Neurons remodel the structure and strength of their synapses during critical periods of development in order to optimize both perception and cognition. Many of these developmental synaptic changes are thought to occur through synapse-specific homosynaptic forms of experience-dependent plasticity. However, homosynaptic plasticity can also induce or contribute to the plasticity of neighboring synapses through heterosynaptic interactions. Decades of research in vitro have uncovered many of the molecular mechanisms of heterosynaptic plasticity that mediate local compensation for homosynaptic plasticity, facilitation of further bouts of plasticity in nearby synapses, and cooperative induction of plasticity by neighboring synapses acting in concert. These discoveries greatly benefited from new tools and technologies that permitted single synapse imaging and manipulation of structure, function, and protein dynamics in living neurons. With the recent advent and application of similar tools for in vivo research, it is now feasible to explore how heterosynaptic plasticity contribute to critical periods and the development of neuronal circuits. In this review, we will first define the forms heterosynaptic plasticity can take and describe our current understanding of their molecular mechanisms. Then, we will outline how heterosynaptic plasticity may lead to meaningful refinement of neuronal responses and observations that suggest such mechanisms are indeed at work in vivo. Finally, we will use a well-studied model of cortical plasticity—ocular dominance plasticity during a critical period of visual cortex development—to highlight the molecular overlap between heterosynaptic and developmental forms of plasticity, and suggest potential avenues of future research.

During sleep, memories formed during the day are consolidated in a dialogue between cortex and hippocampus. The reactivation of specific neural activity patterns -replay -during sleep has been observed in both structures and is hypothesized to represent a neuronal substrate of consolidation. In the hippocampus, replay happens during sharp wave -ripples (SWR), short bouts of excitatory activity in area CA3 which induce high frequency oscillations in area CA1. In particular, recordings of hippocampal cells which spike at a specific location ('place cells') show that recently learned trajectories are reactivated during SWR in the following sleep SWR. Despite the importance of sleep replay, its underlying neural mechanisms are still poorly understood.We developed a model of SWR activity, to study the effects of learning-induced synaptic changes on spontaneous sequence reactivation during SWR. The model implemented a paradigm including three epochs: Pre-sleep, learning and Post-sleep activity. We first tested the effects of learning on the hippocampal network activity through changes in a minimal number of synapses connecting selected pyramidal cells. We then introduced an explicit trajectory-learning task to the model, to obtain behaviorinduced synaptic changes. The model revealed that the recently learned trajectory reactivates during sleep more often than other trajectories in the training field. The study predicts that the gain of reactivation rate during sleep following vs sleep preceding learning for a trained sequence of pyramidal cells depends on Pre-sleep activation of the same sequence, and on the amount of trajectory repetitions included in the training phase.

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Experience‐dependent plasticity refers to the brain’s ability to sculpt and remodel its circuits in an experience‐dependent manner. In the binocular visual cortex, where inputs from both eyes converge onto single neurons, the relative responsiveness of a neuron to input from one eye can shift when that eye is deprived of input. Ocular dominance plasticity (ODP) is a well‐established model for experience‐dependent plasticity, and it is triggered by monocular deprivation (MD) by suturing an eyelid. This shift is classically measured by calculating the ocular dominance index (ODI), a measure of responsiveness to either eye. The cellular and molecular mechanisms for this reorganization during ODP are not well understood. We hypothesize that morphological and molecular changes at dendritic spines (synapses) allow for functional reprogramming of neurons. To test this, we introduced a plasmid into binocular neurons via single‐cell electroporation that encodes for the calcium sensor GCaMP6s, together with a structural marker mRuby2. Using two‐photon microscopy, spines were imaged in vivo in awake mice to determine their ODIs. We then imaged at later time points during MD to measure how spine size and their responsiveness was affected. Finally, the same neurons were visualized using magnified analysis of proteome (MAP), which evenly expanded tissue by 4X to closely examine scaffolding and transmission‐related proteins at the postsynaptic density. Preliminary data suggests that a combination of extensive spine loss and potentiation of few specific spines allows for shifts in responsiveness. In addition to synaptic plasticity being important for learning and memory in adulthood, many autism spectrum disorders (ASDs) have been associated with mutations in synaptic proteins. Investigation of the molecular mechanisms behind changes in synaptic morphology are therefore important to better understand the mechanisms of learning and memory, as well as these disorders. Support or Funding Information This research was supported by:IMSD R25GM076321 (JZ)NIH grants EY007023 and EY028219 (MS).