Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons

Kharkwal, Geetika; Brami‐Cherrier, Karen; Lizardi-Ortiz, José E.; Nelson, Alexandra; Ramos, Maria; Barrio, Daniel Del; Sulzer, David; Kreitzer, Anatol C.; Borrelli, Emiliana

doi:10.1016/j.neuron.2016.06.014

Cited by 98 publications

(105 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Specifically, previous reports have shown that haloperidol administration induces the phosphorylation of rpS6 at the Ser235/236 residue in cholinergic interneurons [46]. Here, we were unable to observe any effect of risperidone on rpS6 phosphorylation in the striatal cholinergic interneurons of the mouse model of EPS.…”

Section: Discussioncontrasting

confidence: 83%

“…The differences in rpS6 responsiveness among studies could be due to differences in the AP drug used and to doses and modes of administration of haloperidol. Kharkwal et al [46] performed immunofluorescence analyses of rpS6 phosphorylation after just a single dose of haloperidol (1 mg/kg), whereas in the present study we treated the animals with risperidone once per day for as many as three consecutive days. In addition, the understanding of the different mechanisms underlying the effects of typical (haloperidol) and atypical (risperidone) AP drugs remains limited and unclear [47].…”

Section: Discussionmentioning

confidence: 93%

“…Recent works have begun to explore the involvement of cholinergic interneurons and their mTOR-mediated mechanism in motor alterations [45,46]. Specifically, previous reports have shown that haloperidol administration induces the phosphorylation of rpS6 at the Ser235/236 residue in cholinergic interneurons [46].…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

García-Cerro¹,

Mas²,

Gortat³

et al. 2018

Neuropsychiatry

View full text Add to dashboard Cite

Objective: Acute extrapyramidal symptoms (EPS) are frequent and serious adverse reactions to antipsychotic (AP) drugs. Although the proposed mechanism is an excessive blockade of dopamine D2 receptors in the striatopallidal pathway of the striatum, previous studies implicated the mTOR pathway in the susceptibility to EPS. The objective of the present study is to analyze the mTOR-mediated response to risperidone in subpopulations of striatal neurons and its relationship to risperidone-induced motor side effects. Methods:Two mouse strains (A/J and DBA/2J) with different susceptibility to developing EPS were treated with risperidone 1 mg/kg for three consecutive days. Here we monitored, by double labeling immunohistochemistry, ribosomal protein S6 (rpS6) phosphorylation (Ser235/236 and Ser244/247 sites), a marker of mTOR signaling, in the striatonigral pathway (D1-medium spiny neurons (MSNs)), the striatopallidal pathway (D2-MSNs) and striatal cholinergic interneurons. Results:We found that EPS-resistant DBA/2J mice show higher baseline levels of phosphoactivated rpS6 protein in striatal MSNs, compared with EPS-prone A/J mice. Moreover, risperidone differentially targeted rpS6 phosphorylation in direct and indirect pathway neurons in a strain-specific manner: a significant decrease in the phosphorylation of rpS6 at Ser235/236 and Ser240/244 in DRD1-MSNs EPS-resistant DBA/2J mice after; and a significant increase of phospho-Ser235/236-rpS6 in the striatopallidal pathway of the EPS-prone A/J mice in response to risperidone. Conclusions:Our results reveal the vital role of genetic background in the response to risperidone, and point to the mTOR pathway as an important factor in EPS susceptibility.

show abstract

Section: Discussioncontrasting

confidence: 83%

Section: Discussionmentioning

confidence: 93%

See 1 more Smart Citation

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

García-Cerro¹,

Mas²,

Gortat³

et al. 2018

Neuropsychiatry

View full text Add to dashboard Cite

show abstract

“…, #5; Kharkwal et al . ). Collectively, these data suggest that D2Rs in CINs play a more prominent role in regulating phasic activity of these interneurons.…”

Section: Cell‐type Specific Cellular and Synaptic Consequences Of D2rmentioning

confidence: 97%

“…A recent study in which D2Rs were selectively deleted from CINs showed no effect on basal locomotion, yet selective disruption of catalepsy induced by D2R‐like antagonists and impaired locomotor response to D1R‐like agonist (Kharkwal et al . ).…”

Section: Summary and Final Conclusionmentioning

confidence: 97%

Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders

Dobbs

Lemos

Alvarez

2017

Genes Brain and Behavior

View full text Add to dashboard Cite

Dopamine D2 receptors (D2Rs) consistently emerge as a critical substrate for the etiology of some major psychiatric disorders. Indeed, a central theory of substance use disorders (SUDs) postulates that a reduction in D2R levels in the striatum is a determining factor that confers vulnerability to abuse substances. A large number of clinical and preclinical studies strongly support this link between SUDs and D2Rs; however, identifying the mechanism by which low D2Rs facilitate SUDs has been hindered by the complexity of circuit connectivity, the heterogeneity of D2R expression and the multifaceted constellation of phenotypes observed in SUD patient. Animal models are well‐suited for understanding the mechanisms because they allow access to the circuitry and the genetic tools that enable a dissection of the D2R heterogeneity. This review discusses recent findings on the functional role of D2Rs and highlights the distinctive contributions of D2Rs expressed on specific neuronal subpopulations to the behavioral responses to stimulant drugs. A circuit‐wide restructuring of local and long‐range inhibitory connectivity within the basal ganglia is observed in response to manipulation of striatal D2R levels and is accompanied by multiple alterations in dopamine‐dependent behaviors. Collectively, these new findings provide compelling evidence for a critical role of striatal D2Rs in shaping basal ganglia connectivity; even among neurons that do not express D2Rs. These findings from animal models have deep clinical implications for SUD patients with low levels D2R availability where a similar restructuring of basal ganglia circuitry is expected to take place.

show abstract

Make a Left Turn: Cortico‐Striatal Circuitry Mediating the Attentional Control of Complex Movements

et al. 2021

View full text Add to dashboard Cite

A BS TRACT: Background: In movement disorders such as Parkinson's disease (PD), cholinergic signaling is disrupted by the loss of basal forebrain cholinergic neurons, as well as aberrant activity in striatal cholinergic interneurons (ChIs). Several lines of evidence suggest that gait imbalance, a key disabling symptom of PD, may be driven by alterations in high-level frontal cortical and cortico-striatal processing more typically associated with cognitive dysfunction. Methods: Here we describe the corticostriatal circuitry that mediates the cognitive-motor interactions underlying such complex movement control. The ability to navigate dynamic, obstacle-rich environments requires the continuous integration of information about the environment with movement selection and sequencing. The corticalattentional processing of extero-and interoceptive cues requires modulation by cholinergic activity to guide striatal movement control. Cue-derived information is "transferred" to striatal circuitry primarily via frontostriatal glutamatergic projections. Result: Evidence from parkinsonian fallers and from a rodent model reproducing the dual cholinergicdopaminergic losses observed in these patients supports the main hypotheses derived from this neuronal circuitryguided conceptualization of parkinsonian falls. Furthermore, in the striatum, ChIs constitute a particularly critical node for the integration of cortical with midbrain dopaminergic afferents and thus for cues to control movements. Conclusion: Procholinergic treatments that enhance or rescue cortical and striatal mechanisms may improve complex movement control in parkinsonian fallers and perhaps also in older persons suffering from gait disorders and a propensity for falls.

show abstract

Parkinsonism Driven by Antipsychotics Originates from Dopaminergic Control of Striatal Cholinergic Interneurons

Cited by 98 publications

References 65 publications

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

Different Modulation of Rps6 Phosphorylation by Risperidone in Striatal Cells Sub Populations: Involvement of the mTOR Pathway in Antipsychotic-Induced Extrapyramidal Symptoms in Mice

Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders

Make a Left Turn: Cortico‐Striatal Circuitry Mediating the Attentional Control of Complex Movements

Contact Info

Product

Resources

About