2015 journal article
Interneuron Transcriptional Dysregulation Causes Frequency-Dependent Alterations in the Balance of Inhibition and Excitation in Hippocampus
Journal of Neuroscience, 35(46), 15276–15290.
MeSH headings : Animals; Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology; Excitatory Postsynaptic Potentials / drug effects; Excitatory Postsynaptic Potentials / physiology; Female; Gene Expression Regulation / drug effects; Gene Expression Regulation / genetics; Gene Expression Regulation / physiology; Hippocampus / cytology; In Vitro Techniques; Inhibitory Postsynaptic Potentials / drug effects; Inhibitory Postsynaptic Potentials / physiology; Interneurons / physiology; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Net / drug effects; Nerve Net / physiology; Nesting Behavior / physiology; Neural Inhibition / physiology; Neurotransmitter Agents / pharmacology; Parvalbumins / metabolism; Patch-Clamp Techniques; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Transcription Factors / genetics; Voltage-Sensitive Dye Imaging
TL;DR:
It is shown that transcriptional dysregulation in hippocampal interneurons causes frequency-dependent alterations in the I/E ratio and in circuit function in hippocampus, suggesting that PGC-1α deficiency in psychiatric and neurological disorders contributes to disease by causing functionally relevant alterations in I-E balance.
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www.jneurosci.org (publisher PDF)
UN Sustainable Development Goal Categories
3. Good Health and Well-being
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Added: July 27, 2019
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.
