Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome.
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.
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
Abhishek
A
Banerjee
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
Rajeev V
RV
Rikhye
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
Vincent
V
Breton-Provencher
The Whitehead Institute for Biomedical Research, Cambridge, MA 02142.
Xin
X
Tang
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Chenchen
C
Li
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
Keji
K
Li
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139.
Caroline A
CA
Runyan
Broad Institute of MIT and Harvard, Cambridge, MA 02142.
Zhanyan
Z
Fu
The Whitehead Institute for Biomedical Research, Cambridge, MA 02142; msur@mit.edu jaenisch@wi.mit.edu.
Rudolf
R
Jaenisch
The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139; msur@mit.edu jaenisch@wi.mit.edu.
Mriganka
M
Sur
D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010320:Parvalbumins; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins; D015518:Rett Syndrome / Q000503:physiopathology*
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D010320:Parvalbumins; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; C000604197:mecasermin
E/I balance; IGF1; MeCP2; chloride transporters; parvalbumin neurons