cGKI supports Schaffer-collateral LTP and facilitates hippocampus- dependent memory formation

Synaptic plasticity, a crucial determinant of learning and memory consolidation, is determined by dynamic modulation of synaptic transmission efficiency. Previous studies highlighted the involvement of 3',5'-cyclic guanosine monophosphate (cGMP)-dependent protein kinase I (cGKI) in synaptic plasticity and cognitive functions; its postsynaptic role, however, remains insufficiently characterized and requires further elucidation. We explore cGKI's contribution to activity-dependent hippocampal synaptic transmission and hippocampus-dependent memory formation using CA1 pyramidal neuron-specific knockout mice (CA1-cGKI-KO) and litter-matched controls (CA1-cGKI-CTRL).

Hippocampal CA1-specific cGKI depletion was confirmed by Western blot and immunofluorescence. In accordance with a significant function of cGKI in spatial memory formation, CA1-cGKI-KO were incapable to develop goal-directed target localization strategies in the Morris Water Maze coupled with deficits in memory acquisition. These learning impairments were consistent with significantly hampered electrically-induced CA3 to CA1 Schaffer-collateral long-term potentiation (LTP) in CA1-cGKI-KO brain slices. This finding was completed by reduced phosphorylation of the AMPAR subunit GluA1 at S845 in slices from CA1-cGKI-cKO compared to CA1-cGKI-CTRL after chemically induced LTP (cLTP). Additional application of the cGMP-elevating pharmacological agents cinaciguat and vardenafil during cLTP augmented GluA1 S845 phosphorylation exclusively in CA1-cGKI-CTRL, but not CA1-cGKI-cKO. Furthermore, cLTP increased the neuronal Ca ²⁺-oscillation frequency recorded using FURA-2AM in primary hippocampal neurons. This effect was amplified by cinaciguat, vardenafil and 8-Br-cGMP.

Based on these findings, we suggest that cGKI regulates hippocampal synaptic plasticity by controlling oscillatory Ca ²⁺ influx during LTP. This suggests cGMP/cGKI has the potential to serve as a pharmacological target for the treatment of cognitive impairment.