AGING LIMITS ADAPTIVE HIPPOCAMPAL NETWORK EXCITABILITY IN NEUROINFLAMMATORY DISEASE​

Background: Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), involve neuroinflammation that impairs neuronal function beyond demyelination, including altered synaptic transmission, excitation–inhibition balance, and network stability. The hippocampus is particularly susceptible because inflammation can disrupt circuit dynamics and synaptic plasticity essential for cognition. How aging shapes the timing of network vulnerability across EAE phases remains unclear.

Objective: To test whether the progression of hippocampal and cortico-hippocampal network hyperexcitability during EAE differs between young and aged mice.

Methods: Multielectrode arrays (MEA) recorded spontaneous extracellular activity from acute hippocampal slices (analyses focused on hippocampal network readouts) at two disease stages: T1 (Dmax; approximately 14–18 days post-immunization, representing peak clinical symptoms) and T2 (approximately 3–4 weeks post-immunization). After baseline recording, extracellular KCl was increased stepwise (5 mM, 7.5 mM), followed by 4-aminopyridine (4-AP) as a positive control. Primary outcomes were firing rate, burst structure, and network synchrony.

Results: In young EAE mice (8 weeks), hippocampal networks showed increased excitability at T1, reflected by higher firing/bursting and stronger synchronization during the potassium ramp, but this phenotype attenuated by T2, approaching control-like levels. In aged EAE mice (10 months), networks were near-control-like at T1 but exhibited a delayed increase in excitability at T2. 4-AP robustly activated networks in all groups, indicating preserved recruitment capacity.

Conclusion: Aging shifts the temporal window of hippocampal network dysfunction in EAE. A standardized potassium-ramp MEA assay enables quantitative comparison of age-dependent changes in circuit recruitment across peak and chronic neuroinflammation.