Mar 10, 2020

Dopaminergic Co-transmission with Sonic Hedgehog Inhibits Expression of Abnormal Involuntary Movements

bioRxiv
Lauren MalaveAndreas H Kottmann

Abstract

Our limited understanding of neuronal co-transmission complicates predicting the effects of pharmacological interventions from neuronal wiring diagrams [1, 2]. For example, dopamine neurons (DAN), whose degeneration causes the motor and cognitive deficits of Parkinson Disease (PD) [3], communicate with all their targets by dopamine (DA) and in addition use the neurotransmitters GABA, Glutamate and secreted peptides including the morphogen Sonic Hedgehog (Shh) to signal to select subsets of neurons [4-8]. It is unknown whether Levodopa (L-Dopa) induced dyskinesia (LID), a debilitating side effect of DA supplementation therapy in PD [9], might appear because DAN targets become exposed to high levels of DA but diminished levels of other DAN produced signaling factors. Here we show that restoring the balance of DA and Shh signaling by agonists of the Shh signaling effector G-protein coupled receptor Smoothened (Smo [10, 11]) attenuates LID in mouse- and macaque- models of PD. Using conditional genetic loss of function approaches of pre- and post-synaptic Shh signaling we found that reducing the activity of Smo selectively in cholinergic neurons facilitates LID. Conversely, the expression of a constitutive active form of Smo (SmoM2 ...Continue Reading

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Mentioned in this Paper

Disease Transmission
Nerve Degeneration
Learning
Levodopa
Protein Expression
Neurons
Smo protein, mouse
Cognition Disorders
Optogenetics
Parkinson Disease

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