NKX2-1 Is Required in the Embryonic Septum for Cholinergic System Development, Learning, and Memory

Cell Rep. 2017 Aug 15;20(7):1572-1584. doi: 10.1016/j.celrep.2017.07.053.

Abstract

The transcription factor NKX2-1 is best known for its role in the specification of subsets of cortical, striatal, and pallidal neurons. We demonstrate through genetic fate mapping and intersectional focal septal deletion that NKX2-1 is selectively required in the embryonic septal neuroepithelium for the development of cholinergic septohippocampal projection neurons and large subsets of basal forebrain cholinergic neurons. In the absence of NKX2-1, these neurons fail to develop, causing alterations in hippocampal theta rhythms and severe deficiencies in learning and memory. Our results demonstrate that learning and memory are dependent on NKX2-1 function in the embryonic septum and suggest that cognitive deficiencies that are sometimes associated with pathogenic mutations in NKX2-1 in humans may be a direct consequence of loss of NKX2-1 function.

Keywords: acetylcholine; development; hippocampus; septum; theta.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcholine / metabolism
  • Animals
  • Cholinergic Neurons / metabolism*
  • Cholinergic Neurons / pathology
  • Cognition / physiology
  • Electrodes, Implanted
  • Embryo, Mammalian
  • Female
  • Gene Expression Regulation, Developmental*
  • Hippocampus / metabolism*
  • Hippocampus / pathology
  • Male
  • Maze Learning
  • Memory / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Rotarod Performance Test
  • Septum of Brain / metabolism*
  • Septum of Brain / pathology
  • Stereotaxic Techniques
  • Theta Rhythm / physiology
  • Thyroid Nuclear Factor 1 / deficiency
  • Thyroid Nuclear Factor 1 / genetics*

Substances

  • Nkx2-1 protein, mouse
  • Thyroid Nuclear Factor 1
  • Acetylcholine