Abstract
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.
Highlights
The multiple actions of the mammalian brain depend on the precise spatiotemporal control of synaptic communication within local and long-range neuronal networks
Previous loss-offunction studies have identified the sequence of transcription factors (TF) that is responsible for regulating interneuron generation and maturation, and demonstrated that interfering with this sequence leads to excitatory/inhibitory imbalance, seizures and behavioral alterations [3, 26, 27]
We were able to demonstrate that the absence of CBP in median ganglionic eminence (MGE) progenitors, to what was observed for some of the afore-discussed TFs, caused a reduction in the number of interneurons derived from this region
Summary
The multiple actions of the mammalian brain depend on the precise spatiotemporal control of synaptic communication within local and long-range neuronal networks. Fewer in number than excitatory neurons, inhibitory neurons play a crucial role in fine-tuning neuronal firing and shaping the activity and rhythms of neuronal circuits [1, 2]. They constitute a highly heterogeneous group of cells with different morphological, neurochemical, and electrophysiological. The production of excitatory and inhibitory neurons is precisely regulated. The development of inhibitory circuits relies on a network of transcription factors (TF) that control the sequential and regionspecific activation of complex gene programs [2, 3, 6, 7]. The TF Nkx, which is expressed in neural progenitors of the MGE [8], and the homeobox TFs Dlx and Dlx, which are expressed by progenitors within
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
