Functional Neuroplasticity in the Nucleus Tractus Solitarius and Increased Risk of Sudden Death in Mice with Acquired Temporal Lobe Epilepsy

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in individuals with refractory acquired epilepsy. Cardiorespiratory failure is the most likely cause in most cases, and central autonomic dysfunction has been implicated as a contributing factor to SUDEP. Neurons of the nucleus tractus solitarius (NTS) in the brainstem vagal complex receive and integrate vagally mediated information regarding cardiorespiratory and other autonomic functions, and GABAergic inhibitory NTS neurons play an essential role in modulating autonomic output. We assessed the activity of GABAergic NTS neurons as a function of epilepsy development in the pilocarpine-induced status epilepticus (SE) model of temporal lobe epilepsy (TLE). Compared with age-matched controls, mice that survived SE had significantly lower survival rates by 150 d post-SE. GABAergic NTS neurons from mice that survived SE displayed a glutamate-dependent increase in spontaneous action potential firing rate by 12 wks post-SE. Increased spontaneous EPSC frequency was also detected, but vagal afferent synaptic release properties were unaltered, suggesting that an increase in glutamate release from central neurons developed in the NTS after SE. Our results indicate that long-term changes in glutamate release and activity of GABAergic neurons emerge in the NTS in association with epileptogenesis. These changes might contribute to increased risk of cardiorespiratory dysfunction and sudden death in this model of TLE.

The incidence and significance of periictal apnea in epileptic seizures

“…Our observation of a positive correlation between duration of epilepsy and ICA duration is intriguing, and suggests potential plasticity in respiratory circuitry that may render relatively benign, short duration ICA into potentially lethal, longer duration ICA that may predispose to SUDEP. For example, functional neuroplasticity in the nucleus of the tractus solitarius, as evidenced by long-term changes in glutamate release and GABAergic neuronal activity, has been shown to occur with epileptogenesis in mice with acquired temporal lobe epilepsy 27 .…”

“…For example, functional neuroplasticity in the nucleus of the tractus solitarius, as evidenced by long-term changes in glutamate release and c-aminobutyric acid (GABA)ergic neuronal activity, has been shown to occur with epileptogenesis in mice with acquired temporal lobe epilepsy. 27 Postictal apnea appears to be a rare phenomenon. Only 3% of ICA persisted (for 16-22 s) beyond electroclinical seizure end in this study.…”

Enhanced synaptic transmission in the extended amygdala and altered excitability in an extended amygdala to brainstem circuit in a Dravet syndrome mouse model

“…Multiple electrophysiological studies demonstrate impaired firing of inhibitory neurons and selective deletion of Scn1a in inhibitory neurons alone is sufficient to cause seizures and premature death (Cheah et al, 2012). Clearly, intrinsic deficits in cortical inhibition are driving hyperexcitability; however, little work has been performed on the electrophysiological changes in downstream subcortical targets (Derera et al, 2017;Kuo et al, 2019).…”

Scurrying to Understand Sudden Expected Death in Epilepsy: Insights From Animal Models

“…Commonalities in mechanisms of death between status epilepticus and SUDEP 46 Epileptic baboon model Sudden unexpected death with similar pathology to SUDEP 47 Kainic acid-induced acute seizure model Glottic closure precedes cardiac arrhythmia and death 48 ; preventing obstructive terminal apnea caused by a large pH reduction within the esophagus can prevent death 49 Pilocarpine-induced chronic seizure model Reduced survival rate 50 with a higher basal heart rate probably due to altered autonomic modulation. 51 GABAergic neurons in the nucleus tractus solitarius have an increased excitability 50,52 Kainic acid-induced chronic seizure model Lower survival rate with no obvious causes of death. 53 A decreased neuronal density in the nucleus tractus solitarius 54 and decreased vagal tone and increased QT dispersion.…”