Early NMDA Receptor Ablation in Interneurons Causes an Activity-Dependent E/I Imbalance in vivo in Prefrontal Cortex Pyramidal Neurons of a Mouse Model Useful for the Study of Schizophrenia

Schizophr Bull. 2021 Aug 21;47(5):1300-1309. doi: 10.1093/schbul/sbab030.

Abstract

Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.

Keywords: adolescence; dendritic retraction; electrophysiology; gamma oscillations; parvalbumin; prefrontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Brain Waves / physiology*
  • Disease Models, Animal
  • Electrophysiological Phenomena / physiology*
  • Hippocampus / metabolism
  • Hippocampus / physiopathology*
  • Interneurons / metabolism
  • Interneurons / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nerve Net / metabolism
  • Nerve Net / physiopathology*
  • Parvalbumins / metabolism
  • Prefrontal Cortex / metabolism
  • Prefrontal Cortex / physiopathology*
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / physiology*
  • Receptors, N-Methyl-D-Aspartate / deficiency*
  • Schizophrenia / metabolism
  • Schizophrenia / physiopathology*

Substances

  • Parvalbumins
  • Receptors, N-Methyl-D-Aspartate