Striatal cholinergic interneurons and D2 receptor-expressing GABAergic medium spiny neurons regulate tardive dyskinesia

Abstract

Tardive dyskinesia (TD) is a drug-induced movement disorder that arises with antipsychotics. These drugs are the mainstay of treatment for schizophrenia and bipolar disorder, and are also prescribed for major depression, autism, attention deficit hyperactivity, obsessive compulsive and post-traumatic stress disorder. There is thus a need for therapies to reduce TD. The present studies and our previous work show that nicotine administration decreases haloperidol-induced vacuous chewing movements (VCMs) in rodent TD models, suggesting a role for the nicotinic cholinergic system. Extensive studies also show that D2 dopamine receptors are critical to TD. However, the precise involvement of striatal cholinergic interneurons and D2 medium spiny neurons (MSNs) in TD is uncertain. To elucidate their role, we used optogenetics with a focus on the striatum because of its close links to TD. Optical stimulation of striatal cholinergic interneurons using cholineacetyltransferase (ChAT)-Cre mice expressing channelrhodopsin2-eYFP decreased haloperidol-induced VCMs (~50%), with no effect in control-eYFP mice. Activation of striatal D2 MSNs using Adora2a-Cre mice expressing channelrhodopsin2-eYFP also diminished antipsychotic-induced VCMs, with no change in control-eYFP mice. In both ChAT-Cre and Adora2a-Cre mice, stimulation or mecamylamine alone similarly decreased VCMs with no further decline with combined treatment, suggesting nAChRs are involved. Striatal D2 MSN activation in haloperidol-treated Adora2a-Cre mice increased c-Fos+ D2 MSNs and decreased c-Fos+ non-D2 MSNs, suggesting a role for c-Fos. These studies provide the first evidence that optogenetic stimulation of striatal cholinergic interneurons and GABAergic MSNs modulates VCMs, and thus possibly TD. Moreover, they suggest nicotinic receptor drugs may reduce antipsychotic-induced TD.

Unilateral Botulinum Neurotoxin-A Injection into the Striatum of C57BL/6 Mice Leads to a Different Motor Behavior Compared with Rats

“…Locally injected BoNT-A is thought to act in two main ways in the striatum, where it blocks the acetylcholine release of the tonically active cholinergic interneurons [ 46 , 47 , 48 ], counteracts the D 2 receptor upregulation found in hemi-PD rats, and reduces D 2 receptor concentrations in naïve rats [ 22 , 23 ]. The assumed BoNT-A-induced reduction of acetylcholine concentration in the injected CPu reduces the firing activity of medium spiny neurons projecting to (i) the external globus pallidus, i.e., those which are part of the indirect basal ganglia loop, and (ii) to the internal globus pallidus, i.e., those which are part of the direct basal ganglia loop [ 49 , 50 , 51 , 52 , 53 ].…”

Botulinum Neurotoxin A Injected Ipsilaterally or Contralaterally into the Striatum in the Rat 6-OHDA Model of Unilateral Parkinson’s Disease Differently Affects Behavior

“…The majority of inhibitory D2 receptors are located on cholinergic interneurons and medium spiny neurons (MSN) projecting to the external pallidum, i.e., being part of the indirect basal ganglia loop (Hurley and Jenner, 2006; Perreault et al, 2011; Bordia et al, 2016; Mamaligas et al, 2016; Rico et al, 2017). As in hemi-PD the tonically active cholinergic interneurons become hyperactive due to loss of D2-mediated DA inhibition, they strongly activate MSN by ACh.…”

Potential Therapeutic Application for Nicotinic Receptor Drugs in Movement Disorders

“…However, it should be noted that nicotine administration maximally reduced abnormal movements only up to 50% in the animal studies. 141,152 Thus, tardive dyskinesia may be less pronounced in schizophrenic patients that smoke. A carefully controlled, double-blind clinical trial is essential to address the question whether smoking reduces tardive dyskinesia in the clinic.…”