Cholinergic inhibition disrupts retrieval-specific phosphorylation of CaMKII-α and CaMKII-β alongside ERK hyperactivation in the hippocampus during novel object recognition memory.

BACKGROUND

Alzheimer's disease (AD), the most common form of dementia, is characterized by cholinergic dysfunction and early impairments in episodic and recognition memory. Although retrieval failure represents a hallmark of cognitive decline in AD, the task- and phase-specific molecular mechanisms underlying cholinergic-dependent memory retrieval remain poorly defined.

OBJECTIVE

This study investigated whether acute muscarinic cholinergic blockade disrupts the retrieval phase of recognition memory. We also examined the associated regulation of hippocampal calcium/calmodulin-dependent protein kinase II (CaMKII) isoforms α and β, together with extracellular signal-regulated kinase (ERK) signaling.

METHODS

Adult male SWR/J mice were trained in the NOR paradigm and administered scopolamine (1 mg/kg, i.p.) or saline 30 min prior to the retrieval phase. Recognition memory performance was assessed using the discrimination index and exploratory preference. Immediately following behavioral testing, hippocampal tissue was collected for Western blot analysis of phosphorylated and total CaMKII-α, CaMKII-β, and ERK.

RESULTS

Scopolamine significantly impaired recognition memory retrieval, as evidenced by a reduced discrimination index and decreased preference for the novel object, without diminishing overall exploratory activity. At the molecular level, scopolamine-induced cholinergic inhibition selectively decreased hippocampal phosphorylation of both CaMKII-α and CaMKII-β while increasing ERK phosphorylation, with no significant changes in total protein expression of any kinase.

CONCLUSIONS

These findings identify a retrieval-specific, scopolamine-induced molecular signature of cholinergic inhibition in the hippocampus, characterized by concurrent suppression of both CaMKII isoform activities (α and β) alongside dissociable ERK hyperactivation. By extending prior molecular observations from aversively motivated paradigms to an ethologically relevant model of recognition memory, this study provides mechanistic insight into how cholinergic dysfunction contributes to memory retrieval deficits and suggests that cholinergic signaling maintains the functional (CaMKII-α) and structural (CaMKII-β) dimensions of hippocampal memory retrieval machinery through coordinated kinase activation.