
@article {53171,
	title = {The high efficacy of muscarinic M4 receptor in D1 medium spiny neurons reverses striatal hyperdopaminergia.},
	journal = {Neuropharmacology},
	volume = {146},
	year = {2019},
	month = {2019 Mar 01},
	pages = {74-83},
	abstract = {<p>The opposing action of dopamine and acetylcholine has long been known to play an important role in basal ganglia physiology. However, the quantitative analysis of dopamine and acetylcholine signal interaction has been difficult to perform in the native context because the striatum comprises mainly two subtypes of medium-sized spiny neurons (MSNs) on which these neuromodulators exert different actions. We used biosensor imaging in live brain slices of dorsomedial striatum to monitor changes in intracellular cAMP at the level of individual MSNs. We observed that the muscarinic agonist oxotremorine decreases cAMP selectively in the MSN subpopulation that also expresses D dopamine receptors, an action mediated by the M muscarinic receptor. This receptor has a high efficacy on cAMP signaling and can shut down the positive cAMP response induced by dopamine, at acetylcholine concentrations which are consistent with physiological levels. This supports our prediction based on theoretical modeling that acetylcholine could exert a tonic inhibition on striatal cAMP signaling, thus supporting the possibility that a pause in acetylcholine release is required for phasic dopamine to transduce a cAMP signal in D1 MSNs. In vivo experiments with acetylcholinesterase inhibitors donepezil and tacrine, as well as with the positive allosteric modulators of M receptor VU0152100 and VU0010010 show that this effect is sufficient to reverse the increased locomotor activity of DAT-knockout mice. This suggests that M receptors could be a novel therapeutic target to treat hyperactivity disorders.</p>
},
	issn = {1873-7064},
	doi = {10.1016/j.neuropharm.2018.11.029},
	author = {Nair, Anu G and Castro, Liliana R V and El Khoury, Marianne and Gorgievski, Victor and Giros, Bruno and Tzavara, Eleni T and Hellgren-Kotaleski, Jeanette and Vincent, Pierre}
}
@article {38424,
	title = {Switch-like PKA responses in the nucleus of striatal neurons.},
	journal = {J Cell Sci},
	year = {2018},
	month = {2018 Jul 02},
	abstract = {<p>Although it is known that Protein Kinase A (PKA) in the nucleus regulates gene expression, the specificities of nuclear PKA signaling remain poorly understood. Here, we combined computational modeling and live-cell imaging of PKA-dependent phosphorylation in mouse brain slices to investigate how transient dopamine signals are translated into nuclear PKA activity in cortical pyramidal neurons and striatal medium spiny neurons. We observed that the nuclear PKA signal in striatal neurons featured an ultrasensitive responsiveness, associated with fast, all or none responses, which is not consistent with the commonly accepted theory of a slow and passive diffusion of catalytic PKA in the nucleus. Our numerical model suggests that a positive feed-forward mechanism inhibiting nuclear phosphatase activity - possibly mediated by DARPP-32 - could be responsible for this non-linear pattern of nuclear PKA response, allowing for a better detection of the transient dopamine signals that are often associated with reward-mediated learning.</p>
},
	issn = {1477-9137},
	doi = {10.1242/jcs.216556},
	author = {Yapo, Cedric and Nair, Anu G and Hellgren Kotaleski, Jeanette and Vincent, Pierre and Castro, Liliana R V}
}
