Circadian changes in CA1 LTP are driven by shifts in excitation–inhibition balance and reverse direction after puberty in mice.

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–CA1 synapse in mice of all sexes indicates that the capacity to support LTP does not differ between the light and dark phases 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. On the other hand, LTD induced with low-frequency stimulation did not change across the circadian cycle. Consistent with a causal relationship between the E/I ratio and TBS-LTP, blockade of inhibition abolishes the light–dark difference in TBS-LTP induction. Likewise, pairing-induced LTP, which is not constrained by inhibitory recruitment, does not differ between cycles. Supporting this model, in the APP/PS1 model of AD we found that neither the E/I ratio nor TBS-LTP varies across the light–dark cycle, despite preserved circadian regulation of locomotor activity. 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. Significance statement Long-term potentiation (LTP) is strongly shaped by circadian rhythms and is typically greater during the dark phase in nocturnal rodents. At the CA3-CA1 synapse, we find that the intrinsic capacity to support LTP is similar across light and dark periods; instead, multiple independent lines of evidence indicate that a daily oscillation in excitation-inhibition (E/I) balance is the primary drivers of the circadian changes in LTP induction. Notably, in the APP/PS1 model of Alzheimer's disease, neither the E/I ratio nor TBS-LTP varies across the day. Finally, we identify a developmental switch in which the direction of these oscillations reverses between two and eight months of age, highlighting an age-dependent reorganization of circadian regulation of hippocampal plasticity in both health and disease.