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Proc Natl Acad Sci U S A DOI:10.1073/pnas.1615330113

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

Publication TypeJournal Article
Year of Publication2016
AuthorsBanerjee, A, Rikhye, RV, Breton-Provencher, V, Tang, X, Li, C, Li, K, Runyan, CA, Fu, Z, Jaenisch, R, Sur, M
JournalProc Natl Acad Sci U S A
Volume113
Issue46
PagesE7287-E7296
Date Published2016 Nov 15
ISSN1091-6490
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 cation-chloride 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 insulin-like 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.

DOI10.1073/pnas.1615330113
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27803317?dopt=Abstract

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27803317
PubMed Central IDPMC5135376
Grant ListR01 MH104610 / MH / NIMH NIH HHS / United States
R01 EY007023 / EY / NEI NIH HHS / United States
R01 MH085802 / MH / NIMH NIH HHS / United States
R01 NS088538 / NS / NINDS NIH HHS / United States
R37 HD045022 / HD / NICHD NIH HHS / United States
R37 CA084198 / CA / NCI NIH HHS / United States
R01 HD045022 / HD / NICHD NIH HHS / United States