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Role of serotonin neurons in pH homeostasis.
Serotonin neurons within the medulla and midbrain are strongly stimulated by acidosis, and some are located immediately adjacent to large blood vessels. We have proposed that these neurons are sensors of blood CO 2 that initiate a homeostatic response to respiratory acidosis that includes increased ventilation, and changes in cardiovascular output, cerebral blood flow and level of arousal. Genetic deletion of transcription factors required for development of these neurons in mice leads to a severe reduction in the ventilatory response to hypercapnia. We are using a combination of electrophysiology, immunohistochemistry, molecular biology and transgenic approaches to define the bsic mechanisms of chemosensitivity in these neurons, their role in normal brain function, and how their dysfunction can lead to diseases such as SIDS, sleep apnea and panic disorder.
Nonvesicular GABA release via reversal of the GABA transporter
GABA can be released from neurons after vesicular fusion is blocked with tetanus toxin or by removing extracellular calcium. This "nonvesicular" GABA release is due to reverse operation of the GABA transporter, and can be induced by a small increase in membrane potential or by anticonvulsants that increase cytosolic [GABA]. We have proposed that this form of GABA release complements vesicular GABA release, and acts as a fail-safe negative feedback system during high frequency firing. We are examining the role that this form of GABA release plays in normal brain function and during seizures.
Selected recent publications:
Du, W., J.F. Bautista, H. Yang, A. Diez-Sampedro, S.A. You, L. Wang, P. Kotagal, H.O. Lüders, J. Shi, J. Cui, G.B. Richerson & Q. Wang. Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal
movement disorder. Nature Genetics 37(7): 733-738, 2005.
Richerson, G.B. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nature Rev Neurosci, 5:449-461, 2004.
Severson, C.A., W. Wang, V.A. Pieribone, C.I. Dohle & G.B. Richerson. Midbrain serotonergic neurons are central pH chemoreceptors. Nature Neurosci 6(11):1139-1140, 2003.
Richerson, G.B. & Y. Wu. The dynamic equilibrium of neurotransmitter transporters: Not just for reuptake anymore. J Neurophysiol 90:1363-1374, 2003.
Bradley, S Risso, V. A. Pieribone, W. Wang, C.A. Severson, R. A. Jacobs & G. B. Richerson. Chemosensitive serotonergic neurons are intimately associated with large arteries of the ventral medulla. Nature Neurosci 5(5): 401-402, 2002.
Wang, W., S. Risso Bradley & G.B. Richerson. Quantification of the response of rat medullary raphe neurones to independent changes in pHo and PCO2. J Physiol (Lond) 540(3): 951-970, 2002.
Wu Y, Wang W, Richerson GB. GABA transaminase inhibition induces spontaneous and enhances depolarization-evoked GABA efflux via reversal of the GABA transporter. J Neurosci. 2001 Apr 15;21(8):2630-9.
george.richerson@yale.edu
http://info.med.yale.edu/neurol/Richerson/
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