ASTROCYTES IN NORADRENERGIC MODULATION OF HIPPOCAMPAL EXCITABILITY: FROM SYNAPSE TO SEIZURE

Epilepsy is characterized by a disrupted excitation–inhibition (E/I) balance, which is regulated by neuromodulators such as noradrenaline. The mechanisms of noradrenergic signaling in epilepsy, particularly via astrocytic α1A-noradrenaline receptors (α1A-NARs), remain unclear. This study aims to determine how astrocytic α1A-NAR activation modulates the E/I balance.
Electrically evoked field postsynaptic potentials (fPSPs) were recorded in the CA1 and DG of hippocampal slices using a multielectrode array. The effect of an α1A-NAR agonist, A61603 hydrobromide (1µM), on the fPSP slope was evaluated in healthy tamoxifen-inducible astrocyte-specific α1A-NAR conditional knockout (cKO) and wild-type (WT) littermate mice. To induce epilepsy, WT and cKO mice were injected with kainic acid (intrahippocampal). EEG monitoring was used to evaluate seizure frequency in WT and cKO mice for 5 weeks and study the effect of A61603 (20µg/kg, intraperitoneal). Locomotor side effects were assessed using a rotarod.
A61603 reduced the fPSP slope in CA1 (n=5, p<0.001) and increased the fPSP2/fPSP1 ratio in CA1 and DG in WT mice only (p<0.001). WT mice experienced less seizures in week 5 post-tamoxifen treatment compared to cKO mice (n=11, p<0.01). A61603 suppressed seizures for 2 hours in WT and cKO mice (p<0.001). Rotarod performance was impaired in WT and cKO mice after A61603 injection (WT: n=7, p<0.05; cKO: n=5, p<0.01).
These findings suggest that the astrocytic α1A-NAR is critical in controlling noradrenergic effects by reducing synaptic strength in CA1. Astrocytic α1A-NAR activation during the chronic phase of epilepsy seems protective against seizure generation. A61603 injection suppresses seizures, but induces locomotor side effects.