Increased Ih Current Is Associated with Reduced Hippocampal CA1 Excitability in a Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by demyelination and neurodegeneration, often accompanied by cognitive and emotional impairments. To investigate neuronal alterations associated with neuropsychiatric disorders, we investigated intrinsic excitability and synaptic properties of hippocampal CA1 pyramidal neurons in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Whole-cell patch-clamp recordings were performed in acute hippocampal slices from presymptomatic and symptomatic female EAE mice and complete Freund's adjuvant-treated controls. Intrinsic properties were significantly altered in symptomatic EAE mice, with a reduction in firing frequency associated with ∼24% decrease in input resistance (Rin). However, action potential threshold, rheobase, and amplitude remained unaltered. Synaptic transmission was also preserved, as spontaneous excitatory and inhibitory postsynaptic current frequency and amplitude, along with paired-pulse ratio, showed no significant differences across groups. Importantly, we found that hyperpolarization-activated (Ih) currents, key regulators of neuronal excitability that have been implicated in neuropsychiatric disorders, were enhanced in symptomatic EAE mice, correlating with the observed decreased Rin. Pharmacological isolation of Ih currents using the blocker ZD7288 confirmed this increase. Western blots from the EAE hippocampal tissue revealed elevated HCN1 expression, a major Ih-conducting channel subunit in CA1 pyramidal neurons, in symptomatic EAE. Together, these findings indicate that upregulated Ih is associated with reduced Rin and may contribute to limiting neuronal excitability in the hippocampus of symptomatic EAE, independent of changes in excitatory and inhibitory synaptic transmission. This intrinsic adaptation may contribute to hippocampal dysfunction associated with MS, highlighting Ih modulation as a potential therapeutic target.