Information processing in the striatum is crucial for voluntary movement control and associative learning and in the normal condition is subject to balanced dopaminergic and cholinergic modulation. However, in Parkinson's disease (PD) striatal dopamine (DA) level falls because of degeneration of DA neurons in the substantia nigra pars compacta and acetylcholine (ACh) release rises. This dissertation elucidates the physiological role of cholinergic interneurons in the striatum and their cellular adaptations in PD. Glutamatergic synapses formed on striatal cells originate from the cerebral cortex and thalamus. I demonstrate that corticostriatal and thalamostriatal synapses on medium spiny neurons (MSNs) have different release probability and short-term plasticity. In addition, I show that cholinergic interneurons primarily receive excitatory inputs from the thalamus. When high frequency stimulation is given at thalamic afferents, cholinergic interneurons display a burst pause firing pattern, the same firing pattern seen in associative learning. The burst pause firing of cholinergic interneurons produces a fast, transient presynaptic inhibition at corticostriatal terminals and a slow, long lasting enhancement of EPSPs summation through postsynaptic muscarinic M1 receptor activation in striatopallidal neurons but not striatonigral neurons. In this way, the thalamus gates corticostriatal signaling through cholinergic interneurons. Following DA depletion, autoreceptor coupling to Cav2 and Kir3 channels in cholinergic interneurons was dramatically attenuated. This adaptation was attributable to up-regulation of RGS4 - a Regulator of G-protein Signaling protein. The results suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal ACh release in PD. The dissertation also demonstrates that there is a profound loss of spines and glutamatergic synapse in indirect pathway striatopallidal neurons but not direct pathway striatonigral neurons. The spine loss is triggered by dysregulation of Cav1.3 channels, which is modulated by D2 and M1 receptors in MSNs

Last modified

• 05/28/2018

Creator

• Jun Ding

DOI

• https://doi.org/10.21985/N2TB0D

Subject

• Neuroscience Institute Graduate Program

Keyword

• Neuroscience

Date created

• 2007-05-10

Resource type

• Dissertation

Rights statement

• In Copyright