Kelsey Patterson1, Christine Brzezinski1, Keenan Kushner1, Allyson Alexander1
1University of Colorado
Objective:
To Investigate the Role of Parvalbumin Interneurons in VNS Efficacy
Background:
Of the 70 million people worldwide living with epilepsy, at least 30 percent develop drug-resistant epilepsy. For about half of those patients, vagus nerve stimulation (VNS) therapy can offer seizure reduction, though the exact mechanisms by which this is accomplished remain unclear. Studies suggest that a key mediator is the locus coeruleus (LC), a noradrenergic brainstem nucleus. More recent evidence demonstrates that cortical parvalbumin interneurons (PV-INs), which are widely believed to generate gamma frequency oscillations (GFOs), are regulated by noradrenergic outputs of the LC. Furthermore, GFOs are altered in epileptic tissue, and these alterations may be a hallmark of the functional deficits often associated with epilepsy.
Design/Methods:
Here, we use ex vivo whole-cell patch clamp electrophysiology and calcium imaging in a genetically encoded mouse model to test the hypothesis that noradrenaline (NE) activates PV-INs leading to decreased ictal activity.
Results:
Initial experiments demonstrate that bath application of NE increases firing rate and decreases firing threshold in inhibitory PV-INs. We also observed an increase in action potential half width and decrease in action potential magnitude in PV-INs with NE application. Further experiments are aimed at identifying: 1) the noradrenergic receptor subtype(s) responsible for this effect, 2) the individual and network effects of noradrenergic signaling under control and ictal conditions, as well as in a mouse model of focal epilepsy, and 3) the effect of VNS on PV-IN and network activity in vivo.
Conclusions:
The observed depolarization, decreased firing threshold, decreased action potential magnitude, and increased action potential half width may all suggest that norepinephrine acts on a potassium channel expressed in this population of PV-INs. Understanding the specific mechanisms by which VNS affects neuronal populations may allow for better prediction of VNS efficacy in patient subsets and improvement in pre-surgical evaluation.