Gamma rhythms link prefrontal interneuron dysfunction with cognitive inflexibility in Dlx5/6+/− mice

Details

• Alternative Title:
  Neuron
• Personal Author:
  Cho, Kathleen K.A. ; Hoch, Renee ; Lee, Anthony T. ; Patel, Tosha ; Rubenstein, John L.R. ; Sohal, Vikaas S.
• Description:
  Abnormalities in GABAergic interneurons, particularly fast-spiking interneurons (FSINs) that generate gamma (γ; ∼30-120 Hz) oscillations, are hypothesized to disrupt prefrontal cortex (PFC)-dependent cognition in schizophrenia. Although γ rhythms are abnormal in schizophrenia, it remains unclear whether they directly influence cognition. Mechanisms underlying schizophrenia's typical post-adolescent onset also remain elusive. We addressed these issues using mice heterozygous for Dlx5/6, which regulate GABAergic interneuron development. In Dlx5/6(+/-) mice, FSINs become abnormal following adolescence, coinciding with the onset of cognitive inflexibility and deficient task-evoked γ oscillations. Inhibiting PFC interneurons in control mice reproduced these deficits, whereas stimulating them at γ-frequencies restored cognitive flexibility in adult Dlx5/6(+/-) mice. These pro-cognitive effects were frequency specific and persistent. These findings elucidate a mechanism whereby abnormal FSIN development may contribute to the post-adolescent onset of schizophrenia endophenotypes. Furthermore, they demonstrate a causal, potentially therapeutic, role for PFC interneuron-driven γ oscillations in cognitive domains at the core of schizophrenia.
• Subjects:
  Animals Article Behavior, Animal Cognition Disease Models, Animal Gamma Rhythm Homeodomain Proteins Interneurons Male Mice Parvalbumins Prefrontal Cortex Schizophrenia

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• Source:
  Neuron. 85(6):1332-1343
• Pubmed ID:
  25754826
• Pubmed Central ID:
  PMC4503262
• Document Type:
  Journal Article
• Funding:
  T32MH89920/MH/NIMH NIH HHSUnited States/ ; DP2MH100011/DP/NCCDPHP CDC HHSUnited States/ ; R01MH100292/MH/NIMH NIH HHSUnited States/ ; R00MH085946/MH/NIMH NIH HHSUnited States/ ; T32 MH089920/MH/NIMH NIH HHSUnited States/ ; DP2 MH100011/MH/NIMH NIH HHSUnited States/ ; R00 MH085946/MH/NIMH NIH HHSUnited States/ ; R37MH049428/MH/NIMH NIH HHSUnited States/ ; R01 MH100292/MH/NIMH NIH HHSUnited States/ ; R37 MH049428/MH/NIMH NIH HHSUnited States/
• Volume:
  85
• Issue:
  6
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:e941d52490475799144d6881c7095738661ee91d5206917fc4bdadd9b8e366ab
• Download URL:
  https://stacks.cdc.gov/view/cdc/32069/cdc_32069_DS1.pdf
• File Type:
  [PDF - 1.97 MB ]