Abstract
Enhancing the brain’s endogenous inhibitory mechanisms represents an important strategy for suppressing epileptic discharges. Indeed, drugs that boost synaptic inhibition can disrupt epileptic seizure activity, although these drugs generate complex effects due to the broad nature of their action. Recently developed chemicogenetic techniques provide the opportunity to pharmacologically enhance endogenous inhibitory mechanisms in a more selective manner. Here we use chemicogenetics to assess the anti-epileptic potential of enhancing the synaptic output from three major interneuron populations in the hippocampus: parvalbumin (PV), somatostatin (SST) and vasoactive intestinal peptide (VIP) expressing interneurons. Targeted pre- and post-synaptic whole cell recordings in an in vitro hippocampal mouse model revealed that all three interneuron types increase their firing rate and synaptic output following chemicogenetic activation. However, the interneuron populations exhibited different anti-epileptic effects. Recruiting VIP interneurons resulted in a mixture of pro-epileptic and anti-epileptic effects. In contrast, recruiting SST or PV interneurons produced robust suppression of epileptiform activity. PV interneurons exhibited the strongest effect per cell, eliciting at least a five-fold greater reduction in epileptiform activity than the other cell types. Consistent with this, we found that chemicogenetic recruitment of PV interneurons was effective in an in vivo mouse model of hippocampal seizures. Following efficient delivery of the chemicogenetic tool, pharmacological enhancement of the PV interneuron population suppressed a range of seizure-related behaviours and prevented generalized seizures. Our findings therefore support the idea that selective chemicogenetic enhancement of synaptic inhibitory pathways offers potential as an anti-epileptic strategy.
Significance statement Drugs that enhance synaptic inhibition can be effective anticonvulsants but often cause complex effects due to their widespread action. Here we examined the anti-epileptic potential of recently developed chemicogenetic techniques, which offer a way to selectively enhance the synaptic output of distinct types of inhibitory neurons. A combination of in vitro and in vivo experimental models were used to investigate seizure activity in the mouse hippocampus. We find that chemicogenetically recruiting the parvalbumin-expressing population of inhibitory neurons produces the strongest anti-epileptic effect per cell, and that recruiting this cell population can suppress a range of epileptic behaviours in vivo. The data therefore support the idea that targeted chemicogenetic enhancement of synaptic inhibition offers promise for developing new treatments.
Acknowledgements
The research leading to these results has received funding from the European Research Council under the European Community’s Seventh Framework Programme FP7/2007-2013, ERC Grant Agreement 617670. A.C. was supported by a Wellcome Trust Doctoral Fellowship [102364/Z/13/Z]. A.S.I. was supported by a Junior Research Fellowship in Medical Sciences from University College Oxford. We thank Miruna Rașcu for help in processing the mouse tracking data. We would also like to thank Professor Peter Somogyi for providing advice and the antibody against vasoactive intestinal polypeptide.
Author contributions
A.C., A.S.I. and C.J.A. conceived the project. All authors contributed to the design of the experiments. A.C. and M.S. performed the experiments. A.C. analysed the data and prepared all figures. A.C. A.S.I. and C.J.A. wrote the manuscript. All authors reviewed the manuscript.
Footnotes
Conflict of Interest The authors declare no competing financial interests.