Abstract
Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3 to CA1 synapse provides evidence that the capacity to express LTP does not differ between the light and dark cycles of the 24-hour day. Instead, the magnitude of theta-burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. Consistent with a causal relationship, blockade of inhibition abolishes the light-dark difference in TBS-LTP induction, likewise, pairing-induced LTP, which is less constrained by inhibitory recruitment, does not differ between cycles. Supporting this model, using the APP/PS1 model of AD we observed that neither the E/I ratio nor TBS-LTP change during the light cycle. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.