Dual Regulation of Spine-Specific and Synapse-to-Nucleus Signaling by PKCδ during Plasticity

Abstract

The activity-dependent plasticity of synapses is believed to be the cellular basis of learning. These synaptic changes are mediated through the coordination of local biochemical reactions in synapses and changes in gene transcription in the nucleus to modulate neuronal circuits and behavior. The protein kinase C (PKC) family of isozymes has long been established as critical for synaptic plasticity. However, due to a lack of suitable isozyme-specific tools, the role of the novel subfamily of PKC isozymes is largely unknown. Here, through the development of FLIM-FRET activity sensors, we investigate novel PKC isozymes in synaptic plasticity in CA1 pyramidal neurons of mice of either sex. We find that PKCδ is activated downstream of TrkB and DAG production and that the spatiotemporal nature of its activation depends on the plasticity stimulation. In response to single-spine plasticity, PKCδ is activated primarily in the stimulated spine and is required for local expression of plasticity. However, in response to multi-spine stimulation, a long-lasting and spreading activation of PKCδ scales with the number of spines stimulated and, by regulating CREB activity, couples spine plasticity to transcription in the nucleus. Thus, PKCδ plays a dual functional role in facilitating synaptic plasticity.SIGNIFICANCE STATEMENT:Synaptic plasticity, or the ability to change the strength of the connections between neurons, underlies learning and memory and is critical for brain health. The protein kinase C (PKC) family is central to this process. However, understanding how these kinases work to mediate plasticity has been limited by a lack of tools to visualize and perturb their activity. Here, we introduce and use new tools to reveal a dual role for PKCδ in facilitating local synaptic plasticity and stabilizing this plasticity through spine-to-nucleus signaling to regulate transcription. This work provides new tools to overcome limitations in studying isozyme-specific PKC function and provides insight into molecular mechanisms of synaptic plasticity.

PKCδ is an activator of neuronal mitochondrial metabolism that mediates the spacing effect on memory consolidation

“…Our work thus sketches a possibly conserved role of neuronal PKCδ in the context of memory formation and consolidation in mammals, which nevertheless remains to be investigated. A possible role of PKCδ in plasticity mechanisms in mice was substantiated by the recent observation, in CA1 pyramidal neurons from mice organotypic slices, that stimulation-induced DAG production downstream of NMDA receptors (Colgan et al, 2018) can activate PKCδ in spines for local plasticity, and, at a longer timescale, its translocation to the nucleus for plasticity-induced transcription upon LTP formation (Colgan et al, 2023).…”

Decoding Arc Transcription: A Live-Cell Study of Stimulation Patterns and Transcriptional Output

“…These results suggest that the activation of CREB phosphorylation at optimal calcium levels further modulates Arc transcription. While some studies have shown that nuclear calcium transients regulate CREB phosphorylation and IEG transcription (Hardingham et al, 2001; Yu et al, 2017), other studies have suggested the importance of submembrane and cytosolic calcium transients to activate other intracellular pathways to initiate IEG transcription (Deisseroth et al, 1996; Nonaka et al, 2014; Colgan et al, 2023). In this study, we focused on the nuclear calcium signaling, but the effects of the calcium transients in other parts of the neurons could also be investigated in the future.…”

Homosynaptic plasticity induction causes heterosynaptic changes at the unstimulated neighbors in an induction pattern and location-specific manner

“…It has recently been shown that PKC activity is not restricted to the stimulated spine when multiple spines are stimulated using 30-Reg (Colgan et al, 2023), which suggests that PKC could spread some distance from the stimulated loci. Additionally, TrkB has previously been shown to regulate long-distance signaling between activated synapses and the nucleus (Harward et al, 2016;Esvald et al, 2020;Moya-Alvarado and Bronfman, 2020).…”