ROLE OF EXTRACELLULAR MATRIX FIBRONECTIN-1 IN COGNITIVE IMPAIRMENT IN EXPERIMENTAL TEMPORAL LOBE EPILEPSY

Introduction: Cognitive and memory impairments are common and debilitating comorbidities of temporal lobe epilepsy (TLE), often persisting despite adequate seizure control. While neuronal hyperexcitability is well studied, the contribution of extracellular matrix (ECM) remodelling to epilepsy-associated cognitive dysfunction remains poorly understood. Fibronectin-1 (FN1), an ECM glycoprotein upregulated following seizures, modulates synaptic excitability and plasticity through integrin-dependent signalling. We hypothesised that FN1 contributes to cognitive deficits in TLE and that blocking FN1–integrin interactions would improve cognitive outcomes.
Methods: TLE was induced in adult rats using the Li-pilocarpine model, which recapitulates chronic seizures and hippocampal-dependent cognitive impairment. Cognitive and memory functions were assessed using the Open Field Test, Novel Object Recognition Test and Morris water maze to evaluate spatial learning, reference memory, and working memory. FN1 signalling was inhibited by intracranial administration of the FN1-blocking RGD peptide during the chronic phase of epilepsy. Behavioural outcomes were compared between control, TLE, and RGD-treated TLE groups.
Results: Li-pilocarpine–treated animals exhibited significant impairments in spatial learning, reduced memory retention, and decreased spontaneous alternation behaviour compared to controls, confirming robust cognitive dysfunction in TLE. Notably, RGD treatment resulted in significant improvement in spatial learning and memory performance, with partial restoration of working memory. These behavioural improvements occurred without overt adverse effects.
Conclusion: Our findings demonstrate that FN1-mediated ECM signalling contributes to cognitive and memory dysfunction in TLE. Pharmacological inhibition of FN1–integrin interactions using an RGD peptide improves cognitive outcomes, identifying FN1 as a potential therapeutic target for addressing cognitive comorbidities in ​TLE.