Timothy C. Cope (Committee Member), Lynn K. Hartzler (Committee Member), Bradley S. Jacobs (Committee Member), Lawrence J. Prochaska (Committee Member), Robert W. Putnam (Committee Chair), Christopher N. Wyatt (Committee Member)
Doctor of Philosophy (PhD)
Chemosensitive LC neurons increase their firing rate in response to increased CO2 (hypercapnia) in part via inhibition of K+ channels. This increase gets smaller during the first two postnatal weeks (neonatal rats aged P3-P16). Alterations of this "accelerating" pathway may account for the developmental changes in the magnitude of the chemosensitive response in LC neurons. Alternatively, Ca2+ and Ca2+ channels may play a role in the response to hypercapnia, but little is known about the role of Ca2+ in central chemosensitivity. Whole cell patch clamp and fluorescence imaging microscopy were used to study a different basis for the developmental changes in the chemosensitive response of LC neurons, a "braking" pathway. In the presence of tetrodotoxin (TTX-inhibitor of Na+ channels), currents composed of both a rhythmic cycling (SRO-subthreshold rhythmic oscillation) and voltage-sensitive spikes were observed. These currents developed over the first 10 postnatal days. Since both currents were abolished by the L-type Ca2+ channel inhibitor nifedipine, both were assumed to be due to the activity of L-type Ca2+ channels. Hypercapnia increased the frequency of oscillations and the accompanying spikes in a HCO3--dependent but pH-independent fashion. Voltage clamp studies supported the presence of L-type Ca2+ currents in LC neurons that increased in postnatal rats aged P3 to P12 and were enhanced by hypercapnia, resulting in increased intracellular Ca2+ (Ca2+i). Hypercapnia activated Ca2+ channels in LC neurons via a HCO3--dependent pathway involving soluble adenylate cyclase-cAMP-channel phosphorylation. The hypercapnic increase in Ca2+i activated hyperpolarizing Ca2+-activated K+ currents (KCa). The BK (a large conductance KCa) channel inhibitor paxilline and voltage clamp were used to study this KCa current. Inhibition of the BK current removed the "brake" and increased the firing rate response to hypercapnia in LC neurons. Notably, the "braking" pathway increased during neonatal development in a fashion that paralleled the decrease in the chemosensitive firing rate response to hypercapnia. These findings suggest a unique role for Ca2+ in controlling the magnitude of the firing rate response to hypercapnia. Abnormalities in this pathway could be associated with disorders involving elevated central sensitivity to changes in CO2, such as sleep apnea and panic disorders.
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