Improving effects of melatonin on memory and synaptic potentiation in a mouse model of Alzheimer's-like disease: the involvement of glutamate homeostasis and mGluRs receptors.

BACKGROUND

Alzheimer's disease (AD) is characterized by progressive cognitive decline and synaptic dysfunction, largely driven by amyloid plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. These pathological hallmarks disrupt glutamate signaling, which is essential for synaptic plasticity and memory consolidation. This study investigates the therapeutic potential of melatonin on memory and synaptic plasticity in an AD-like mouse model, with a focus on its regulatory effects on glutamate homeostasis and metabotropic glutamate receptors (mGluRs).

METHODS

The study began with an in-silico bioinformatics analysis of RNA-seq datasets from hippocampal tissues of AD patients to identify differentially expressed genes (DEGs) related to glutamate signaling and tau pathology. An AD-like model was induced via intra-hippocampal injection of cis-phospho tau in C57BL/6 mice. Memory function was assessed using behavioral tests. Synaptic plasticity was evaluated using in vitro field potential recording of hippocampal slices. Histological analyses included Nissl staining for neuronal density, Luxol Fast Blue for myelin integrity, and immunofluorescence for tau hyperphosphorylation. Molecular studies employed qPCR and Western blot to assess glutamate-related markers and tau phosphorylation. Melatonin (10 mg/kg) was administered intraperitoneally, starting either two weeks (early intervention) or four weeks (late intervention) post-induction.

RESULTS

Key molecular targets in glutamate signaling pathways were identified using bioinformatics. AD-like mice displayed memory deficits and synaptic dysfunction. Melatonin improved cognitive function, especially with early intervention, as confirmed by behavioral tests. Histological studies revealed reduced neuronal loss, improved myelin integrity, and decreased tau hyperphosphorylation. Molecular findings showed restored mGluR expression and reduced GSK3 activity. Early intervention yielded superior outcomes, with partial restoration of synaptic plasticity observed in LTP recordings.

CONCLUSIONS

These findings underscore the neuroprotective properties of melatonin, mediated by its ability to modulate glutamate signaling and mGluR activity, offering new insights into its potential as a therapeutic agent for AD. Additionally, the results suggest that earlier administration of melatonin may significantly enhance its efficacy, highlighting the importance of timely intervention in neurodegenerative diseases.