Muscarinic receptors, tics and GSK3b

A freshly published article found that stimulation of M4 muscarinic receptors reduce symptoms of Tourette Syndrome model in rodents:

Systemic and intrastriatal xanomeline reduced TS-related behaviours in CIN-d and D1CT-7 mice.

Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline-like ameliorative effects in both models.

M4, but not M1, receptors were down-regulated in the striatum of CIN-d mice. Additionally, VU0467154 reduced striatal c-Fos levels in these animals.

Activation of striatal M4, but not M1, receptors reduced tic-like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS. (R1)

Another paper shows that activation of muscarinic receptors inhibits GSK3b by phosphorylation of Ser9:

The levels of phospho-Ser21-GSK3α and phospho-Ser9-GSK3β increased in all three subcellular fractions after pilocarpine treatment.

No changes in the total levels of GSK3 were observed in any fraction, indicating that muscarinic receptor stimulation with pilocarpine did not change the subcellular distribution of GSK3. Thus, muscarinic receptor stimulation increased the serine-phosphorylation of GSK3 throughout the cell. (R2)

This is another clue that dysregulated GSK3b may contribute to pathophysiology of Tourette Syndrome. Lowering it’s activation and helping Nrf2 to activate properly helps to reduce TS symptoms in the mouse model of TS.