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Cholinergic modulation of ion channels in the CNS Tai, Chao

Abstract

The cholinergic system is one of the most important modulatory neurotransmitter systems in the CNS. In this dissertation, I report novel cholinergic modulations of three Ca²⁺ permaable ion channels, including R-type voltage-gated calcium channels (VGCCs), TRPC5 channels and NMDA receptors, in hippocampal CA1 pyramidal neurons and the potential functional roles of these modulations in both physiological and pathophysiological conditions. I first studied the “toxin-resistant” R-type VGCCs, and found that muscarinic activation specifically enhances R-type, but does not affect T-type, Ca²⁺ currents in hippocampal CAl pyramidal neurons. The muscarinic stimulation of R-type Ca²⁺ channels is mediated by M1/M3 receptors and requires the activation of a Ca²⁺-indepenadent PKC pathway. Furthermore, the enhancement of R-type Ca²⁺ currents resulted in remarkable changes in the firing pattern of the de novo R-type Ca²⁺ spikes, which could fire repetitively in the theta frequency. Therefore, muscarinic enhancement of R-type Ca²⁺ channels could play an important role in the intrinsic resonance properties of neurons. Next, I studied the muscarinic-induced prolonged seizure-like depolarizations called plateau potentials (PPs) in CAl pyramidal neurons. I found that muscarinic stimulation significantly and specifically triggered rapid translocation of TRPC5 channels into plasma membrane. Moreover, TRPC channels contribute to the generation of PPs, the underlying tail currents (Itail) and the associated dendritic Ca²⁺ influx in CA1 pyramidal neurons, via a calmodulin- and PI₃K-dependent pathway. Thus the muscarinic-induced membrane insertion of TRPC5 channels could contribute to the generation of PPs and the prolonged neuronal depolarization during the ictal discharges in epilepsy. And finally, I report that muscarinic modulation of NMDA-evoked current (INMDA) in CA1 pyramidal neurons is age-dependent. I found that muscarinic stimulation potentiated INMDA in both young and old animals. However, in young animals, muscarinic stimulation potentiated INMDA through a [Ca²⁺]i-independent but PKC- and Src-dependent pathway. While in old animals, muscarinic stimulation potentiated INMDA through a [Ca²⁺]i-dependent but PKC-independent pathway. Interestingly, the activity of the Gαq -coupled M1-like muscarinic receptors was required for the potentiation of INMDA in both cases. These findings may provide a crucial mechanism by which cholinergic input modulates learning and memory.

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