177 | A dual approach to ablate Nkx2.1+ striatal interneurons: Implications in understanding Tourette syndrome

Disorders of the Nervous System

Author: Camila Coll | Email: collcami@gmail.com

Camila Coll , Lucia Garbini , Juan E. Belforte , M. Gustavo Murer

1° Universidad de Buenos Aires – CONICET. Instituto de Fisiología y Biofísica Bernardo Houssay (IFIBIO Houssay), Facultad de Medicina, Departamento de Ciencias Fisiológicas. Grupo de Neurociencia en Sistemas. Buenos Aires, Argentina.

Tourette Syndrome (TS) is a disorder marked by motor and vocal tics, impulsivity and repetitive behaviors. Postmortem studies reveal reduced PV+, NOS+ and ChAT+ striatal interneurons (SI) in TS patients. Notably, all the SI subtypes affected in TS derive from a cell precursor expressing Nkx2.1. To reproduce the striatal changes reported, we performed a combined ablation of SI using two different approaches.
First, a specific Nkx2.1+ SI ablation was produced by administrating intrastriatally diphtheria toxin (DT) in adult mice that express human diphtheria toxin receptor (hDTR) in the Nkx2.1+ cell lineage. With this approach, we obtained ablations of all SI that ever-expressed Nkx2.1. Ablated mice developed abnormal involuntary movements akin to motor tics and repetitive behaviors.
Next, we injected Nkx2.1-Cre adult mice intrastriatally with a virus that expresses hDTR in a Cre-dependent manner. After three weeks of expression we administrated DT intraperitoneally to produce a specific ablation of SI that at time of infection were expressing Nkx2.1. Lesioned mice showed exacerbated hyperlocomotion but did not develop tic-like movements.
Although preliminary, our findings suggest that tics are only induced after targeting the Nkx2.1 cell lineage early during development. Also, that alterations of the Nkx2.1 cell lineage at different postnatal moments may result in diverse behavioral syndromes relevant to understanding basal ganglia related neuropsychiatric disorders.