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Publication : Bicuculline restores frequency-dependent hippocampal I/E ratio and circuit function in PGC-1ɑ null mice.

First Author  Bhattacharya D Year  2022
Journal  Neurosci Res PubMed ID  35842011
Mgi Jnum  J:328008 Mgi Id  MGI:7334625
Doi  10.1016/j.neures.2022.07.003 Citation  Bhattacharya D, et al. (2022) Bicuculline restores frequency-dependent hippocampal I/E ratio and circuit function in PGC-1a null mice. Neurosci Res
abstractText  Altered inhibition/excitation (I/E) balance contributes to various brain disorders. Dysfunctional GABAergic interneurons enhance or reduce inhibition, resulting in I/E imbalances. Differences in short-term plasticity between excitation and inhibition cause frequency-dependence of the I/E ratio, which can be altered by GABAergic dysfunction. However, it is unknown whether I/E imbalances can be rescued pharmacologically using a single dose when the imbalance magnitude is frequency-dependent. Loss of PGC-1alpha (peroxisome proliferator activated receptor gamma coactivator 1alpha) causes transcriptional dysregulation in hippocampal GABAergic interneurons. PGC-1alpha(-/-) slices have enhanced baseline inhibition onto CA1 pyramidal cells, causing increased I/E ratio and impaired circuit function. High frequency stimulation reduces the I/E ratio and recovers circuit function in PGC-1alpha(-/-) slices. Here we tested if using a low dose of bicuculline that can restore baseline I/E ratio can also rescue the frequency-dependent I/E imbalances in these mice. Remarkably, bicuculline did not reduce the I/E ratio below that of wild type during high frequency stimulation. Interestingly, bicuculline enhanced the paired-pulse ratio (PPR) of disynaptic inhibition without changing the monosynaptic inhibition PPR, suggesting that bicuculline modifies interneuron recruitment and not GABA release. Bicuculline improved CA1 output in PGC-1alpha(-/-) slices, enhancing EPSP-spike coupling to wild type levels at high and low frequencies. Our results show that it is possible to rescue frequency-dependent I/E imbalances in an animal model of transcriptional dysregulation with a single treatment.
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