MEK-ERK inhibition enhances synaptic input-output coupling and neuronal excitability in the rat dentate gyrus:...

Synaptic plasticity in the dentate gyrus requires a balance between synaptic transmission and excitability. Although the mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling pathway is well known for its role in long-term plasticity, its function in the regulation of excitatory postsynaptic potential-to-spike (E-S) coupling remains comparatively underexplored. In this study, 40 adult male Wistar albino rats were used to investigate the effects of MEK-ERK inhibition on changes in synaptic transmission, neuronal excitability, and Kv4.2 potassium channel phosphorylation following low-frequency stimulation (LFS) in the in vivo hippocampus. Field potentials were recorded from the dentate gyrus in response to medial perforant pathway stimulation. Inhibition of MEK with PD98059 did not alter basal field excitatory postsynaptic potential (fEPSP) slopes but significantly increased population spike (PS) amplitudes. Under LFS, MEK-ERK inhibition paradoxically increased neuronal output while decreasing excitatory synaptic input, indicating enhanced E-S coupling between synaptic input and output. Western blot analyses confirmed reduced ERK phosphorylation without changes in total ERK levels after PD98059 application. Despite decreased ERK activity, phosphorylation of Kv4.2 increased at specific sites: Thr602 was elevated selectively under LFS, whereas Thr607 increased independently of stimulation. A significant main effect of decreased total Kv4.2 protein levels was also observed. These findings indicate that the MEK-ERK pathway differentially modulates synaptic transmission and neuronal excitability in the dentate gyrus. Site-specific Kv4.2 phosphorylation at Thr602/Thr607, together with reduced total Kv4.2 expression, may contribute to the observed E-S potentiation. This mechanism may underlie hyperexcitability associated with neurological disorders.