Interplay of multiple pathways and activity-dependent rules in STDP

Hebbian plasticity describes a basic mechanism for synaptic plasticity whereby synaptic weights evolve depending on the relative timing of paired activity of the pre- and postsynaptic neurons. Spike-timing-dependent plasticity (STDP) constitutes a central experimental and theoretical synaptic Hebbian learning rule. Various mechanisms, mostly calcium-based, account for the induction and maintenance of STDP. Classically STDP is assumed to gradually emerge in a monotonic way as the number of pairings increases. However, non-monotonic STDP accounting for fast associative learning led us to challenge this monotonicity hypothesis and explore how the existence of multiple plasticity pathways affects the dynamical establishment of plasticity. To account for distinct forms of STDP emerging from increasing numbers of pairings and the variety of signaling pathways involved, we developed a general class of simple mathematical models of plasticity based on calcium transients and accommodating various calcium-based plasticity mechanisms. These mechanisms can either compete or cooperate for the establishment of long-term potentiation (LTP) and depression (LTD), that emerge depending on past calcium activity. Our model reproduces accurately the striatal STDP that involves endocannabinoid and NMDAR signaling pathways. Moreover, we predict how stimulus frequency alters plasticity, and how triplet rules are affected by the number of pairings. We further investigate the general model with an arbitrary number of pathways and show that depending on those pathways and their properties, a variety of plasticities may emerge upon variation of the number and/or the frequency of pairings, even when the outcome after large numbers of pairings is identical. These findings, built upon a biologically realistic example and generalized to other applications, argue that in order to fully describe synaptic plasticity it is not sufficient to record STDP curves at fixed pairing numbers and frequencies. In fact, considering the whole spectrum of activity-dependent parameters could have a great impact on the description of plasticity, and a better understanding of the engram.Author summary: The brain’s capacity to treat information, learn and store memory relies on synaptic connectivity patterns, which are altered through synaptic plasticity mechanisms. Experimentally, such plasticities were evidenced through protocols involving numerous repetitive stimulations of a given synapse, and were shown to be supported by multiple pathways. Using a simple biologically grounded mathematical model, we show how activation timescales and inactivation levels of each pathway interact and alter plasticity in an intricate manner as stimuli are presented. Building upon data from the synapse between cortex and striatum, we show that synaptic changes may revert or re-emerge as stimuli are presented, and predict specific responses to changes in stimulus frequency or to distinct simulation patterns. Our general model shows that a given plasticity profile emerging in response to a repetitive stimulation protocol can unfold into various scenarii upon variations of the number of stimulus presentations or patterns, which tightly depends on the underlying activated pathways. Altogether, these results argue that in order to better understand learning and memory, single plasticity responses obtained through intensive stimulations do not reveal the complexity of the responses for smaller number of presentations, which may have a strong impact in fast learning of stimuli with low numbers of presentations.