Nauclea officinalis extract rescues working memory deficits in adolescent maternal immune activation offspring by restoring cholinergic signaling

Abstract

Objective Maternal immune activation (MIA) is a key risk factor for schizophrenia-related cognitive deficits, linked to prefrontal cholinergic dysfunction. Nauclea officinalis extract (NOE) possesses documented anti-inflammatory and neuroprotective properties, but its effects on MIA-induced cognitive and neuronal dysfunctions are unknown. This study aimed to investigate whether NOE ameliorates MIA-induced working memory deficits by modulating infralimbic medial prefrontal cortex (IL-mPFC) cholinergic signaling and neuronal activity. Methods Using a poly (I:C)-induced MIA rat model, adolescent offspring were treated with NOE (5, 10 and 20 mg/kg). Behavioral tests, in vivo electrophysiology, and molecular assays were conducted. Results NOE dose-dependently attenuated MIA-induced neuroinflammation (IL-1β, IL-6, TNF-α) in the IL-mPFC. It restored acetylcholine (ACh) levels, reduced acetylcholinesterase (AChE) activity, but did not alter M1/M3 receptor expression. NOE (20 mg/kg) significantly improved 30-s delay working memory performance, an effect blocked by the muscarinic receptor antagonist scopolamine (SCO) and mimicked by the AChE inhibitor physostigmine (PHY). Electrophysiologically, NOE rescued MIA-impaired long-term potentiation (LTP) and paired-pulse ratio (PPR), and enhanced delay-related firing of IL pyramidal neurons. These restorative effects were similarly replicated by PHY and antagonized by SCO. Conclusion NOE alleviates MIA-induced working memory deficits by reducing neuroinflammation and, crucially, by functionally potentiating cholinergic transmission in the IL-mPFC. The findings highlight the IL cholinergic system as a critical therapeutic target and position NOE as a promising multi-target agent for cognitive impairments in neurodevelopmental disorders.