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Published on: July 23, 2020
Enhanced responses to somatostatin interneuron activation in developmentally malformed cortex
Nicole B Ekanem1, Laura K Reed1, Nicole Weston1
1Department of Anatomy and Neurobiology Virginia Commonwealth University Richmond Virginia.
Somatostatin (SSt) interneurons in malformed brain regions show enhanced inhibitory output, paradoxically leading to hyperexcitability and seizures in epilepsy. This finding offers a new target for epilepsy treatment.
Area of Science:
- Neuroscience
- Epileptology
- Developmental Neuroscience
Background:
- Intractable epilepsy frequently co-occurs with developmental cortical malformations.
- Previous work identified altered non-fast-spiking somatostatin (SSt) interneurons in the epileptogenic paramicrogyral region (PMR).
Purpose of the Study:
- To investigate the functional output of SSt interneurons in the PMR using optogenetics.
- To determine the circuit-level impact of SSt interneuron activity on neuronal excitability and epileptiform activity.
Main Methods:
- Utilized SSt-Cre mice crossed with channelrhodopsin-2 expressing mice for optogenetic manipulation.
- Performed voltage clamp recordings in layer V pyramidal neurons to assess SSt-evoked inhibition.
- Induced epileptiform activity in ex vivo brain slices using low-Mg2+ artificial cerebrospinal fluid (aCSF).
Main Results:
- SSt interneurons exhibited significantly enhanced evoked inhibitory postsynaptic currents in PMR pyramidal neurons compared to controls.
- Optogenetic activation of SSt neurons triggered field potential epileptiform activity specifically in the PMR cortex.
- Despite enhanced inhibition, the net network effect was hyperexcitability and seizure-like activity.
Conclusions:
- SSt interneurons in the PMR exert a stronger inhibitory influence on excitatory neurons.
- Enhanced SSt inhibition paradoxically leads to network hyperexcitability and epileptiform discharges.
- SSt interneurons represent a novel therapeutic target for modulating epilepsy associated with cortical malformations.
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