Abstract

Olfactory dysfunction is one of the most consistent and earliest sensory abnormalities observed in schizophrenia, often preceding the onset of overt psychotic symptoms and reflecting central neural circuit dysfunction rather than peripheral sensory loss. Growing evidence suggests that olfactory deficits may provide a unique window into the molecular and cellular mechanisms underlying disease vulnerability. In this hypothesis-driven framework, we propose that schizophrenia arises, in part, from the convergence of disrupted GNAL-mediated signaling, impaired inhibitory Gαi/o pathways and inflammation-associated dysregulation of phosphoinositide 3-kinase delta (PI3Kδ). We suggest that altered GNAL-dependent cAMP signaling contributes to deficits in sensory and dopaminergic amplification, while impaired Gαi/o signaling represents a primary driver of excitatory/inhibitory imbalance underlying cognitive and psychotic symptoms. Concurrently, chronic inflammatory states may destabilize PI3Kδ signaling, indirectly influencing olfactory and cortical neural function. Impaired neural resilience within olfactory circuits, including reduced Sirt1-dependent neurogenic support and genomic stability, may further exacerbate early olfactory dysfunction. Together, this integrative model provides a testable mechanistic link between peripheral inflammatory processes, olfactory system vulnerability and central inhibitory signaling deficits in schizophrenia, with implications for early biomarker development and novel therapeutic targeting.

Keywords: Olfactory dysfunction; GNAL signaling; Gαi/o inhibitory pathways; PI3Kδ dysregulation; Schizophrenia pathophysiology