Cholinergic modulation on spike timing-dependent plasticity in hippocampal CA1 network

Cholinergic inputs from the medial septum are projected to pyramidal neurons in the hippocampal CA1 region and release acetylcholine (ACh) from their terminals. The cholinergic inputs are considered to be integrated with sensory inputs and to play a crucial role in learning and memory. Meanwhile, it has been reported that the relative timing between pre- and post-synaptic spiking determines the direction and extent of synaptic changes in a critical temporal window, a process known as spike timing-dependent plasticity (STDP). Positive timing where excitatory postsynaptic potential (EPSP) precedes the postsynaptic action potential induces long-term potentiation (LTP) while negative timing where EPSP follows the action potential induces long-term depression (LTD). To investigate the influence of muscarinic activation by cholinergic inputs on synaptic plasticity, STDP-inducing stimuli were applied during the muscarinic induction of a slow EPSP followed by repetitive stimulation in the stratum oriens. As a result, LTP was facilitated and LTD was abolished by the muscarinic activation. Furthermore, interestingly, LTP was also facilitated and LTD was switched to LTP with an increase in ACh concentration following application of the cholinesterase inhibitor eserine. These results indicate that the orientation of plasticity was shifted for potentiation by muscarinic activation. On the other hand, the application of excess ACh concentration completely suppressed STDP, LTP and LTD. In addition, STDP was suppressed in the presence of atropine, a muscarinic ACh receptor antagonist. Taken together, the findings suggest that synaptic plasticity modulation depends on the amount of cholinergic inputs. The modulation of synaptic plasticity by muscarinic activation might be an important stage in the integration of top-down and bottom-up information in hippocampal CA1 neurons.