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5HT neuromodulation of hippocampal pyramidal cells: effects of increased Ihon cell excitability
BMC Neurosciencevolume 8, Article number: P118 (2007)
During waking, serotonin (5HT) levels in the hippocampus are high but during REM sleep hippocampal 5HT levels drop so low that it is virtually absent. We investigate how differing levels of 5HT affect the properties of hippocampal pyramidal cells through analysis of biophysical models of CA1 pyramidal neurons. Studies in the hippocampal slice show that 5HT increases Ih, the hyperpolarization-activated current, by affecting its maximal conductance and its half-activation voltage . In hippocampal pyramidal cells, Ih has been shown to have a normalizing influence on the temporal summation of dendritic synaptic inputs  that has been analyzed in modeling studies where Ih was the only active conductance in the model cell membrane [3–5]. Recently, dopaminergic neuromodulation of Ih has been shown to influence excitability of pyramidal cells in the entorhinal cortex . While the action of dopamine on the kinetics of Ih was not determined in these cells, dopamine had the general effect of increasing Ih which resulted in a decrease of excitability. We consider how the specific 5HT modulation of Ih affects cell excitability in model hippocampal pyramidal neurons. Our analysis pays particular attention to rectifying the well-known depolarizing effects of Ih on resting potential with its inhibitory effect on excitability.
To concentrate on the interaction of Ih with spike generating currents, we constructed a single compartment model neuron that contains biophysically accurate Na+, K+-delayed rectifier and h currents with parameters set to replicate CA1 pyramidal cell subthreshold and firing behaviors . We also constructed a simplified single compartment model that includes Ih and the Morris-Lecar model equations for spike generating currents in order to analyze Ih effects on cell firing using phase plane techniques. In these models, we simulate the changes to Ih that the slice studies indicate occur when 5HT is present.
Preliminary simulations using both the biophysical and simplified models show that neuronal excitability decreases with increased Ih. However, there is a voltage-dependence of the effects of increased Ih: if cell voltage is held around -70 mV and a current pulse is given, excitability decreases but if cell voltage is held around -50 mV when the pulse is given, excitability increases. We also investigate how the changes to Ih due to variations in serotonin level affect the cell response to a stimulus.
While the rectifying effects of Ih on resting potential are well understood, we concentrate on understanding the interaction of Ih with spiking currents and its nonintuitive effects on cell excitability. 5HT modulation of Ih suggests that excitability and, hence, synaptic processing in hippocampal pyramidal cells may change in different behavioral states such as waking and REM sleep. Understanding this change in neuronal processing during waking hippocampal activity which is involved in memory formation and during reactivation firing in REM sleep may lead to insight into the role of REM sleep in learning and memory.
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