Abstract
Current anti-epileptic medications that boost synaptic inhibition are effective in reducing several types of epileptic seizure activity. Nevertheless, these drugs can generate significant side-effects and even paradoxical responses due to the broad nature of their action. Recently developed chemogenetic techniques provide the opportunity to pharmacologically recruit endogenous inhibitory mechanisms in a selective and circuit-specific manner. Here, we use chemogenetics to assess the potential of suppressing epileptiform activity by enhancing the synaptic output from three major interneuron populations in the rodent hippocampus: parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP) expressing interneurons. To target different neuronal populations, promoter-specific cre-recombinase mice were combined with viral-mediated delivery of chemogenetic constructs. Targeted electrophysiological recordings were then conducted in an in vitro model of chronic, drug-resistant epilepsy. In addition, behavioral video-scoring was performed in an in vivo model of acutely triggered seizure activity. Pre-synaptic and post-synaptic whole cell recordings in brain slices revealed that each of the three interneuron types increase their firing rate and synaptic output following chemogenetic activation. However, the interneuron populations exhibited different effects on epileptiform discharges. Recruiting VIP interneurons did not change the total duration of epileptiform discharges. In contrast, recruiting SST or PV interneurons produced robust suppression of epileptiform synchronization. PV interneurons exhibited the strongest effect per cell, eliciting at least a fivefold greater reduction in epileptiform activity than the other cell types. Consistent with this, we found that in vivo chemogenetic recruitment of PV interneurons suppressed convulsive behaviors by more than 80%. Our findings support the idea that selective chemogenetic enhancement of inhibitory synaptic pathways offers potential as an anti-seizure strategy.
Highlights
Drugs that enhance GABA-mediated synaptic inhibition can be potent anticonvulsants (Czapinski et al, 2005)
While GABAergic signaling can become altered in cells within the epileptic focus (Cohen et al, 2002; Huberfeld et al, 2007), inhibitory mechanisms remain effective within the ‘penumbra’ surrounding the epileptic focus and are able to oppose
To examine the potential of enhancing the synaptic output of hippocampal interneurons chemogenetically, we used mouse organotypic hippocampal brain slices. This system enabled us to perform targeted patch clamp recordings to determine the pre-synaptic and post-synaptic efficacy of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), as well as the opportunity to examine the impact of interneuron recruitment upon spontaneously generated epileptiform activity
Summary
Drugs that enhance GABA-mediated synaptic inhibition can be potent anticonvulsants (Czapinski et al, 2005). Because of their intrinsic properties and perisomatic targeting of multiple postsynaptic pyramidal neurons, parvalbumin-expressing (PV) interneurons have been considered effective at inhibiting principal neurons (Cobb et al, 1995; Freund and Buzsáki, 1996; Miles et al, 1996) and at restricting the propagation of network activity (Trevelyan et al, 2006; Cammarota et al, 2013) Because of their post-synaptic targeting, somatostatin-expressing (SST) interneurons have been associated with the regulation of dendritic excitability (Miles et al, 1996; Paz and Huguenard, 2015), which can affect the spiking output of principal neurons (Lovett-Barron et al, 2012). Other interneuron subtypes, such as vasoactive intestinal polypeptide-expressing (VIP) interneurons, can mediate disinhibitory effects as well as inhibitory effects, apparently because many of their postsynaptic targets are interneurons (Acsády et al, 1996)
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