Alexandru Cǎlin, Mihai Stancu, Ana-Maria Zagrean, John G. R. Jefferys, Andrei S. Ilie, Colin J. Akerman
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.
This research output has an Altmetric Attention Score of 6. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 21 September 2018.
All research outputs
#6,852,846
of 26,411,386 outputs
Outputs from Frontiers in Cellular Neuroscience
#1,233
of 4,823 outputs
Outputs of similar age
#108,150
of 349,650 outputs
Outputs of similar age from Frontiers in Cellular Neuroscience
#47
of 155 outputs
Altmetric has tracked 26,411,386 research outputs across all sources so far. This one has received more attention than most of these and is in the 74th percentile.
So far Altmetric has tracked 4,823 research outputs from this source. They typically receive a little more attention than average, with a mean Attention Score of 6.9. This one has gotten more attention than average, scoring higher than 74% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 349,650 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 68% of its contemporaries.
We're also able to compare this research output to 155 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 69% of its contemporaries.
