title: Ketamine Administration During the Second Postnatal Week Alters Synaptic Properties of Fast-Spiking Interneurons in the Medial Prefrontal Cortex of Adult Mice.
abstract: The N-methyl-D-aspartic acid (NMDA)-hypofunction theory of schizophrenia suggests that schizophrenia is associated with a loss of NMDA receptors, specifically on corticolimbic parvalbumin (PV)-expressing GABAergic interneurons, leading to disinhibition of pyramidal cells and cortical desynchronization. However, the presumed changes in glutamatergic inputs onto PV interneurons have not been tested directly. We treated mice with the NMDAR antagonist ketamine during the second postnatal week and investigated persistent cellular changes in the adult medial prefrontal cortex (mPFC) using whole-cell patch-clamp recordings and immunohistochemistry. Parvalbumin expression in the mPFC was reduced in ketamine-treated (KET) mice, and γ-aminobutyric acid release onto pyramidal cells was reduced in layers 2/3, but not layer 5. Consistent with pyramidal cell disinhibition the frequency of spontaneous glutamatergic inputs onto PV cells was also increased in KET mice. Furthermore, developmental ketamine treatment resulted in an increased NMDA:AMPA ratio in evoked synaptic currents and larger amplitudes of spontaneous NMDAR currents, indicating a homeostatic upregulation of NMDARs in PV interneurons. This upregulation was specific to NR2B subunits, without concomitant alterations in currents through NR2A subunits. These changes altered synaptic integration at PV cells during trains of excitatory postsynaptic potentials. These changes likely impact synaptic coincidence detection and impair cortical network function in the NMDAR antagonism model of schizophrenia.
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Jeevakumar
authors.affiliation: School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX 75080, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Kroener
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D007649:Ketamine / Q000633:toxicity*; D008297:Male; D008822:Mice, Transgenic; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology*; D017966:Pyramidal Cells / Q000473:pathology / Q000502:physiology; D018091:Receptors, AMPA / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000503:physiopathology; D013569:Synapses / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; D010320:Parvalbumins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D007649:Ketamine
keywords: cortical disinhibition; developmental NMDAR antagonism; glutamate; parvalbumin; schizophrenia