Seminar – Matthias OLLIVIER

Crym-positive striatal astrocytes in health and Huntington’s disease

Astrocytes exhibit region-specific molecular diversity, but the functional roles of distinct populations remain poorly understood. Crym identifies a specific subpopulation of striatal astrocytes. Using CRISPR/Cas9-mediated knockdown, we demonstrated that astrocytic Crym depletion induces repetitive and perseverative behaviors, associated with an imbalance in excitatory and inhibitory synaptic transmission and overactivation of the frontostriatal pathway. We further showed that Crym expression is reduced in postmortem brain tissue from patients with Huntington’s disease and in the R6/2 mouse model. Restoring µ-crystallin expression in striatal astrocytes rescued neuronal morphology, dendritic spine density, and synaptic balance, while improving repetitive behaviors and some early cognitive deficits. Together, these findings identify Crym-positive astrocytes as potential therapeutic targets in Huntington’s disease and highlight the functional importance of astrocyte diversity in both health and disease.