title: Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus.
abstract: Circuit dysfunction in complex brain disorders such as schizophrenia and autism is caused by imbalances between inhibitory and excitatory synaptic transmission (I/E). Short-term plasticity differentially alters responses from excitatory and inhibitory synapses, causing the I/E ratio to change as a function of frequency. However, little is known about I/E ratio dynamics in complex brain disorders. Transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, is a consistent pathophysiological feature of schizophrenia. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α) is a transcriptional coactivator that in hippocampus is highly concentrated in inhibitory interneurons and regulates parvalbumin transcription. Here, we used PGC-1α(-/-) mice to investigate effects of interneuron transcriptional dysregulation on the dynamics of the I/E ratio at the synaptic and circuit level in hippocampus. We find that loss of PGC-1α increases the I/E ratio onto CA1 pyramidal cells in response to Schaffer collateral stimulation in slices from young adult mice. The underlying mechanism is enhanced basal inhibition, including increased inhibition from parvalbumin interneurons. This decreases the spread of activation in CA1 and dramatically limits pyramidal cell spiking, reducing hippocampal output. The I/E ratio and CA1 output are partially restored by paired-pulse stimulation at short intervals, indicating frequency-dependent effects. However, circuit dysfunction persists, indicated by alterations in kainate-induced gamma oscillations and impaired nest building. Together, these results show that transcriptional dysregulation in hippocampal interneurons causes frequency-dependent alterations in I/E ratio and circuit function, suggesting that PGC-1α deficiency in psychiatric and neurological disorders contributes to disease by causing functionally relevant alterations in I/E balance.
  
  
  CONCLUSIONS
  Alteration in the inhibitory and excitatory synaptic transmission (I/E) balance is a fundamental principle underlying the circuit dysfunction observed in many neuropsychiatric and neurodevelopmental disorders. The I/E ratio is dynamic, continuously changing because of synaptic short-term plasticity. We show here that transcriptional dysregulation in interneurons, particularly parvalbumin interneurons, causes frequency-dependent alterations in the I/E ratio and in circuit function in hippocampus. Peroxisome proliferator activated receptor γ coactivator 1α (PGC-1α-deficient) mice have enhanced inhibition in CA1, the opposite of what is seen in cortex. This study fills an important gap in current understanding of how changes in inhibition in complex brain disorders affect I/E dynamics, leading to region-specific circuit dysfunction and behavioral impairment. This study also provides a conceptual framework for analyzing the effects of short-term plasticity on the I/E balance in disease models.
authors.affiliation: Department of Neurobiology and Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Aundrea F
authors.identifier: http://orcid.org/0000-0002-2764-3060
authors.initials: AF
authors.lastname: Bartley
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, and.
authors.forename: Elizabeth K
authors.identifier: http://orcid.org/0000-0002-0632-4538
authors.initials: EK
authors.lastname: Lucas
authors.affiliation: Department of Neurobiology and Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Lillian J
authors.identifier: http://orcid.org/0000-0002-7851-025X
authors.initials: LJ
authors.lastname: Brady
authors.affiliation: Department of Neurobiology and Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Qin
authors.identifier: http://orcid.org/0000-0002-9522-073X
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Neurobiology and Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama, Birmingham, Alabama 35294.
authors.forename: John J
authors.identifier: http://orcid.org/0000-0003-3847-8547
authors.initials: JJ
authors.lastname: Hablitz
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, and Civitan International Research Center, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Rita M
authors.identifier: http://orcid.org/0000-0001-5814-9412
authors.initials: RM
authors.lastname: Cowell
authors.affiliation: Department of Neurobiology and Evelyn F. McKnight Brain Institute, Civitan International Research Center, University of Alabama, Birmingham, Alabama 35294 dobrunz@uab.edu.
authors.forename: Lynn E
authors.identifier: http://orcid.org/0000-0002-3317-554X
authors.initials: LE
authors.lastname: Dobrunz
mesh_terms: D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D007395:Interneurons / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009425:Nesting Behavior / Q000502:physiology; D009433:Neural Inhibition / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000235:genetics; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D018377:Neurotransmitter Agents; D010320:Parvalbumins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D014157:Transcription Factors; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
keywords: E/I ratio; circuit function; inhibitory interneurons; parvalbumin; schizophrenia; short-term plasticity