Enhanced Neuronal Excitability in Adult Rat Brainstem Causes Widespread Repetitive Brainstem Depolarizations with Cardiovascular Consequences

Abstract

The brainstem of the adult rat is relatively resistant to spreading depolarization (SD) but after enhancement of excitability SD can be evoked by local application of KCl. In the present experiments, we observed that the enhanced excitability even triggers prolonged periods of repetitive depolarizations (RDs), which elicit significant cardiovascular changes. In contrast to KCl-evoked SDs with amplitudes of B24 mV and spreading velocity of 4 mm/min, spontaneous RDs had amplitudes of 7 to 12 mV, propagated up to 30 times faster than KCl-evoked SDs, and depolarized larger brainstem areas including the contralateral side. Similarly as SD, RDs depended on glutamatergic neurotransmission and were blocked by MK-801 or by the calcium channel blocker agatoxin. They depended on sodium channels and were blocked by tetrodotoxin. Functionally, the invasion of RDs into the spinal trigeminal and other nuclei evoked bursts of action potentials, indicating that specific neuronal systems are affected. In fact, during episodes of RDs the blood pressure and the local blood flow at the surface of the brainstem and the cortex increased substantially. Brainstem RDs did not propagate into the cerebral cortex. We propose to consider brainstem RPs as a pathophysiological mechanism whose significance for brainstem disease states should be further explored.

A Distinct Boundary between the Higher Brain’s Susceptibility to Ischemia and the Lower Brain’s Resistance

“…The striatum supports robust ID even though it is structurally similar to brainstem gray matter which resists ID [13]. Each region is non-laminar with interspersed axon tracts and similar neuronal densities.…”

“…How does the brainstem survive? Unlike higher brain regions such as thalamus, the adult rat brainstem does not support strong spreading depolarizations [12] unless chemically depolarized [13]. Such events promote acute neuronal injury in stroke and head trauma[14].…”

Knock‐in mouse model of alternating hemiplegia of childhood: Behavioral and electrophysiologic characterization

“…2 Such failure could influence the pathophysiology of seizure activity of any etiology, as well as contribute to its long-term consequences and possibly even to sudden unexpected death in epilepsy (SUDEP). 3 Indeed, disruption of the Na + /K + gradient has been linked to seizures in humans 4 as well as to epileptiform activity and spreading depression (SD) in animals. 5,6 In addition to secondary ATP1a3 dysfunction, primary dysfunction can occur due to mutations in the ATP1A3 gene.…”

Characterization of cognitive deficits in mice with an alternating hemiplegia-linked mutation.

“…During seizures, there is often an energy crisis in neurons, which can lead to Na + ,K + -ATPase pump failure ( Araujo et al, 2014 ). Such failure could influence the pathophysiology of seizure activity of any etiology, as well as contribute to its long-term consequences and possibly even to sudden unexpected death in epilepsy (SUDEP; Richter et al, 2012 ). Indeed, two further missense mutations in ATP1A3 have been found in a child with catastrophic early life epilepsy (G358V), and in another child with epilepsy, episodic prolonged apnea, postnatal microcephaly, and severe developmental disability (I363N; Paciorkowski et al, 2015 ).…”