Faculty A-Z
Xihua Chen
Professor of Neurosciences (Biological Psychiatry) M.B. China, Ph.D. CambridgeBioMedical Sciences Psychiatry
Regulation of dopaminergic cell firing behavior.
Dopamine is an important neurotransmitter for reward processing, affective expression, motor coordination and cognitive functions. The level of dopaminergic transmission is regulated at the synapse by autoreceptor-mediated feedback and the availability of dopamine receptors and transporters. It is also affected by the firing behavior of the dopaminergic cell bodies that are primarily located in the ventral midbrain. In essence, the faster a dopaminergic cell fires action potentials, the more dopamine it releases at its terminals. Dopaminergic cells are also capable of firing action potentials in clusters referred to as burst firing that leads to greater accumulation of dopamine at the synapse. Behavioral testing in primates shows that burst firing precedes procurement of reward and is believed to be the initial step in reward processing.
Burst firing has been shown to be synaptic dependent, one of the earlier observations is that dopaminergic cells in acute brain slices do not display burst firing. However, it has been shown that activation of the NMDA glutamate receptors can induce burst firing in slices. We have reported that carbachol, an agent that activate both nicotinic and muscarinic cholinoceptors, induces burst firing of dopaminergic cells in slices that is similar to natural bursting and does not require a hyperpolarizing current for its induction. Moreover, we found that this induction is dependent on the opening of L-type calcium channels. Direct opening of L-type channels using allosteric DHP activators induces burst firing that is last-lasting and sensitive to PKC inhibitors that bind to the catalytic subunit. Further analysis revealed that calcium influx through the L-type channel leads to cleavage of PKC for the full expression of bursting.
Currently, we are trying to find out which L-type subtype mediates burst firing using transgenic mice developed and provided by Dr. Striessnig, University of Innsbruck, Austria. Since there are only two subtypes, Cav1.2 and Cav1.3, expressed in dopaminergic cells, use of Cav1.3 knock-out gives the differential contribution of the two subtypes to bursting. Results will also be corroborated with the Cav1.2(DHP) strain in which Cav1.2 carries a mutant DHP site that does not respond to DHP modulators. We are also collaborating with Dr. Kobayshi, Fukushima Medical University, Japan, who developed a mouse strain that carries a green fluorescence protein in catecholaminergic cells. In these mice, dopaminergic cells can be selectively recorded under a fluorescence microscope.
Recent publications:
- Liu Y and Chen X (2008). Cholinergic excitation of dopaminergic cells depends on sequential activation of protein kinase C and the L-type calcium channel in ventral tegmental area slices. Brain Res. 1245:41-51.
- Liu Y, Dore J, and Chen X (2007). Calcium influx through L-type channels generates protein kinase M to induce burst firing of dopamine cells in the rat ventral tegmental area. J. Biol. Chem. 282:8594-8603.
- Zhang L, Y. Liu, and Chen X (2005). Carbachol induces burst firing of dopamine cells in the ventral tegmental area by promoting calcium entry through L type calcium channels in the rat. J. Physiol. 568:469-481.
- Chen X, Zhang L, and Kombian SB (2004). Dopamine-induced synaptic depression in the parabrachial nucleus is independent of CTX- and PTX-sensitive G-proteins, PKA and PLC signalling pathways. Brain Res. 995:236-246.