title: Mechanisms of Functional Hypoconnectivity in the Medial Prefrontal Cortex of Mecp2 Null Mice.
abstract: Frontal cortical dysfunction is thought to contribute to cognitive and behavioral features of autism spectrum disorders; however, underlying mechanisms are poorly understood. The present study sought to define how loss of Mecp2, the gene mutated in Rett syndrome (RTT), disrupts function in the murine medial prefrontal cortex (mPFC) using acute brain slices and behavioral testing. Compared with wildtype, pyramidal neurons in the Mecp2 null mPFC exhibit significant reductions in excitatory postsynaptic currents, the duration of excitatory UP-states, evoked population activity, and the ratio of NMDA:AMPA currents, as well as an increase in the relative fraction of NR2B currents. These functional changes are associated with reductions in the density of excitatory dendritic spines, the ratio of vesicular glutamate to GABA transporters and GluN1 expression. In contrast to recent reports on circuit defects in other brain regions, we observed no effect of Mecp2 loss on inhibitory synaptic currents or expression of the inhibitory marker parvalbumin. Consistent with mPFC hypofunction, Mecp2 nulls exhibit respiratory dysregulation in response to behavioral arousal. Our data highlight functional hypoconnectivity in the mPFC as a potential substrate for behavioral disruption in RTT and other disorders associated with reduced expression of Mecp2 in frontal cortical regions.
authors: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: Michael P
authors: MP
authors: Sceniak
authors: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: Min
authors: M
authors: Lang
authors: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: Addison C
authors: AC
authors: Enomoto
authors: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: C
authors: C
authors: James Howell
authors: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: Douglas J
authors: DJ
authors: Hermes
authors: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors: David M
authors: DM
authors: Katz
mesh_terms: D000200:Action Potentials; D000818:Animals; D020013:Calcium Signaling; D049229:Dendritic Spines; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials; D053444:Inhibitory Postsynaptic Potentials; D008564:Membrane Potentials; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D017397:Prefrontal Cortex / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018091:Receptors, AMPA / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism / Q000502:physiology; D012119:Respiration / Q000235:genetics; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology; D050495:Vesicular Inhibitory Amino Acid Transport Proteins / Q000378:metabolism
chemical_list: C121673:Gprin1 protein, mouse; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D050495:Vesicular Inhibitory Amino Acid Transport Proteins; C492244:Viaat protein, mouse
keywords: AMPA; E/I balance; EPSC; Fluo-4 AM; GABA; IPSC; MeCP2; NMDA; Rett syndrome; medial prefrontal cortex; synaptic