Learning and memory depend on neuronal plasticity originating at the synapse and requiring nuclear gene expression to persist. However, how synapse-to-nucleus communication supports long-term plasticity and behavior has remained elusive. Among cytonuclear signaling proteins, γCaMKII stands out in its ability to rapidly shuttle Ca2+/CaM to the nucleus and thus activate CREB-dependent transcription. Here we show that elimination of γCaMKII prevents activity-dependent expression of key genes (BDNF, c-Fos, Arc), inhibits persistent synaptic strengthening, and impairs spatial memory in vivo. Deletion of γCaMKII in adult excitatory neurons exerts similar effects. A point mutation in γCaMKII, previously uncovered in a case of intellectual disability, selectively disrupts CaM sequestration and CaM shuttling. Remarkably, this mutation is sufficient to disrupt gene expression and spatial learning in vivo. Thus, this specific form of cytonuclear signaling plays a key role in learning and memory and contributes to neuropsychiatric disease.

Highlights d Chronic spike blockade with tetrodotoxin causes homeostatic spike broadening d Alternative splicing of BK channels by exclusion of a specific exon is responsible d Synaptic homeostasis starts CaM kinase signaling to drive nuclear exit of Nova-2 d Chronic inactivity and hyperactivity can initiate similar LTPlike events

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In this study, pairs of subjects performed a team-intensive task with the shared goal of clearing a virtual room from threats. The neurobehavioral dynamics of both subjects was analyzed to identify signatures of efficient team work. An ecologically valid task of room clearing was designed and a novel analysis framework was developed to address the challenge of understanding complex, continuous social processes at both behavioral and brain levels. A companion paper detailed the design of the neurobehavioral task and its associated dynamical analysis framework. In this paper, we present candidate neuromarkers for efficient room clearing and discuss key theoretical issues relating to successful team coordination.

Neurons use various forms of negative feedback to maintain their synaptic strengths within an operationally useful range. While this homeostatic plasticity is thought to distinctly counteract the destabilizing positive feedback of Hebbian plasticity, there is considerable overlap in the molecular components mediating both forms of plasticity. The varying kinetics of these components spurs additional inquiry into the dynamics of synaptic homeostasis. We discovered that upscaling of synaptic weights in response to prolonged inactivity is nonmonotonic. Surprisingly, this seemingly oscillatory adaptation involved transient appropriation of molecular effectors associated with Hebbian plasticity, namely CaMKII, L-type Ca2+ channels, and Ca2+-permeable AMPARs, and homeostatic elements such as calcineurin. We created a dynamic model that shows how traditionally "Hebbian" and "homeostatic" mechanisms can cooperate to autoregulate postsynaptic Ca2+ levels. We propose that this combination of mechanisms allows excitatory synapses to adapt to prolonged activity changes and safeguard the capability to undergo future strengthening on demand.