Cortical inhibitory neurons contact each other to form a network of inhibitory synaptic connections. Our knowledge of the connectivity pattern underlying this inhibitory network is, however, still incomplete. Here we discover a simple and complementary interaction scheme between three large molecularly distinct interneuron populations in mouse visual cortex: Parvalbumin expressing interneurons strongly inhibit one another but, surprisingly, provide little inhibition to other populations. In contrast, somatostatin expressing interneurons avoid inhibiting one another, yet strongly inhibit all other populations. Finally, vasoactive intestinal peptide expressing interneurons preferentially inhibit somatostatin interneurons. This scheme occurs in supra- and infra-granular layers, suggesting that inhibitory networks operate similarly at the input and output of visual cortex. Thus, as the specificity of connections between excitatory neurons forms the basis for the cortical canonical circuit, the scheme described here outlines a standard connectivity pattern among cortical inhibitory neurons.

Summary Mutations in the X-linked MECP2, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2) cause Rett syndrome (RTT) and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia, and encephalopathy with early lethality. RTT is characterized by apparently normal early development followed by regression, motor abnormalities, seizures, and features of autism, especially stereotyped behaviors. The mechanisms mediating these striking features are poorly understood. Here we show that mice lacking Mecp2 from γ-amino-butyric-acid-(GABA)-ergic neurons recapitulate numerous RTT and autistic features, including repetitive behaviors. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of RTT. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size consistent with presynaptic reduction in glutamic acid decarboxylase-1 and -2 levels and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal GABAergic neuronal function and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

The relationship between synaptic excitation and inhibition (E/I ratio), two opposing forces in the mammalian cerebral cortex, affects many cortical functions like feature selectivity and gain1,2. Individual pyramidal cells show stable E/I ratios in time despite fluctuating cortical activity levels because when excitation increases, inhibition increases proportionally through the increased recruitment of inhibitory neurons, a phenomenon referred to as excitation-inhibition balance3–9. However, little is known about the distribution of E/I ratios across pyramidal cells. Through their highly divergent axons inhibitory neurons indiscriminately contact most neighboring pyramidal cells10,11. Is inhibition homogeneously distributed or is it individually matched to the different amounts of excitation received by distinct pyramidal cells? Here we discover that pyramidal cells in layer 2/3 of mouse primary visual cortex (V1) each receive inhibition in a similar proportion to their excitation. As a consequence E/I ratios are equalized across pyramidal cells. This matched inhibition is mediated by parvalbumin-expressing (PV) but not somatostatin-expressing (SOM) inhibitory neurons and results from the independent adjustment of synapses originating from the same PV cell but targeting different pyramidal cells. Furthermore, this match is activity-dependent as it is disrupted by perturbing pyramidal cell activity. Thus, the equalization of E/I ratios across pyramidal cells reveals an unexpected degree of order in the spatial distribution of synaptic strengths and indicates that the relationship between cortex’s two opposing forces is stabilized not only in time but also in space.