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Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Lookup NU author(s): Dr Abhishek Banerjee

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Abstract

Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. Targeted recordings reveal that parvalbumin-expressing (PV+) interneurons in mutant mice have reduced responses. PV-specific MeCP2 deletion alone recapitulates effects of global MeCP2 deletion on cortical circuits, including reduced pyramidal neuron responses and reduced response reliability and selectivity. Furthermore, MeCP2 mutant mice show reduced expression of the cationchloride cotransporter KCC2 (K+/Cl- exporter) and a reduced KCC2/ NKCC1 (Na+/K+/Cl- importer) ratio. Perforated patch recordings demonstrate that the reversal potential for GABA is more depolarized in mutant mice, but is restored by application of the NKCC1 inhibitor bumetanide. Treatment with recombinant human insulinlike growth factor-1 restores responses of PV+ and pyramidal neurons and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.


Publication metadata

Author(s): Banerjee A, Rikhye RV, Breton-Provencher V, Tang X, Li C, Li K, Runyan CA, Fu Z, Jaenisch R, Sur M

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2016

Volume: 113

Issue: 46

Pages: E7287-E7296

Print publication date: 12/11/2016

Online publication date: 01/11/2016

Acceptance date: 12/06/2016

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: https://doi.org/10.1073/pnas.1615330113

DOI: 10.1073/pnas.1615330113

PubMed id: 27803317


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