A Fundamental Role for Hippocampal Parvalbumin in the Dopamine Hyperfunction Associated With Schizophrenia

Schizophr Res. 2014 Aug;157(1-3):238-43. doi: 10.1016/j.schres.2014.05.005. Epub 2014 Jun 2.

Abstract

Postmortem studies in schizophrenia patients have demonstrated robust alterations in GABAergic markers throughout the neuraxis. It has been suggested that these alterations are restricted to subpopulations of interneurons, such as those containing the calcium binding protein parvalbumin. Indeed, a reduction in parvalbumin expression is a consistent observation in human postmortem studies, as well as, in a wide and diverse variety of animal models. However, it still remains to be determined whether this decrease in parvalbumin expression contributes to, or is a consequence of the disease. Here we utilize lentiviral delivered shRNA and demonstrate that a selective reduction in parvalbumin mRNA expression induces hyperactivity within the ventral hippocampus. In addition, we observe downstream increases in dopamine neuron population activity without changes in average firing rate or percent burst firing. These changes in dopamine neuron activity were associated with an enhanced locomotor response to amphetamine administration. These data therefore demonstrate that a reduction in ventral hippocampal parvalbumin expression is sufficient, in and of itself, to induce an augmented dopamine system function and behavioral hyper-responsivity to amphetamine, implicating a potential key role for parvalbumin in the pathophysiology of schizophrenia.

Keywords: Dopamine; Hippocampus; Parvalbumin; Schizophrenia.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / physiology
  • Amphetamine / pharmacology
  • Animals
  • Central Nervous System Stimulants / pharmacology
  • Disease Models, Animal
  • Dopamine / metabolism*
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / physiology*
  • Gene Knockdown Techniques
  • Genetic Vectors
  • Hippocampus / drug effects
  • Hippocampus / physiopathology*
  • Immunohistochemistry
  • Lentivirus / genetics
  • Male
  • Microelectrodes
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Parvalbumins / genetics
  • Parvalbumins / metabolism*
  • RNA, Messenger / metabolism
  • RNA, Small Interfering
  • Rats, Sprague-Dawley
  • Schizophrenia / physiopathology*
  • Ventral Tegmental Area / drug effects
  • Ventral Tegmental Area / physiopathology

Substances

  • Central Nervous System Stimulants
  • Parvalbumins
  • RNA, Messenger
  • RNA, Small Interfering
  • Amphetamine
  • Dopamine