Low-Frequency-Induced Synaptic Potentiation: a Paradigm Shift in the Field of Memory-Related Plasticity Mechanisms?
Long-Term Potentiation , Hippocampus
It is assumed that plasticity involving up-and down regulation of synaptic strength (i.e., long-term potentiation, LTP; long-term depression, LTD) mediates learning and memory processes. Typically, high-frequency stimulation (HFS) of afferent fibers results in LTP, while low-frequency stimulation (LFS) elicits LTD. In stark contrast to this “HFS- LTP vs. LFS-LTD” dogma, the present thesis characterizes a novel form of LFS-induced LTP in the septohippocampal system. The first set of experiments show that alternating, single pulse stimulation (1 Hz) of the medial septum (MS) and CA3 hippocampal (H) commissural fibres results in a long-lasting potentiation of field excitatory postsynaptic potentials (fEPSPs) in CA1 of urethane-anesthetised rats (MS-H-LTP). MS-H LTP is long lasting (>5 h), requires a specific inter-stimulus interval of 1 s between MS and CA3 stimulation, saturates with repeated stimulation episodes and depends on NMDA receptor activation. In the third chapter (review) I suggest that LFS protocols may more accurately mimic some oscillatory activity patterns (~ 1Hz) present in hippocampal and neocortical circuits during sleep-related memory consolidation. Moreover, I compare the mechanisms underlying classical, HFS-LTP to those mediating MS-H LTP as well as several other types of LFS-LTP in the hippocampus and amygdala in vitro. Subsequently, I investigated cellular mechanisms of MS-H LTP and their similarity to classical HFS-LTP via drug application at the CA1 recording site and showed that MS-H LTP depends on protein kinase A and protein synthesis. This surprising similarity between mechanisms mediating HFS-LTP and MS-H LTP was further supported by occlusion experiments whereby LFS and HFS, delivered to the same animal, competed for the available synaptic potentiation of CA3-CA1 synapses. The final experiments showed that MS-H LTP is compromised in early aged rats, while similar levels of potentiation are expressed in the juvenile and adult hippocampus. Interestingly, MS-H LTP could not be induced (i.e., was occluded) 3 h after training on the hidden platform version of the Morris water maze, while it was unaltered at 8 and 24 h intervals. This thesis characterizes a novel form of hippocampal plasticity at the cellular, synaptic and behavioural level and suggests that LFS-LTP may mediate processes of sleep-related memory consolidation.