Untangling the two-way signalling route from synapses to the nucleus, and from the nucleus back to the synapses

Abstract

During learning and memory, it has been suggested that the coordinated electrical activity of hippocampal neurons translates information about the external environment into internal neuronal representations, which then are stored initially within the hippocampus and subsequently into other areas of the brain. A widely held hypothesis posits that synaptic plasticity is a key feature that critically modulates the triggering and the maintenance of such representations, some of which are thought to persist over time as traces or tags. However, the molecular and cell biological basis for these traces and tags has remained elusive. Here, we review recent findings that help clarify some of the molecular and cellular mechanisms critical for these events, by untangling a two-way signalling crosstalk route between the synapses and the neuronal soma. In particular, a detailed interrogation of the soma-to-synapse delivery of immediate early gene product Arc/Arg3.1, whose induction is triggered by heightened synaptic activity in many brain areas, teases apart an unsuspected ‘inverse’ synaptic tagging mechanism that likely contributes to maintaining the contrast of synaptic weight between strengthened and weak synapses within an active ensemble.

Ethanol Exposure Induces Neonatal Neurodegeneration by Enhancing CB1R Exon1 Histone H4K8 Acetylation and Up-regulating CB1R Function causing Neurobehavioral Abnormalities in Adult Mice

“…While the precise signaling cascades involved in Arc transcription are not well defined, one study has shown that PKA/MAPK cascades regulate Arc expression ( Waltereit et al, 2001 ) and that the MAPK/CREB pathway is also essential for Arc expression ( Ying et al, 2002 ; Nonaka et al, 2014 ). Given the impaired ERK1/2 and pCREB in postnatal ethanol-exposed neonatal mice, Arc protein levels were also significantly reduced in ethanol-exposed neonatal as well as adult mice and blockade or genetic deletion of CB1R prior to P7 ethanol treatment–restored Arc protein levels in neonatal and adult mice.…”

Sustained Arc expression in adult-generated granule cells

“…Based on Arc's role in multiple bi-directional plasticity pathways [14][15][16], it is possible that the sustained presence of Arc in the vicinity of synapses can modulate the response to further patterns of stimulation. This molecular "priming" of activated synapses could conceivably lead to distinct functional outcomes in granule cell circuits relative to pyramidal cells.…”

Actin remodeling, the synaptic tag and the maintenance of synaptic plasticity

“…Interestingly, LTP induction leads to the synthesis and specific localization of Arc/Arg3.1 in non‐potentiated synapses, a phenomenon described as an inverse‐tagging mechanism . Synaptic recruitment of Arc/Arg3.1 to inactive synapses was due to a preferential interaction between the inactive form of CaMKIIβ and Arc/Arg3.1 and it may represent a mechanism by which neurons increase contrast and prevent undesired enhancement at non‐stimulated synapse . It remains to be addressed the spatial rules of the inverse tagging.…”