Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et. al., 2019; 25). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)- and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity.
Epilepsy is an umbrella term used to define a wide variety of seizure disorders and sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in epilepsy. Although some SUDEP risk factors have been identified, it remains largely unpredictable, and underlying mechanisms remain poorly understood. Most seizures start in the cortex, but the high mortality rate associated with certain types of epilepsy indicates brainstem involvement. Therefore, to help understand SUDEP we discuss mechanisms by which seizure activity propagates to the brainstem. Specifically, we highlight clinical and pre-clinical evidence suggesting how seizure activation of: (i) descending inhibitory drive or (ii) spreading depolarization might contribute to brainstem dysfunction. Furthermore, since epilepsy is a highly heterogenous disorder, we also considered factors expected to favor or oppose mechanisms of seizure propagation. We also consider whether epilepsy-associated genetic variants directly impact brainstem function. Because respiratory failure is a leading cause of SUDEP, our discussion of brainstem dysfunction focuses on respiratory control.
A brainstem homeostatic system senses CO2/H+ to regulate ventilation, blood gases and acid‐base balance. Neurons of the retrotrapezoid nucleus (RTN) and medullary raphe are both implicated in this mechanism as respiratory chemosensors, but recent pharmacological work suggested that the CO2/H+‐sensitivity of RTN neurons is mediated indirectly – by raphe‐derived serotonin acting on 5‐HT7 receptors. To investigate this further, we characterized Htr7 transcript expression in phenotypically identified RTN neurons using multiplex single cell qRT‐PCR and RNAscope. Although present in multiple neurons in the parafacial region of the ventrolateral medulla, Htr7 expression was undetectable in most RTN neurons (Nmb+/Phox2b+) concentrated in the densely packed cell group ventrolateral to the facial nucleus. Where detected, Htr7 expression was modest and often associated with RTN neurons that extend dorsolaterally to partially encircle the facial nucleus. These more dorsolateral Nmb+/Htr7+ neurons tended to express high levels of Nmb and low levels of the intrinsic RTN proton detectors, Gpr4 and Kcnk5. In mouse brainstem slices, CO2‐stimulated firing in RTN neurons was mostly unaffected by a 5‐HT7 receptor antagonist, SB269970 (n=11/12). At the whole animal level, microinjection of SB269970 into the RTN of conscious mice blocked respiratory stimulation by co‐injected LP‐44, a 5‐HT7 receptor agonist, but had no effect on CO2‐stimulated breathing in those same mice. We conclude that Htr7 is expressed by a minor subset of RTN neurons with a molecular profile distinct from the established chemoreceptors and that 5‐HT7 receptors have negligible effects on CO2‐evoked firing activity in RTN neurons or on CO2‐stimulated breathing in mice.
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