Frequency dependency of NMDA receptor-dependent synaptic plasticity in the hippocampal CA1 region of freely behaving mice

Hippocampal synaptic plasticity in the form of long-term potentiation (LTP) and long-term depression (LTD) is likely to enable synaptic information storage in support of memory formation. The mouse brain has been subjected to intensive scrutiny in this regard; however, a multitude of studies has examined synaptic plasticity in the hippocampal slice preparation, whereas very few have addressed synaptic plasticity in the freely behaving mouse. Almost nothing is known about the frequency or N-methyl-D-aspartate receptor (NMDAR) dependency of hippocampal synaptic plasticity in the intact mouse brain. Therefore, in this study, we investigated the forms of synaptic plasticity that are elicited at different afferent stimulation frequencies. We also addressed the NMDAR dependency of this phenomenon. Adult male C57BL/6 mice were chronically implanted with a stimulating electrode into the Schaffer collaterals and a recording electrode into the Stratum radiatum of the CA1 region. To examine synaptic plasticity, we chose protocols that were previously shown to produce either LTP or LTD in the hippocampal slice preparation. Low-frequency stimulation (LFS) at 1 Hz (900 pulses) had no effect on evoked responses. LFS at 3 Hz (ranging from 200 up to 2 × 900 pulses) elicited short-term depression (STD, <45 min). LFS at 3 Hz (1,200 pulses) elicited slow-onset potentiation, high-frequency stimulation (HFS) at 100 Hz (100 or 200 pulses) or at 50 Hz was ineffective, whereas 100 Hz (50 pulses) elicited short-term potentiation (STP). HFS at 100 Hz given as 2 × 30, 2 × 50, or 4 × 50 pulses elicited LTP (>24 h). Theta-burst stimulation was ineffective. Antagonism of the NMDAR prevented STD, STP, and LTP. This study shows for the first time that protocols that effectively elicit persistent synaptic plasticity in the slice preparation elicit distinctly different effects in the intact mouse brain. Persistent LTD could not be elicited with any of the protocols tested. Plasticity responses are NMDAR dependent, suggesting that these phenomena are relevant for hippocampus-dependent learning.