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The development of inhibitory circuits depends on the action of a network of transcription factors and epigenetic regulators that are critical for interneuron specification and differentiation. Although the identity of many of these transcription factors is well established, much less is known about the specific contribution of the chromatin-modifying enzymes that sculpt the interneuron epigenome. Here, we generated a mouse model in which the lysine acetyltransferase CBP is specifically removed from neural progenitors at the median ganglionic eminence (MGE), the structure where the most abundant types of cortical interneurons are born. Ablation of CBP interfered with the development of MGE-derived interneurons in both sexes, causing a reduction in the number of functionally mature interneurons in the adult forebrain. Genetic fate mapping experiments not only demonstrated that CBP ablation impacts on different interneuron classes, but also unveiled a compensatory increment of interneurons that escaped recombination and cushion the excitatory-inhibitory imbalance. Consistent with having a reduced number of interneurons, CBP-deficient mice exhibited a high incidence of spontaneous epileptic seizures, and alterations in brain rhythms and enhanced low gamma activity during status epilepticus. These perturbations led to abnormal behavior including hyperlocomotion, increased anxiety and cognitive impairments. Overall, our study demonstrates that CBP is essential for interneuron development and the proper functioning of inhibitory circuitry in vivo.

During thymocyte maturation, enhancers of genes encoding for TCRdelta (Tcrd) and TCRalpha (Tcra), Edelta(8), and Ealpha, work as a developmental switch controlling transition from Tcrd to Tcra activity at the Tcrad locus. Previous experiments revealed that an Ealpha fragment, Talpha1-Talpha2, which constitutes a well-characterized compact nucleoprotein structure led to premature activation of V(D)J recombination compared with that observed for the entire Ealpha or Talpha1-Talpha4. These experiments indicated that Talpha3-Talpha4 collaborates with factors bound to Talpha1-Talpha2 for the strict developmental regulation of Tcra rearrangement. The compact enhanceosome created on Talpha1-Talpha2 explained the molecular basis for requirement of intact Talpha2 TCF/LEF and ets sites for enhancer function. We have created a mutant version of Ealpha, EalphaMC, in which Edelta myb and runx sites have been substituted for Talpha2 runx and ets sites, that argues against the notion of a requirement for strict Ealpha enhanceosome structure for function. EalphaMC resulted in a very potent enhancer indicating that stereospecific interactions among proteins that form an Ealpha enhanceosome are rather flexible. Activation of V(D)J recombination by EalphaMC during thymocyte development resulted, however, to be premature and indistinguishable from that of Talpha1-Talpha2. These results indicate that Talpha3-Talpha4 itself is not sufficient to impart a developmental delay to a chimeric "early" enhancer, and indicate the need for functional collaboration between Talpha2 runx/ets sites binding proteins and proteins bound to Talpha3-Talpha4 for proper developmental activation. The possibility of assembly of distinct sets of proteins on Ealpha might represent a more flexible form of information processing during thymocyte development.