Teneurin-4 in the nucleus accumbens modulates affective-like behaviors with potential effects on astrocytes in male mice

Affective disorders represent a major global health burden with limited therapeutic options. Teneurin-4 (TENM4), a cell adhesion molecule crucial for synaptic organization, has been implicated in neural circuit function, but its specific role in the nucleus accumbens (NAc) and its contribution to mood regulation are poorly understood. Here, we used adeno-associated virus (AAV)-mediated CRISPR for a targeted knockdown of Tenm4 mRNA in the mouse NAc. TENM4 knockdown (TENM4KD) induced robust anxiety- and depression-like behaviors, accompanied by simplified astrocyte morphology with reduced branching complexity and territorial area, without affecting microglia. To probe the underlying circuit deficit, we performed regimen with etizolam (ETZ), a positive allosteric modulator of GABA-A receptors, for seven days normalized both behavioral and astrocyte morphological alterations. Mechanistically, TENM4KD disrupted FAK/Wnt signaling, which was restored by ETZ. Our findings indicate that neuronal TENM4 in the NAc maintains astrocyte structure through neuron–glia crosstalk. Disruption of this interaction contributes to affective-like behaviors, revealing a novel neuron-to-astrocyte signaling mechanism for TENM4 in mood regulation. • Knockdown of TENM4 in the nucleus accumbens induces affective-like behaviors. • TENM4 deficiency causes astrocytic pathology in nucleus accumbens. • Astrocyte pathology is linked to a simplified morphological and reduced cell number. • Loss of TENM4 is associated with dysregulation of the FAK/Wnt signaling pathway. • Enhancing GABAergic tone pharmacologically reverses both behavioral and astrocytic deficits.