Summary: Researchers have identified a circuit within the brain that may be responsible for respiratory dysfunction and sudden death associated with Dravet syndrome.
Source: Vanderbilt University
Risk of sudden unexpected death in epilepsy (SUDEP) is among comorbidities present in Dravet Syndrome (DS), a rare, catastrophic form of epilepsy in which seizures begin in infancy, with most cases due to mutations in a single gene, SCN1A.
Breathing issues have been reported in patients and in mouse models of DS, and a recent study implicated respiratory decline in SUDEP in DS mice.
In the journal eNeuro, William Nobis, MD, PhD, Wen Wei Yan, MD, Maya Xia and colleagues report experiments in DS mice showing altered excitability in a complex of neurons deep in the brain, the bed nucleus of the stria terminalis (BNST), and significant under-excitability of neurons projecting from the BNST to the parabrachial nucleus, which is located atop the brainstem and is involved in respiration.
Noting that this circuit might be driving respiratory dysfunction and sudden death in DS, the authors call for further study of the role of deep brain structures in epilepsy models.
Also on the study from Vanderbilt University Medical Center were Jeremy Chiang, Alyssa Levitt and Dane Chetkovich, MD, PhD. They were joined by researchers from Northwestern University. This work was supported by the American Epilepsy Society, NINDS Center for SUDEP Research, and Vanderbilt Faculty Research Scholars award.
Enhanced Synaptic Transmission in the Extended Amygdala and Altered Excitability in an Extended Amygdala to Brainstem Circuit in a Dravet Syndrome Mouse Model
Dravet syndrome (DS) is a developmental and epileptic encephalopathy with an increased incidence of sudden death. Evidence of interictal breathing deficits in DS suggests that alterations in subcortical projections to brainstem nuclei may exist, which might be driving comorbidities in DS.
The aim of this study was to determine whether a subcortical structure, the bed nucleus of the stria terminalis (BNST) in the extended amygdala, is activated by seizures, exhibits changes in excitability, and expresses any alterations in neurons projecting to a brainstem nucleus associated with respiration, stress response, and homeostasis.
Experiments were conducted using F1 mice generated by breeding 129.Scn1a+/− mice with wild-type C57BL/6J mice. Immunohistochemistry was performed to quantify neuronal c-fos activation in DS mice after observed spontaneous seizures.
Whole-cell patch-clamp and current-clamp electrophysiology recordings were conducted to evaluate changes in intrinsic and synaptic excitability in the BNST. Spontaneous seizures in DS mice significantly enhanced neuronal c-fos expression in the BNST. Further, the BNST had altered AMPA/NMDA postsynaptic receptor composition and showed changes in spontaneous neurotransmission, with greater excitation and decreased inhibition.
BNST to parabrachial nucleus (PBN) projection neurons exhibited intrinsic excitability in wild-type mice, while these projection neurons were hypoexcitable in DS mice. The findings suggest that there is altered excitability in neurons of the BNST, including BNST-to-PBN projection neurons, in DS mice.
These alterations could potentially be driving comorbid aspects of DS outside of seizures, including respiratory dysfunction and sudden death.