The Epigenetic Factor CBP Is Required for the Differentiation and Function of Medial Ganglionic Eminence-Derived Interneurons

Mol Neurobiol. 2019 Jun;56(6):4440-4454. doi: 10.1007/s12035-018-1382-4. Epub 2018 Oct 17.

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.

Keywords: CBP; Epilepsy; Intellectual disability; Interneurons; Neuroprogenitor; Rubinstein-Taybi syndrome.

MeSH terms

  • Action Potentials
  • Animals
  • Anxiety / complications
  • Anxiety / physiopathology
  • Behavior, Animal
  • Cell Differentiation / genetics*
  • Chromosome Mapping
  • Cognition Disorders / complications
  • Cognition Disorders / physiopathology
  • Epigenesis, Genetic*
  • Epilepsy / complications
  • Epilepsy / pathology
  • Epilepsy / physiopathology
  • Female
  • Hippocampus / metabolism
  • Interneurons / cytology*
  • Interneurons / metabolism
  • Kainic Acid
  • Learning
  • Male
  • Median Eminence / cytology*
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Parvalbumins / metabolism
  • Phosphoproteins / metabolism*
  • Somatostatin / metabolism
  • Thyroid Nuclear Factor 1 / metabolism

Substances

  • Membrane Proteins
  • Nkx2-1 protein, mouse
  • Pag1 protein, mouse
  • Parvalbumins
  • Phosphoproteins
  • Thyroid Nuclear Factor 1
  • Somatostatin
  • Kainic Acid