Activation of acid-sensing ion channels contributes to the hypercapnia-induced neurovascular response in the neonatal cerebral cortex.

The cerebral microcirculation undergoes dynamic changes regarding neurovascular responses through the perinatal period. CO2 is one of the most potent regulator of cerebral blood flow, however its effector mechanisms involve multiple possibly yet unknown pathways in the neonate. Acid-sensing ion channel-1A (ASIC1A) appears to play a decisive role in this cerebrovascular response in adult mice, however, cortical ASIC1A expression and its possible contribution to the response in the translational piglet model of term neonates is unknown. Therefore, we investigated neocortical ASIC1A expression and the effect of the specific ASIC1A-inhibitor psalmotoxin-1 on the neurovascular response to graded hypercapnia in piglets. Anesthetized, mechanically ventilated newborn pigs were equipped with a closed or open cranial window to assess the cortical blood flow (CoBF) with laser speckle contrast imaging or the neuronal activity with multichannel electrodes, respectively. Graded hypercapnia was elicited by ventilation of 5%-10% CO2. ASIC1A was found to be ubiquitously expressed in neocortical neurons. Psalmotoxin-1 while unaffected the CoBF response to 5% CO2, it significantly attenuated further increases in CoBF to 10% CO2, accompanying the highly altered hypercapnia-induced changes in neuronal activity. We conclude that ASIC1A activation by hypercapnia-induced acidosis is partially responsible for the neurovascular response in the neonatal brain.