Impaired central respiratory chemoreflex in an experimental genetic model of epilepsy

Abstract

Respiratory disorders may involve changes in serotonergic neurotransmission at the level of the chemosensitive neurons located in the retrotrapezoid nucleus (RTN). Here, we investigated the central respiratory chemoreflex and the role of serotonergic neurotransmission in the RTN with a rat model of tonic-clonic seizures, the Wistar audiogenic rat (WAR). We found that naive or kindled WARs have reduced resting ventilation and ventilatory response to hypercapnia (7% CO ). The number of chemically coded (Phox2b /TH ) RTN neurons, as well as the serotonergic innervation to the RTN, was reduced in WARs. We detected that the ventilatory response to serotonin (1 mm, 50 nl) within the RTN region was significantly reduced in WARs. Our results uniquely demonstrated a respiratory impairment in a genetic model of tonic-clonic seizures, the WAR strain. More importantly, we demonstrated an overall decrease in the number of neurons located in the ventral respiratory column (VRC), as well as a reduction in serotonergic neurons in the midline medulla. This is an important step forward to demonstrate marked changes in neuronal activity and breathing impairment in the WAR strain, a genetic model of epilepsy.

The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy

“…We speculate this could reflect immediate consumption following a recent seizure prior to death ( Ryvlin et al , 2013 ) or accumulative depletion from recent poor seizure control ( Chen et al , 2017 ). Experimental models have shown an acute reduction of NK1R labelled neurons in the pre-BötC in the ventral respiratory column at 10 days following seizures ( Totola et al , 2017 ). Furthermore, in status epilepticus, depletion or ‘neurochemical exhaustion’ of reserves of neuropeptides, galanin and SST, and an increase in neurokinin and endocytosis of receptors, is recognized ( Chen et al , 2007 ).…”

Going to WAR: using a rat model of audiogenic seizure to uncover potential links to ventilatory dysfunction in epilepsy

“…In an article in this issue of The Journal of Physiology , Totola et al . () sought to assess differences in breathing and ventilatory chemoreflexes in a rat strain with a genetic predisposition to audiogenic seizure (AGS), the Wistar Audiogenic Rat (WAR). Similar to other mouse and rat models of AGS (De Sarro et al .…”

“…There are several animal models of seizure disorders derived from genetic or inducible (pharmacological, audiogenic and other) triggers. In an article in this issue of The Journal of Physiology, Totola et al (2017) sought to assess differences in breathing and ventilatory chemoreflexes in a rat strain with a genetic predisposition to audiogenic seizure (AGS), the Wistar Audiogenic Rat (WAR). Similar to other mouse and rat models of AGS (De Sarro et al 2015), tonic-clonic seizures can be readily produced in WAR rats with the introduction of mixed frequency and high intensity (120 dB) sound for up to 1 min in duration.…”

Análise de biomarcadores e déficit comportamental associados à doença de Alzheimer em um modelo animal de predisposição genética à epilepsia

“…Além da maior susceptibilidade às crises audiogênicas, estes animais apresentam uma série de outras alterações que podem se refletir em comorbidades. Dentre as alterações observadas em diversos estudos, é possível citar: pressão arterial e frequência cardíaca aumentada em animais WAR adultos, mesmo na ausência de estímulos de qualquer natureza, indicando perturbações inatas no controle do sistema circulatório (FAZAN et al, 2011); reduzida ventilação de repouso e resposta ventilatória a condições de hipercapnia e hipóxia, além de redução na quantidade de neurônios quimiosensitivos da coluna respiratória ventral e na neurotransmissão serotonérgica nesta região, que implica em déficit respiratório e torna a cepa WAR um modelo adequado para o estudo de riscos respiratórios associados à epilepsia (GRANJEIRO et al, 2016;TOTOLA et al, 2016); embora apresentem uma curva de crescimento diminuída em comparação aos ratos Wistar controles, possuem hiperplasia da glândula adrenal, com menor liberação basal de hormônio adenocorticotrófico e corticosterona, indicando distúrbios neuroendócrinos (UMEOKA et al, 2011); alteração na expressão de genes da família EGR (do inglês early growth response genes) principalmente dos genes Egr 1, Egr 2 e Egr 3, responsáveis pela expressão de fatores de crescimento envolvidos em processos como crescimento celular, apoptose, potenciação de longo prazo, mielinização e sinalização corticosteroide, em neurônios da região do colículo inferior, após submissão ao estímulo sonoro de alta intensidade (LÓPEZ-LÓPEZ et al, 2016).…”