MGLU4-TARGETING NANOBODIES RESTORE SOCIAL BEHAVIOR IN MOUSE MODELS OF AUTISM SPECTRUM DISORDERS

Autism spectrum disorders (ASD) are neurodevelopmental conditions characterized by persistent deficits in social communication and interaction, as well as restricted and repetitive behaviors, for which no pharmacological treatment targeting core symptoms is currently available. Converging evidence from animal models and clinical studies suggests that these behavioral alterations arise from dysfunction of striatal circuits, in particular from hyperactivity of dopamine D2 receptor–expressing striatal projection neurons (D2-SPNs) within the nucleus accumbens, a key structure involved in social reward processing.
The metabotropic glutamate receptor type 4 (mGlu4), preferentially expressed at presynaptic sites of D2-SPNs, represents a promising therapeutic target. Chronic facilitation of mGlu4 activity using positive allosteric modulators (PAMs) improves sociability and reduces repetitive behaviors in several genetic and environmental mouse models of ASD. However, currently available chemical compounds suffer from limitations, including suboptimal specificity, poor solubility, and limited brain penetration.
Here, we propose an alternative strategy based on the development of mGlu4-targeting nanobodies. These single-domain antibodies derived from camelids display high affinity, strong specificity, and pharmacokinetic properties well suited for applications in the central nervous system. We have identified a nanobody acting as a PAM of mGlu4, which potentiates glutamate-induced signaling in vitro and significantly improves social interactions and behavioral flexibility following intranasal administration in Fmr1 knockout mice, a well-established model of ASD. Our work opens new avenues for modulating the neural circuits underlying sociability and developing innovative treatments for ASD.