Homeostatic Control of Hebbian Plasticity Exerted by Action Potential‐Mediated Metaplasticity

Hebbian plasticity, in particular long-term potentiation (LTP) of excitatory synapses, is a positive feed-back mechanism and has the potential to saturate its effects with negative consequences at both the single neuron and the circuit level. Metaplasticity is one of the mechanisms that can help overcome this problem. During one form of metaplasticity, a high (or low) level of neuronal activity impedes (or favors) the expression of future LTP. Although much is known about the role of synaptic activity in driving this metaplasticity effect, the specific role of postsynaptic action potential (AP) firing activity is still controversial and largely unknown. Experimentally, a high level of AP firing has resulted in either the suppression (a pro-homeostatic effect) or the enhancement (an anti-homeostatic effect) of a later induced LTP. Accordingly, we tested a wide range of AP firing frequencies generated by postsynaptic current pulses at different time intervals relative to the time of LTP induction at Schaffer collateral synapses of hippocampal CA1 neurons in Sprague-Dawley rats. We found that a wide range of AP firing frequencies, from 3 to 90 Hz, consistently inhibited the expression of future LTP at all time intervals tested, with no modulation of NMDA glutamate receptors. Moreover, the generation of APs, as opposed to the average level of somatic depolarization during priming, was necessary for triggering the metaplasticity. Our results provide solid evidence for a pro-homeostatic metaplasticity that is engaged by postsynaptic AP firing, thus impeding the saturation of Hebbian plasticity and associated hyperexcitability.