Restoration of Sp4 in Forebrain GABAergic Neurons Rescues Hypersensitivity to Ketamine in Sp4 Hypomorphic Mice

Int J Neuropsychopharmacol. 2015 Jun 2;18(11):pyv063. doi: 10.1093/ijnp/pyv063.


Background: Ketamine produces schizophrenia-like behavioral phenotypes in healthy people. Prolonged ketamine effects and exacerbation of symptoms after the administration of ketamine have been observed in patients with schizophrenia. More recently, ketamine has been used as a potent antidepressant to treat patients with major depression. The genes and neurons that regulate behavioral responses to ketamine, however, remain poorly understood. Sp4 is a transcription factor for which gene expression is restricted to neuronal cells in the brain. Our previous studies demonstrated that Sp4 hypomorphic mice display several behavioral phenotypes relevant to psychiatric disorders, consistent with human SP4 gene associations with schizophrenia, bipolar disorder, and major depression. Among those behavioral phenotypes, hypersensitivity to ketamine-induced hyperlocomotion has been observed in Sp4 hypomorphic mice.

Methods: In the present study, we used the Cre-LoxP system to restore Sp4 gene expression, specifically in either forebrain excitatory or GABAergic inhibitory neurons in Sp4 hypomorphic mice. Mouse behavioral phenotypes related to psychiatric disorders were examined in these distinct rescue mice.

Results: Restoration of Sp4 in forebrain excitatory neurons did not rescue deficient sensorimotor gating nor ketamine-induced hyperlocomotion. Restoration of Sp4 in forebrain GABAergic neurons, however, rescued ketamine-induced hyperlocomotion, but did not rescue deficient sensorimotor gating.

Conclusions: Our studies suggest that the Sp4 gene in forebrain GABAergic neurons regulates ketamine-induced hyperlocomotion.

Keywords: GABAergic; Sp4; genetic rescue; ketamine; locomotor activity.

Publication types

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

MeSH terms

  • Akathisia, Drug-Induced / physiopathology*
  • Animals
  • Cohort Studies
  • Excitatory Amino Acid Antagonists / toxicity*
  • Female
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / physiology*
  • Ketamine / toxicity*
  • Male
  • Mice, 129 Strain
  • Mice, Transgenic
  • Prosencephalon / drug effects
  • Prosencephalon / physiopathology*
  • Sensory Gating / physiology
  • Sp4 Transcription Factor / genetics
  • Sp4 Transcription Factor / metabolism*


  • Excitatory Amino Acid Antagonists
  • Sp4 Transcription Factor
  • Sp4 protein, mouse
  • Sp4 protein, rat
  • Ketamine