During the early postnatal period, the mammalian cortex undergoes rapid changes in cellular properties, laminar structure, and synaptic connectivity. Proper maturation of these properties is essential to normal brain function, and several diseases of the brain may reflect abnormal patterns of development (e.g. schizophrenia, epilepsy, depression). Many of these changes are sensitive to patterns of synaptic input and the degree of cellular activity. Increases in intracellular Ca2+ levels are thought to be an important mechanism by which firing behavior and the pattern of synaptic inputs are translated into changes in synaptic strength or connectivity. In adult cortical pyramidal cells, several ionic conductances interact to shape the activity of the cell. This interplay is incompletely understood in adult cells and even less examined in immature neurons. Neuromodulators such as norepinephrine (NE) and serotonin (5HT) activate G-proteins and second messenger systems to alter ionic conductances and firing behavior in adult neurons. These transmitter systems mature over the same time period as the intrinsic cellular properties of pyramidal cells, and may influence cortical plasticity. We have designed experiments to investigate the properties of Ca2+ and Ca-dependent K+ currents, and the effects of NE and 5HT at various postnatal ages in rat sensorimotor cortical pyramidal neurons. The central hypothesis driving this work is that NE and 5HT have multiple convergent and divergent effects on voltage-gated Ca2+ currents in immature and adult neocortical pyramidal cells. Furthermore, these effects may be age-dependent due to developmental changes in the expression of Ca2+ and K+ channels and receptors for NE and 5HT, as well as in the maturation of Ca2+ regulatory mechanisms.
The Specific Aims of this proposal are (1) To investigate the ontogeny of different Ca2+ currents in neocortical neurons. (2) To determine the signalling pathways involved in the modulation of Ca2+ currents by NE and 5HT. (3) To determine the functional roles of different Ca2+ currents in eliciting Ca-dependent K+ currents and after hyperpolarizations. We will employ intracellular recordings in a brain slice preparation, whole cell patch clamp recordings from acutely dissociated neurons, pharmacological agents, and single cell mRNA amplification techniques. Data derived from these experiments are expected to help in the understanding of (1) the development of ion channels, and (2) the actions of NE and 5HT in modulating Ca2+ currents and cellular integration in cortical pyramidal cells. These mechanisms are likely to be important in the development of normal cortical function, as well as in disease processes.
Showing the most recent 10 out of 18 publications
