Modeling receptor induced signaling in MSNs

Basal Ganglia are evolutionarily conserved brain nuclei involved in several physiologically important behaviors like motor control and reward learning. Striatum, which is the input nucleus of basal ganglia, integrates inputs from several types of neurons, like cortical and thalamic projection neurons and local GABAergic neurons. Several neuromodulators, such as dopamine, accetylcholine and serotonin modulate the functional properties of striatal neurons. Aberrations in the intracellular signaling of these neurons lead to several debilitating neurodegenerative diseases, like Parkinson’s disease. In order to understand these aberrations we should first identify the role of different molecular players in the normal physiology. The long term goal of the research described in this thesis is to understand the molecular mechanisms responsible for the integration of different neuromodulatory signals by striatal medium spiny neurons (MSN). This signal integration is known to play an important role in learning and is manifested via changes in the synaptic weights between different neurons. The group of synapses taken into consideration for the current work is the corticostriatal one, which are synapses between the cortical projection neurons and MSNs. These synapses are modulated bu dopamine and ACh and a molecular process of considerable interest is the interaction between dopaminergic and cholinergic inputs. In this thesis I have investigated the interactions between the biochemical cascades triggered by dopaminergic, cholinergic (ACh) and glutamatergic inputs to the striatal MSN. The dopamine induced signaling increases the levels of cAMP in the striatonigral MSNs. The sources of dopamine and acetylcholine are dopaminergic neurons (DAN) from the midbrain and tonically active cholinergic interneurons (TAN) localized in the striatum, respectively. A sub-second burst activity in DAN along with a simultaneous pause in TAN is a characteristic effect elicited by a salient stimulus. This, in turn, leads to a dopamine peak and an acetylcholine (ACh) dip in striatum. I have looked into the possibility of sensing this ACh dip and the dopamine peak at striatonigral MSNs. These neurons express D1 dopamine receptor (D1R) coupled to Golf and M4 Muscarinic ACh receptor (M4R) coupled to Gi/o. These receptors are expressed significantly in the dendritic spines of these neurons where the Adenylate Cyclase 5 (AC5) is a point of convergence for these two signals. Golf stimulates the production of cAMP by AC5 whereas Gi/o inhibits the Golf mediated cAMP production. I have performed a kinetic-modeling exercise to explore how dopamine and ACh interact with each other via these receptors and what are the effects on the downstream signaling events. The results of the simulations suggest that the striatonigral MSNs are able to sense the ACh dip via M4R. They integrate the dip with the dopamine peak to activate AC5 synergistically. I also found that the ACh tone may act as a potential noise filter against noisy dopamine signals. The small set of possible parameters for the G-protein GTPase activity indicate towards an important role of GTPase Activating Proteins (GAPs), like RGS, in the ACh dip sensing process. Besides this we also hypothesize that M4R may have therapeutic potential.