The objective of this proposal is to study dendritic events in prefrontal pyramidal neurons (PPNs) and their modulation by the monoamines dopamine (DA) and serotonin (5-HT). Abnormalities in DA and 5-HT signaling in the prefrontal cortex (PFC) have long been thought to underlie the symptoms seen in a variety of neurological illnesses such as depression and schizophrenia. The apical dendrites of PPNs are enriched with DA and 5-HT receptors that are targeted by antipsychotic drugs. The dendrites of PPNs are also the recipients of the vast majority of excitatory input. These dendrites are not passive, but are richly invested with ion channels that endow dendrites with complex integrative properties. Back-propagating action potentials (BPAPs) generated by injecting current to the soma can propagate hundreds of microns along the main apical dendritic shaft providing a tool for probing dendritic excitability. The experiments described in this proposal combine two-photon excitation laser scanning microscopy (2P LSM) and whole-cell patch clamp electrophysiology methodologies to accomplish three specific aims.
Specific aim 1 is to determine the extent to which BPAPs invade the distal apical dendrites of PPNs and the contribution of the voltage-gated ion channels to dendritic excitability. The neurons will be loaded with Ca2+-sensitive dyes through the patch pipette, and Ca2+ transients in the dendrites associated with the BPAPs will be measured using 2P LSM.
Specific aim 2 is to identify the impact of DA and 5-HT receptor activation on dendritic excitability. This will be accomplished using the paradigm outlined in specific aim 1 while focally applying DA and 5-HT-receptor agonists.
Specific aim 3 is to determine if 5-HT2A agonists affect Ca2+ signals associated with action potentials generated by directly depolarizing the PPN dendrites with NMDA. Assessing the dendritic phenomena that potentially underlie the most prominent intrinsic cellular mechanisms involved in neuromodulation by monoamines will aid in the development of rational therapies for people suffering from schizophrenia. This Career Development Award (K01) will support this research and allow me to undertake a new line of intensive training that will enable me to develop and refine skills that will greatly enhance my ability to conduct meaningful research in the area of brain disorders, and facilitate my transition into an independent investigator. ? ?
| Day, Michelle; Wokosin, David; Plotkin, Joshua L et al. (2008) Differential excitability and modulation of striatal medium spiny neuron dendrites. J Neurosci 28:11603-14 |
