Universität zu Köln

Winkelmann, Aline, Maggio, Nicola ORCID: 0000-0001-5041-2108, Eller, Joanna, Caliskan, Guersel, Semtner, Marcus, Haeussler, Ute, Juettner, Rene, Dugladze, Tamar, Smolinsky, Birthe, Kowalczyk, Sarah, Chronowska, Ewa, Schwarz, Guenter ORCID: 0000-0002-2118-9338, Rathjen, Fritz G., Rechavi, Gideon, Haas, Carola A., Kulik, Akos, Gloveli, Tengis, Heinemann, Uwe and Meier, Jochen C. (2014). Changes in neural network homeostasis trigger neuropsychiatric symptoms. J. Clin. Invest., 124 (2). S. 696 - 712. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

The mechanisms that regulate the strength of synaptic transmission and intrinsic neuronal excitability are well characterized; however, the mechanisms that promote disease-causing neural network dysfunction are poorly defined. We generated mice with targeted neuron type-specific expression of a gain-of-function variant of the neurotransmitter receptor for glycine (GlyR) that is found in hippocampectomies from patients with temporal lobe epilepsy. In this mouse model, targeted expression of gain-of-function GlyR in terminals of glutamatergic cells or in parvalbumin-positive interneurons persistently altered neural network excitability. The increased network excitability associated with gain-of-function GlyR expression in glutamatergic neurons resulted in recurrent epileptiform discharge, which provoked cognitive dysfunction and memory deficits without affecting bidirectional synaptic plasticity. In contrast, decreased network excitability due to gain-of-function GlyR expression in parvalbumin-positive interneurons resulted in an anxiety phenotype, but did not affect cognitive performance or discriminative associative memory. Our animal model unveils neuron type-specific effects on cognition, formation of discriminative associative memory, and emotional behavior in vivo. Furthermore, our data identify a presynaptic disease-causing molecular mechanism that impairs homeostatic regulation of neural network excitability and triggers neuropsychiatric symptoms.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Winkelmann, Aline UNSPECIFIED UNSPECIFIED UNSPECIFIED Maggio, Nicola UNSPECIFIED orcid.org/0000-0001-5041-2108 UNSPECIFIED Eller, Joanna UNSPECIFIED UNSPECIFIED UNSPECIFIED Caliskan, Guersel UNSPECIFIED UNSPECIFIED UNSPECIFIED Semtner, Marcus UNSPECIFIED UNSPECIFIED UNSPECIFIED Haeussler, Ute UNSPECIFIED UNSPECIFIED UNSPECIFIED Juettner, Rene UNSPECIFIED UNSPECIFIED UNSPECIFIED Dugladze, Tamar UNSPECIFIED UNSPECIFIED UNSPECIFIED Smolinsky, Birthe UNSPECIFIED UNSPECIFIED UNSPECIFIED Kowalczyk, Sarah UNSPECIFIED UNSPECIFIED UNSPECIFIED Chronowska, Ewa UNSPECIFIED UNSPECIFIED UNSPECIFIED Schwarz, Guenter UNSPECIFIED orcid.org/0000-0002-2118-9338 UNSPECIFIED Rathjen, Fritz G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rechavi, Gideon UNSPECIFIED UNSPECIFIED UNSPECIFIED Haas, Carola A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kulik, Akos UNSPECIFIED UNSPECIFIED UNSPECIFIED Gloveli, Tengis UNSPECIFIED UNSPECIFIED UNSPECIFIED Heinemann, Uwe UNSPECIFIED UNSPECIFIED UNSPECIFIED Meier, Jochen C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-447021
DOI:	10.1172/JCI71472
Journal or Publication Title:	J. Clin. Invest.
Volume:	124
Number:	2
Page Range:	S. 696 - 712
Date:	2014
Publisher:	AMER SOC CLINICAL INVESTIGATION INC
Place of Publication:	ANN ARBOR
ISSN:	1558-8238
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Chemistry > Institute of Biochemistry
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SPONTANEOUS GLUTAMATE RELEASE; GLYCINE RECEPTOR ALPHA-3; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; GAMMA-OSCILLATIONS; PLASMA-MEMBRANE; IN-VITRO; SUBUNIT; LOCALIZATION; EXPRESSION Multiple languages Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/44702