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.
Wood
Lydia
L
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Gray
Noah W
NW
Zhou
Zhaolan
Z
Greenberg
Michael E
ME
Shepherd
Gordon M G
GM
D000818:Animals; D001931:Brain Mapping; D004268:DNA-Binding Proteins / Q000172:deficiency*; D005260:Female; D051379:Mice; D009044:Motor Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010775:Photic Stimulation; D017966:Pyramidal Cells / Q000002:abnormalities* / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*
D004268:DNA-Binding Proteins; C489326:Mbd2 protein, mouse