title: Changes in neural network homeostasis trigger neuropsychiatric symptoms.
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.
authors.forename: Aline
authors.initials: A
authors.lastname: Winkelmann
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
authors.forename: Joanna
authors.initials: J
authors.lastname: Eller
authors.forename: Gürsel
authors.initials: G
authors.lastname: Caliskan
authors.forename: Marcus
authors.initials: M
authors.lastname: Semtner
authors.forename: Ute
authors.initials: U
authors.lastname: Häussler
authors.forename: René
authors.initials: R
authors.lastname: Jüttner
authors.forename: Tamar
authors.initials: T
authors.lastname: Dugladze
authors.forename: Birthe
authors.initials: B
authors.lastname: Smolinsky
authors.forename: Sarah
authors.initials: S
authors.lastname: Kowalczyk
authors.forename: Ewa
authors.initials: E
authors.lastname: Chronowska
authors.forename: Günter
authors.initials: G
authors.lastname: Schwarz
authors.forename: Fritz G
authors.initials: FG
authors.lastname: Rathjen
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Carola A
authors.initials: CA
authors.lastname: Haas
authors.forename: Akos
authors.initials: A
authors.lastname: Kulik
authors.forename: Tengis
authors.initials: T
authors.lastname: Gloveli
authors.forename: Uwe
authors.initials: U
authors.lastname: Heinemann
authors.forename: Jochen C
authors.initials: JC
authors.lastname: Meier
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003072:Cognition Disorders / Q000503:physiopathology*; D003593:Cytoplasm / Q000378:metabolism; D005838:Genotype; D005973:Glutamine / Q000737:chemistry; D005982:Glutathione Transferase / Q000378:metabolism; D005998:Glycine / Q000737:chemistry; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007395:Interneurons / Q000378:metabolism; D008297:Male; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009415:Nerve Net; D009473:Neuronal Plasticity / Q000502:physiology; D009991:Oscillometry; D010320:Parvalbumins / Q000737:chemistry; D010641:Phenotype; D018009:Receptors, Glycine / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission
chemical_list: D010320:Parvalbumins; D018009:Receptors, Glycine; D005973:Glutamine; D049452:Green Fluorescent Proteins; D005982:Glutathione Transferase; D005998:Glycine