Restoring wild-type-like CA1 network dynamics and behavior during adulthood in a mouse model of schizophrenia

Nat Neurosci. 2018 Oct;21(10):1412-1420. doi: 10.1038/s41593-018-0225-y. Epub 2018 Sep 17.

Abstract

Schizophrenia is a severely debilitating neurodevelopmental disorder. Establishing a causal link between circuit dysfunction and particular behavioral traits that are relevant to schizophrenia is crucial to shed new light on the mechanisms underlying the pathology. We studied an animal model of the human 22q11 deletion syndrome, the mutation that represents the highest genetic risk of developing schizophrenia. We observed a desynchronization of hippocampal neuronal assemblies that resulted from parvalbumin interneuron hypoexcitability. Rescuing parvalbumin interneuron excitability with pharmacological or chemogenetic approaches was sufficient to restore wild-type-like CA1 network dynamics and hippocampal-dependent behavior during adulthood. In conclusion, our data provide insights into the network dysfunction underlying schizophrenia and highlight the use of reverse engineering to restore physiological and behavioral phenotypes in an animal model of neurodevelopmental disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 22q11 Deletion Syndrome / complications
  • 22q11 Deletion Syndrome / genetics
  • Action Potentials / drug effects
  • Action Potentials / physiology
  • Animals
  • Animals, Newborn
  • CA1 Region, Hippocampal / pathology*
  • Clozapine / analogs & derivatives
  • Clozapine / pharmacology
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mental Disorders / etiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nerve Net / pathology*
  • Nerve Net / physiopathology
  • Neuregulins / pharmacology
  • Neurons / drug effects
  • Neurons / physiology
  • Nonlinear Dynamics*
  • Parvalbumins / genetics
  • Parvalbumins / metabolism
  • Prepulse Inhibition / physiology
  • Reflex, Startle / physiology
  • Schizophrenia / etiology
  • Schizophrenia / genetics
  • Schizophrenia / pathology*
  • Schizophrenia / physiopathology*

Substances

  • Neuregulins
  • Parvalbumins
  • Clozapine
  • clozapine N-oxide