title: Impaired synaptic plasticity in the prefrontal cortex of mice with developmentally decreased number of interneurons.
abstract: Interneurons are inhibitory neurons, which protect neural tissue from excessive excitation. They are interconnected with glutamatergic pyramidal neurons in the cerebral cortex and regulate their function. Particularly in the prefrontal cortex (PFC), interneurons have been strongly implicated in regulating pathological states which display deficits in the PFC. The aim of this study is to investigate the adaptations in the adult glutamatergic system, when defects in interneuron development do not allow adequate numbers of interneurons to reach the cerebral cortex. To this end, we used a mouse model that displays ~50% fewer cortical interneurons due to the Rac1 protein loss from Nkx2.1/Cre expressing cells (Rac1 conditional knockout (cKO) mice), to examine how the developmental loss of interneurons may affect basal synaptic transmission, synaptic plasticity and neuronal morphology in the adult PFC. Despite the decrease in the number of interneurons, basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks, is not altered in the PFC of Rac1 cKO mice. However, there is decreased paired-pulse ratio (PPR) and decreased long-term potentiation (LTP), in response to tetanic stimulation, in the layer II PFC synapses of Rac1 cKO mice. Furthermore, expression of N-methyl-d-aspartate (NMDA) subunits is decreased and dendritic morphology is altered, changes that could underlie the decrease in LTP in the Rac1 cKO mice. Finally, we find that treating Rac1 cKO mice with diazepam in early postnatal life can reverse changes in dendritic morphology observed in non-treated Rac1 cKO mice. Therefore, our data show that disruption in GABAergic inhibition alters glutamatergic function in the adult PFC, an effect that could be reversed by enhancement of GABAergic function during an early postnatal period.
authors.affiliation: Department of Biology, University of Crete, Voutes University Campus, Vassilika Vouton, GR 70013 Heraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Vassilika Vouton, GR 70013 Heraklion, Greece.
authors.forename: X
authors.initials: X
authors.lastname: Konstantoudaki
authors.affiliation: Department of Biology, University of Crete, Voutes University Campus, Vassilika Vouton, GR 70013 Heraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Vassilika Vouton, GR 70013 Heraklion, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Chalkiadaki
authors.affiliation: Medical School, University of Crete, Voutes University Campus, Vassilika Vouton, GR 71003 Heraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Vassilika Vouton, GR 70013 Heraklion, Greece.
authors.forename: S
authors.initials: S
authors.lastname: Tivodar
authors.affiliation: Medical School, University of Crete, Voutes University Campus, Vassilika Vouton, GR 71003 Heraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Vassilika Vouton, GR 70013 Heraklion, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Karagogeos
authors.affiliation: Department of Biology, University of Crete, Voutes University Campus, Vassilika Vouton, GR 70013 Heraklion, Greece; Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology, Hellas, Vassilika Vouton, GR 70013 Heraklion, Greece. Electronic address: sidirop@uoc.gr.
authors.forename: K
authors.initials: K
authors.lastname: Sidiropoulou
mesh_terms: D000818:Animals; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D003975:Diazepam / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D008297:Male; D018345:Mice, Knockout; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D046509:Tissue Culture Techniques; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D018757:GABA Modulators; D009479:Neuropeptides; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; C484602:Rac1 protein, mouse; D016194:Receptors, N-Methyl-D-Aspartate; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D020830:rac1 GTP-Binding Protein; D003975:Diazepam
keywords: MGE-derived interneurons; NMDA; Rac1; dendritic spines; diazepam; synaptic plasticity