$68,580
														Subtotal = $68,580

Issue Date FY: 2020 ( Subtotal = $68,580 )
2020	2020	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/1/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$68,580
														Subtotal = $68,580

Grand Total All Awards = $274,320

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PSD-95 deficiency alters glutamatergic synapses during development in the prefrontal cortex

Award Number: K00MH124182

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/28/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2024

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