Endogenous Neuroprotection in the Respiratory Control System PDF Download

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Languages : en
Pages : 462

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Book Description
Breathing must be robust and highly adaptable to maintain adequate oxygen and CO2 levels during birth, development, pregnancy, and disease. This is achieved by a delicate balance of inhibitory and excitatory neuronal signaling. Both sustained, and intermittent changes in respiratory neuron activity can create long-lasting changes in respiratory motor output (i.e., plasticity). As a constant requirement from birth until death, the respiratory control system must have endogenous mechanisms to maintain appropriate excitability during physiological or pathological stress, and express multiple types of plasticity. Reproduction is an example of an essential biological function with serious maternal and fetal risks. During late pregnancy, maternal brain allopregnanolone levels increase and augment the function of inhibitory GABAA receptors (GABAARs), posing the risk of excessively inhibiting respiratory neurons. Here, we show that respiratory-related hypoglossal motoneurons increase epsilon subunit incorporation into GABAA receptors, which confers insensitivity to allopregnanolone. Similarly, brain allopregnanolone levels increase during the critical period in respiratory control development (occurs during the second postnatal week). We also found that epsilon subunit-containing GABAARs dynamically change in respiratory-related brain regions during the second postnatal week. Thus, increased epsilon subunit incorporation in GABAARs appears to protect breathing from excessive inhibition during pregnancy and postnatal development under physiological conditions. Thus, these studies suggest that adjusting GABAAR subunit composition may be a little recognized, fundamental property of the respiratory control network. On the other hand, pregnancy and the neonatal period are also associated with pathological events, such as ischemic stroke. One potential strategy for protecting neurons from ischemia is to apply principles learned from ischemia-hypoxia resistant extremophile vertebrates, such as activating delta opioid receptors (DORs). We hypothesized that activating spinal DORs would prolong respiratory output (i.e., provide neuroprotection) during oxygen-glucose deprivation (OGD; in vitro stroke model). We found that spinal DOR activation provides flexible neuroprotection against OGD, regardless of whether DOR drugs are applied to the spinal cord before, during or after the onset of OGD. These studies suggest that understanding and controlling endogenous protective mechanisms is a compelling strategy for developing novel therapies and treatments to protect neuronal function against ischemia.