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Role of neuroligins in long-term plasticity at excitatory and inhibitory synapses

Award Number: F32MH086224
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/27/2009
PERIOD OF PERFORMANCE END DATE: 06/30/2014

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Role of neuroligins in long-term plasticity at excitatory and inhibitory synapses - DESCRIPTION (provided by applicant): Neuroligins are cell-surface proteins expressed postsynaptically at excitatory and inhibitory synapses, and mutations in the genes coding for these proteins and their binding partners have been found in autism spectrum disorders. These disorders are characterized by impaired social interactions, and several mice with either knockout of neuroliginl or knock-in of a mutation found in autistic patients are known to have impaired social behavior. Recent studies have found mutations in many activity-dependent genes in autistic patients, and it is possible that the neuroligins are important in activity-dependent synaptic plasticity. The objective of this study is to investigate the role of neuroligins in synaptic plasticity at excitatory and inhibitory synapses, in order to better understand the role of neuroligins in physiology and pathophysiology. Neuroliginl (NL1) is believed to recruit NMDA receptors (NMDA R) to synapses. Long-term potentiation (LTP) of NMDA R current has been demonstrated at the mossy fiber-CA3 synapse in acute hippocampal slices. To test whether NL1 is necessary for this plasticity, acute hippocampal slices will be prepared from NL-1 knockout mice and their wild-type littermates. Whole cell recordings will be made from CAS neurons while stimulating the mossy fiber pathway to induce NMDA R LTP. The basal NMDA Rexcitatory postsynaptic current (EPSC) will also be measured in WT and KO animals. To determine the region of NL1 necessary for this plasticity, various deletion constructs of NL1 will be delivered via stereotactic injection of viral vectors to try to rescue the NMDA R LTP in the NL1-KO. To determine the specificity of the NL isoform necessary for the LTP, the NL2 and NL3-KO mice will also be tested. Neuroligin2 (NL2) appears to recruit GABAA receptors postsynaptically. Insulin application and NMDA application have been shown to cause insertion of GABAA receptors in hippocampal neurons. These drugs will be applied individually to acute hippocampal slices from NL2 KO mice and their WT littermates, while monitoring inhibitory postsynaptic currents (IPSCs) via whole cell recording from CA1 pyramidal cells. In addition, recordings will be performed in which the pipette solution will contain either the activated form of Protein Kinase B/Akt, which mediates the effect of insulin, or calcium/calmodulin to activate CaM Kinase II, the effector of the NMDA response, while monitoring elPSCs in WT and NL2-KO slices. Synaptic plasticity is believed to underlie learning and memory, the basis for behavior. Neuroligins are synaptic proteins that have been implicated by genetic studies in autism spectrum disorders. This proposal strives to determine the role of neuroligins in synaptic plasticity in the brain.


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: 2014 ( Subtotal = $0 )
2014	2010	MILTON S HERSHEY MEDICAL CENTER	500 UNIVERSITY DRIVE, POB 850	HERSHEY	PA	17033	DAUPHIN	USA	Mental Health National Research Service Awards for Research Training	000	3	12/23/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2013 ( Subtotal = $0 )
2013	2010	MILTON S HERSHEY MEDICAL CENTER	500 UNIVERSITY DRIVE, POB 850	HERSHEY	PA	17033	DAUPHIN	USA	Mental Health National Research Service Awards for Research Training	000	3	6/24/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$59,918
2013	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	001	2	6/24/2013	NON-COMPETING CONTINUATION	-$59,918
														Subtotal = $0

Issue Date FY: 2012 ( Subtotal = $0 )
2012	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	000	2	2/1/2012	NON-COMPETING CONTINUATION	$0
2012	2009	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	001	1	2/1/2012	NEW	$0
														Subtotal = $0

Issue Date FY: 2010 ( Subtotal = $59,918 )
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	000	2	3/17/2010	NON-COMPETING CONTINUATION	$59,918
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	002	2	9/30/2010	NON-COMPETING CONTINUATION	$0
2010	2010	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	001	2	8/5/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $59,918

Issue Date FY: 2009 ( Subtotal = $57,194 )
2009	2009	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	000	1	5/26/2009	NEW	$57,194
2009	2009	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Mental Health National Research Service Awards for Research Training	001	1	7/31/2009	NEW	$0
														Subtotal = $57,194

Grand Total All Awards = $117,112

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Role of neuroligins in long-term plasticity at excitatory and inhibitory synapses

Award Number: F32MH086224

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/27/2009

PERIOD OF PERFORMANCE END DATE: 06/30/2014

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