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The Journal of Neuroscience, October 7, 2009, 29(40):12440-12448; doi:10.1523/JNEUROSCI.3321-09.2009

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Neurobiology of Disease
Synaptic Circuit Abnormalities of Motor-Frontal Layer 2/3 Pyramidal Neurons in an RNA Interference Model of Methyl-CpG-Binding Protein 2 Deficiency

Lydia Wood,¹ Noah W. Gray,² Zhaolan Zhou,³ Michael E. Greenberg,^4,5 and Gordon M. G. Shepherd¹

¹Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, 60611, ²Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, ³Department of Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, ⁴Neurobiology Program, Children's Hospital Boston, Boston, Massachusetts 02115, and ⁵Departments of Neurology and Neurobiology, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to Dr. Gordon Shepherd, Department of Physiology, Feinberg School of Medicine, Northwestern University, Morton 5-660, 303 East Chicago Avenue, Chicago, IL 60611. Email: g-shepherd{at}northwestern.edu

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.

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Received July 12, 2009; revised Aug. 26, 2009; accepted Sept. 2, 2009.

Correspondence should be addressed to Dr. Gordon Shepherd, Department of Physiology, Feinberg School of Medicine, Northwestern University, Morton 5-660, 303 East Chicago Avenue, Chicago, IL 60611. Email: g-shepherd{at}northwestern.edu

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