Neuronal IL-18 Signaling in the Medial Habenula Contributes to Schizophrenia-Like Behavioral Deficits via ERK-Associated BDNF Suppression.

Current antipsychotics for schizophrenia (SCZ) are notably ineffective against the debilitating cognitive and negative symptoms, creating a major therapeutic gap. Neuroinflammation in the medial habenula (MHb) is implicated in SCZ; however, the underlying cell-type-specific mechanisms remain unknown. This study aimed to determine whether pathologically elevated neuronal interleukin-18 (IL-18) in the MHb contributes to schizophrenia-like behavioral abnormalities through ERK-associated downregulation of brain-derived neurotrophic factor (BDNF). Utilizing an MK-801-treated rat model, we adopted a multi-modal approach. Single-cell RNA sequencing was used to identify the cellular origin of pathological IL-18. We then combined neuron-specific viral manipulations to test functional involvement, chemogenetics to manipulate MHb neuronal activity, and ex vivo electrophysiology to measure neuronal excitability. Finally, targeted pharmacological interventions were used to test the functional contribution of this signaling pathway. MHb neurons exhibited marked hypoactivity and pathological changes in MK-801-treated rats. Single-cell RNA sequencing and histological analyses indicated that MHb neurons are the predominant cellular source of the pathological IL-18 signal in this model. Functionally, neuron-specific IL-18 overexpression was sufficient to induce schizophrenia-like behavioral abnormalities, whereas its knockdown ameliorated negative-like and cognitive deficits. Mechanistically, our data support a model in which elevated neuronal IL-18 is associated with ERK overactivation, reduced BDNF expression, and neuronal hypoactivity. Furthermore, pharmacological inhibition of the ERK pathway in the MHb ameliorated deficits at the molecular (BDNF), cellular (neuronal firing), and behavioral levels. Our findings support a neuron-centered IL-18/ERK/BDNF signaling framework in the MHb that contributes to schizophrenia-like pathological changes in this model and warrants further preclinical investigation as a potential target for cognitive and negative symptoms relevant to schizophrenia.