Pathway-specific hippocampal plasticity gated by theta-frequency medial septal stimulation

The medial septal area (MSA) plays a crucial role in modulating hippocampal function through cholinergic signaling, yet how physiologically patterned MSA activity shapes synaptic plasticity in hippocampal-entorhinal cortex (EC) circuits remains unclear. Here, we investigated in vivo the effects of theta-frequency MSA stimulation (4 Hz and 7 Hz) on synaptic transmission at two key hippocampal pathways: the lateral perforant path (LPP) to dentate gyrus (DG) and the temporoammonic path (TAP) to CA1. Using in vivo electrophysiology in urethane-anesthetized rats, we found that prolonged 7 Hz MSA stimulation induced postsynaptic potentiation at LPP and TAP, as evidenced by an unchanged paired-pulse ratio (PPR). The potentiation was stronger at LPP-DG synapses than at TAP-CA1 synapses. In contrast, 4 Hz stimulation did not alter synaptic efficacy at either pathway. The synaptic potentiation at LPP-DG synapses was abolished by depletion of MSA cholinergic neurons with 192IgG-saporin, confirming its dependence on intact cholinergic neurons in the MSA. Our results suggest that the septohippocampal system employs frequency-tuned cholinergic signaling to gate cortical-hippocampal communication, with 7 Hz oscillations enhancing transmission most strongly at LPP-DG synapses and to a lesser degree at TAP-CA1 synapses.