Human mutations in high-confidence Tourette disorder genes affect sensorimotor behavior, reward learning, and striatal dopamine in mice.

Tourette disorder (TD) is poorly understood, despite affecting 1/160 children. A lack of animal models possessing construct, face, and predictive validity hinders progress in the field. We used CRISPR/Cas9 genome editing to generate mice with mutations orthologous to human de novo variants in two high-confidence Tourette genes, CELSR3 and WWC1. Mice with human mutations in Celsr3 and Wwc1 exhibit cognitive and/or sensorimotor behavioral phenotypes consistent with TD. Sensorimotor gating deficits, as measured by acoustic prepulse inhibition, occur in both male and female Celsr3 TD models. Wwc1 mice show reduced prepulse inhibition only in females. Repetitive motor behaviors, common to Celsr3 mice and more pronounced in females, include vertical rearing and grooming. Sensorimotor gating deficits and rearing are attenuated by aripiprazole, a partial agonist at dopamine type II receptors. Unsupervised machine learning reveals numerous changes to spontaneous motor behavior and less predictable patterns of movement. Continuous fixed-ratio reinforcement shows that Celsr3 TD mice have enhanced motor responding and reward learning. Electrically evoked striatal dopamine release, tested in one model, is greater. Brain development is otherwise grossly normal without signs of striatal interneuron loss. Altogether, mice expressing human mutations in high-confidence TD genes exhibit face and predictive validity. Reduced prepulse inhibition and repetitive motor behaviors are core behavioral phenotypes and are responsive to aripiprazole. Enhanced reward learning and motor responding occur alongside greater evoked dopamine release. Phenotypes can also vary by sex and show stronger affection in females, an unexpected finding considering males are more frequently affected in TD.

Activation of M4 muscarinic receptors in the striatum reduces tic-like behaviours in two distinct murine models of Tourette syndrome.

BACKGROUND AND PURPOSE: Current pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors-the two most abundant muscarinic receptors in the striatum-reduced tic-related behaviours in mouse models of TS. EXPERIMENTAL APPROACH: Studies were conducted using CIN-d and D1CT-7 mice, two TS models characterized by early-life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic-like and other TS-related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c-Fos. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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.

Factores asociados a la calidad de vida de sujetos con enfermedad de Parkinson y a la carga en el cuidador / Factors associated with the quality of life of subjects with Parkinson's disease and burden on their caregivers

Introducción: La enfermedad de Parkinson impacta en la calidad de vida del sujeto que la presenta, pero también ocasiona una carga para el cuidador. Los factores relacionados con estos efectos incluyen aspectos motores y no motores de la enfermedad, así como características inherentes al cuidador. Métodos: Se evaluó a sujetos con enfermedad de Parkinson mediante los siguientes instrumentos: cuestionario de calidad de vida PDQ-8, escala unificada de la enfermedad de Parkinson de la Sociedad de Trastornos del Movimiento parte i a iv (MDS-UPDRS) y estadio de Hoehn y Yahr (HY). A los cuidadores primarios, se les aplicó el inventario de carga del cuidador de Zarit. Adicionalmente, se registraron las principales variables demográficas y clínicas. Resultados: Se incluyó a 250 sujetos con enfermedad de Parkinson, de los cuales 201 contaban con un cuidador primario. En el análisis multivariado los factores predictores de una peor calidad de vida del sujeto con enfermedad de Parkinson fueron la puntuación de la MDS-UPDRS I (β = 0,39, p < 0,001), puntuación de la MDS-UPDRS II (β = 0,21, p < 0,001) y puntuación de la MDS-UPDRS III (β = 0,07, p = 0,004). En lo que respecta a la carga en el cuidador, la puntuación de la MDS-UPDRS II (β = 0,54, p = 0,007) fue el que más influyó. Conclusiones: El presente estudio muestra una relación entre la calidad de vida del sujeto con enfermedad de Parkinson y la percepción de carga del cuidador. No obstante, los factores que determinan cada una de estas parecen ser distintos

Introduction: Parkinson's disease affects the quality of life of the individual with the disease in addition to creating a burden on the caregiver. Factors related to these effects include motor and non-motor aspects of the disease, as well as traits inherent to the caregiver. Methods: We evaluated subjects with Parkinson's disease using the following instruments: Quality of Life Questionnaire PDQ-8, Movement Disorders Society Unified Parkinson's disease Rating Scale part i to iv (MDS-UPDRS), and Hoehn and Yahr staging. The Zarit Burden Inventory was used to assess all primary caregivers. Major demographic and clinical variables were also recorded. Results: A total of 250 subjects with Parkinson's disease were included, of whom 201 had a primary caregiver. In the multivariate analysis, predictors of poor quality of life for a subject with Parkinson's disease were the MDS-UPDRS I score (β = .39, P < .001), MDS-UPDRS II score (β = .21, P < .001), and MDS-UPDRS III score (β = .07, P = .004). Regarding caregiver burden, the MDS-UPDRS II score (β = .54, P = .007) was the most influential factor. Conclusions: The present study shows a relationship between quality of life for the subject with Parkinson's disease and the caregiver's perceived burden. However, the factors that determine each situation appear to be distinct

Doença dos tiques: aspectos genéticos e neuroquímicos atuais / Tic disease: current genetic and neurochemical factors

Após breve revisão dos dados históricos, do conceito, do quadro clínico e dos critérios para o diagnóstico, analisamos os principais aspectos genéticos e neuroquímicos atuais dos tiques e da síndrome de Gilles de La Tourette. Dados epidemiológicos sugerem que todo tique seja de natureza orgânica, a maioria de origem genética, e que obedecem a transmissão autossômica dominante com penetrância aproximada de 100 por cento. Ressaltamos, ainda, os recentes estudos imuno-histoquímicos, particularmente os que se referem aos sistemas dopaminérgico, noradrenérgico e serotoninérgico, que modulam a atividade dos circuitos córtico-estriato-talâmico-cortical, envolvidos na gênese dos tiques e dos transtornos obsessivos-compulsivos.