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Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout

Muhia, Mary and Willadt, Silvia and Yee, Benjamin K. and Feldon, Joram and Paterna, Jean-Charles and Schwendener, Severin and Vogt, Kaspar and Kennedy, Mary B. and Knuesel, Irene (2012) Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout. Learning and Memory, 19 (7). pp. 268-281. ISSN 1072-0502. https://resolver.caltech.edu/CaltechAUTHORS:20120716-102059619

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Abstract

The synaptic Ras/Rap-GTPase-activating protein (SynGAP1) plays a unique role in regulating specific downstream intracellular events in response to N-methyl-D-aspartate receptor (NMDAR) activation. Constitutive heterozygous loss of SynGAP1 disrupts NMDAR-mediated physiological and behavioral processes, but the disruptions might be of developmental origin. Therefore, the precise role of SynGAP1 in the adult brain, including its relative functional significance within specific brain regions, remains unexplored. The present study constitutes the first attempt in achieving adult hippocampal-specific SynGAP1 knockout using the Cre/loxP approach. Here, we report that this manipulation led to a significant numerical increase in both small and large GluA1 and NR1 immunoreactive clusters, many of which were non-opposed to presynaptic terminals. In parallel, the observed marked decline in the amplitude of spontaneous excitatory currents (sEPSCs) and inter-event intervals supported the impression that SynGAP1 loss might facilitate the accumulation of extrasynaptic glutamatergic receptors. In addition, SynGAP1-mediated signaling appears to be critical for the proper integration and survival of newborn neurons. The manipulation impaired reversal learning in the probe test of the water maze and induced a delay-dependent impairment in spatial recognition memory. It did not significantly affect anxiety or reference memory acquisition but induced a substantial elevation in spontaneous locomotor activity in the open field test. Thus, the present study demonstrates the functional significance of SynGAP1 signaling in the adult brain by capturing several changes that are dependent on NMDAR and hippocampal integrity.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1101/lm.026351.112DOIArticle
http://learnmem.cshlp.org/content/19/7/268PublisherArticle
ORCID:
AuthorORCID
Kennedy, Mary B.0000-0003-1369-0525
Additional Information:© 2012 Cold Spring Harbor Laboratory Press. The Authors acknowledge that six months after the full-issue publication date, the Article will be distributed under a Creative Commons CC-BY-NC License (Attribution-NonCommercial 4.0 International License, http://creativecommons.org/licenses/by-nc/4.0/). Received March 13, 2012; accepted in revised form April 12, 2012. This study was supported by the Swiss Federal Institute of Technology Zurich, Grant Nr TH-22a/04-03 and SNF Grant Nr 310000-117806 (IK). We thank Corinne Sidler (Institute of Pharmacology and Toxicology, University of Zurich) for her help with the immunohistochemical stainings. We also thank Dr. Oleg Georgiev (Institute of Molecular Life Sciences, University of Zurich) for providing the Klenow-blunted SalI-NLS Cre-XbaI fragment of pCMV-NLS Cre.We are grateful to Jean-Marc Fritschy for his invaluable advice and support. We also thank the Animal Services Department Schwerzenbach for animal husbandry and care and Dr. Frank Bootz for his veterinary expertise and supervision.
Funders:
Funding AgencyGrant Number
Swiss Federal Institute of Technology ZurichNr TH-22a/04-03
Swiss National Science Foundation (SNF)Nr 310000-117806
Issue or Number:7
Record Number:CaltechAUTHORS:20120716-102059619
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120716-102059619
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:32463
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:16 Jul 2012 19:25
Last Modified:03 Oct 2019 04:00

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