MECHANISMS OF LONG-TERM DEPRESSION AT ENTORHINAL CORTEX LAYER III–CA1 SYNAPSES

Learning and memory require coordinated processing within the hippocampus and entorhinal cortex, which integrate sensory, spatial, and temporal information. Synapses between entorhinal cortex layer III (ECIII) neurons and CA1 pyramidal cells are essential for temporal associative memory and may be involved in Alzheimer’s disease. We investigated the mechanisms of long-term depression (LTD) at ECIII–CA1 synapses using whole-cell patch-clamp recordings in acute mouse hippocampal slices. LTD was induced with paired-pulse low-frequency stimulation (900 pairs at 1 Hz, 40 ms inter-pulse interval), producing robust synaptic depression (53±9%, n=7) without changes in paired-pulse ratio, indicating postsynaptic expression. Postsynaptic NMDA receptor blockade with MK-801 prevented LTD (91±4%, n=6), and inhibition of group I metabotropic glutamate receptors showed that mGluR1, but not mGluR5, is required (LY367385: 125±10%, n=5; MPEP: 88±17%, n=6). Postsynaptic calcium signaling was necessary, as chelation with BAPTA (98±10%, n=7), L-type channel blockade with nimodipine (118±12%, n=6), or inhibition of Ca²⁺ release from stores with thapsigargin (115±18%, n=5) abolished LTD. Interference with postsynaptic endocannabinoid signaling (U = 1, n=6) also abolished LTD, suggesting receptor-mediated involvement. Astrocytic Ca²⁺ chelation prevented LTD, whereas bath application of D-serine restored it, indicating a key modulatory role of astrocytes. Together, these results demonstrate that LTD at ECIII–CA1 synapses is postsynaptically expressed and relies on NMDAR and mGluR1 activation, postsynaptic calcium dynamics, endocannabinoid receptor signaling, and astrocytic modulation, providing insight into mechanisms that may underlie memory processing and disease-related synaptic dysfunction.