Interneurons Are Necessary for Coordinated Activity During Reversal Learning in Orbitofrontal Cortex

Biol Psychiatry. 2015 Mar 1;77(5):454-64. doi: 10.1016/j.biopsych.2014.07.023. Epub 2014 Aug 1.

Abstract

Background: Cerebral cortical gamma-aminobutyric acidergic interneuron dysfunction is hypothesized to lead to cognitive deficits comorbid with human neuropsychiatric disorders, including schizophrenia, autism, and epilepsy. We have previously shown that mice that harbor mutations in the Plaur gene, which is associated with schizophrenia, have deficits in frontal cortical parvalbumin-expressing interneurons. Plaur mice have impaired reversal learning, similar to deficits observed in patients with schizophrenia.

Methods: We examined the role of parvalbumin interneurons in orbitofrontal cortex during reversal learning by recording single unit activity from 180 control and 224 Plaur mouse neurons during a serial reversal task. Neural activity was analyzed during correct and incorrect decision choices and reward receipt.

Results: Neurons in control mice exhibited strong phasic responses both during discrimination and reversal learning to decisions and rewards, and the strength of the response was correlated with behavioral performance. Although baseline firing was significantly enhanced in Plaur mice, neural selectivity for correct or erroneous decisions was diminished and not correlated with behavior, and reward encoding was downscaled. In addition, Plaur mice showed a significant reduction in the number of neurons that encoded expected outcomes across task phases during the decision period.

Conclusions: These data indicate that parvalbumin interneurons are necessary for the representation of outcomes in orbitofrontal cortex. Deficits in inhibition blunt selective neural firing during key decisions, contributing to behavioral inflexibility. These data provide a potential explanation for disorders of cognitive control that accompany the loss of these gamma-aminobutyric acidergic interneurons in human neuropsychiatric disorders, such as autism, epilepsy, and schizophrenia.

Keywords: Autism; Interneuron; OFC; Parvalbumin; Plaur; Reversal learning; Schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Decision Making / physiology
  • Discrimination Learning / physiology
  • Frontal Lobe / physiology*
  • Interneurons / physiology*
  • Male
  • Mice, 129 Strain
  • Mice, Transgenic
  • Microelectrodes
  • Neuropsychological Tests
  • Parvalbumins / metabolism
  • Receptors, Urokinase Plasminogen Activator / genetics
  • Receptors, Urokinase Plasminogen Activator / metabolism
  • Reversal Learning / physiology*
  • Reward

Substances

  • Parvalbumins
  • Plaur protein, mouse
  • Receptors, Urokinase Plasminogen Activator