Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome

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Abstract

Motor and cognitive functions are severely impaired in Rett syndrome (RTT). Here, we examined local synaptic circuits of layer 2/3 (L2/3) pyramidal neurons in motor-frontal cortex of male hemizygous MeCP2-null mice at 3 to 4 weeks of age. We mapped local excitatory input to L2/3 neurons using glutamate uncaging and laser scanning photostimulation, and compared synaptic input maps recorded from MeCP2-null and wild type (WT) mice. Local excitatory input was significantly reduced in the mutants. The strongest phenotype was observed for lateral (horizontal, intralaminar) inputs, that is, L2/3→2/3 inputs, which showed a large reduction in MeCP2−/y animals. Neither the amount of local inhibitory input to these L2/3 pyramidal neurons nor their intrinsic electrophysiological properties differed by genotype. Our findings provide further evidence that excitatory networks are selectively reduced in RTT. We discuss our findings in the context of recently published parallel studies using selective MeCP2 knockdown in individual L2/3 neurons.

Section snippets

MeCP2−/y mice

Male wild type (WT) and hemizygous MeCP2−/y littermates were obtained from colonies of heterozygous mutant females and WT males (MeCP2tm1.1Bird, Jackson Laboratories) (Guy et al., 2001). Experiments involving MeCP2−/y mice were performed with the experimenter blind to genotype. Tail samples were collected at the time of recordings, and genotyped according to the vendor's PCR protocol (http://jaxmice.jax.org). Primers were MeCP2-common (5′-ggT AAA gAC CCA TgT gAC CC-3), MeCP2 wild type (5′-ggC

Reduced cortical thickness in MeCP2−/y mice

We prepared brain slices from 3 to 4 week old mice, using an off-sagittal angle to obtain slices with M1 and adjacent somatosensory (S1) cortex (Weiler et al., 2008) (Figs. 1 A, B). M1 was identified as agranular cortex anterior to somatosensory ‘barrel’ cortex. Because cortical thickness has been shown to be reduced in older MeCP2-null mice (Fukuda et al., 2005, Kishi and Macklis, 2004), we examined M1 cortical thickness in these slices prepared from WT (Fig. 1A) and mutant (Fig. 1B) mice.

Discussion

In this study we examined neocortical synaptic circuits in presymptomatic hemizygous male MeCP2tm1.1Bird mice (“Bird” strain, in which exons 3 and 4 of the MeCP2 gene are deleted), a model of RTT (Guy et al., 2001). We used LSPS to map local sources of excitatory input to L2/3 pyramidal neurons in the motor-frontal area of WT and MeCP2−/y mice. We observed a reduction in excitatory synaptic input, extending previous observations of generally decreased excitation onto cortical neurons (Chao et

Acknowledgments

We thank M. Bevan, A. Contractor, M. Hooks, G. Maccaferri, and M. Tresch for valuable input. We are especially grateful to N. Weiler for experimental efforts in the early stages of this work and for comments on earlier drafts. We thank M. Hooks for statistical advice and comments on a draft. Support: Simons Foundation, Rett Syndrome Research Foundation (International Rett Syndrome Foundation), and National Institutes of Health (NS061534 to LW; NS061963 to GS).

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