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Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in an RNA interference model of methyl-CpG-binding protein 2 deficiency.

Rett syndrome, an autism spectrum disorder with prominent motor and cognitive features, results from mutations in the gene for methyl-CpG-binding protein 2 (MeCP2). Here, to identify cortical circuit abnormalities that are specifically associated with MeCP2 deficiency, we used glutamate uncaging and laser scanning photostimulation to survey intracortical networks in mouse brain slices containing motor-frontal cortex. We used in utero transfection of short hairpin RNA constructs to knock down MeCP2 expression in a sparsely distributed subset of layer (L) 2/3 pyramidal neurons in wild-type mice, and compared input maps recorded from transfected-untransfected pairs of neighboring neurons. The effect of MeCP2 deficiency on local excitatory input pathways was severe, with an average reduction in excitatory synaptic input from middle cortical layers (L3/5A) of >30% compared with MeCP2-replete controls. MeCP2 deficiency primarily affected the strength, rather than the topography, of excitatory intracortical pathways. Inhibitory synaptic inputs and intrinsic eletrophysiological properties were unaffected in the MeCP2-knockdown neurons. These studies indicate that MeCP2 deficiency in individual postsynaptic cortical pyramidal neurons is sufficient to induce a pathological synaptic defect in excitatory intracortical circuits.

Pubmed ID: 19812320

Authors

  • Wood L
  • Gray NW
  • Zhou Z
  • Greenberg ME
  • Shepherd GM

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

October 7, 2009

Associated Grants

  • Agency: NINDS NIH HHS, Id: F31 NS061534-01
  • Agency: NINDS NIH HHS, Id: K99 NS058391
  • Agency: NINDS NIH HHS, Id: K99 NS058391-01
  • Agency: NINDS NIH HHS, Id: K99 NS058391-02
  • Agency: NINDS NIH HHS, Id: NS048276
  • Agency: NINDS NIH HHS, Id: NS058391
  • Agency: NINDS NIH HHS, Id: NS061534
  • Agency: NINDS NIH HHS, Id: NS061963
  • Agency: NICHD NIH HHS, Id: P30 HD026979
  • Agency: NICHD NIH HHS, Id: P30 HD026979-218156
  • Agency: NINDS NIH HHS, Id: R00 NS058391
  • Agency: NINDS NIH HHS, Id: R00 NS058391-03
  • Agency: NINDS NIH HHS, Id: R00 NS058391-04
  • Agency: NINDS NIH HHS, Id: R00 NS058391-05
  • Agency: NINDS NIH HHS, Id: R01 NS048276
  • Agency: NINDS NIH HHS, Id: R01 NS048276-05
  • Agency: NINDS NIH HHS, Id: R01 NS061963
  • Agency: NINDS NIH HHS, Id: R01 NS061963-01

Mesh Terms

  • Animals
  • Brain Mapping
  • DNA-Binding Proteins
  • Female
  • Mice
  • Motor Cortex
  • Patch-Clamp Techniques
  • Photic Stimulation
  • Pyramidal Cells
  • Synapses