Rem2 signaling affects neuronal structure and function in part by regulation of gene expression

Abstract

The central nervous system has the remarkable ability to convert changes in the environment in the form of sensory experience into long-term alterations in synaptic connections and dendritic arborization, in part through changes in gene expression. Surprisingly, the molecular mechanisms that translate neuronal activity into changes in neuronal connectivity and morphology remain elusive. Rem2, a member of the Rad/Rem/Rem2/Gem/Kir (RGK) subfamily of small Ras-like GTPases, is a positive regulator of synapse formation and negative regulator of dendritic arborization. Here we identify that one output of Rem2 signaling is the regulation of gene expression. Specifically, we demonstrate that Rem2 signaling modulates the expression of genes required for a variety of cellular processes from neurite extension to synapse formation and synaptic function. Our results highlight Rem2 as a unique molecule that transduces changes in neuronal activity detected at the cell membrane to morphologically relevant changes in gene expression in the nucleus.

Experience-dependent development of dendritic arbors in mouse visual cortex

“…Likewise, loss of such inhibition leading to increased CaMKII catalytic activity, such as by Rem2 deletion, could lead to widespread changes in cellular structure and function. This is consistent with the many alterations we observe in our past and current studies of Rem2 deletion [51, 54, 55, 67, 76–79]. Compellingly, the ability for Rem2 to inhibit CaMKII catalytic activity has already been linked to regulation of dendritic complexity [79].…”

“…Rem2 function has previously been shown to be regulated by neuronal activity [51, 54, 67]. Therefore, we investigated whether visual experience was required for Rem2-dependent regulation of segment number.…”

Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

“…Our injection strategy causes expression of GFP (AAV-GFP), or expression of GFP and deletion of Rem2 (AAV-GFP-Cre), from a few dozen neurons, while leaving the majority of the circuit unaffected. We previously verified using qPCR that 3–5 days of viral infection is sufficient to delete Rem2 exons 2 and 3 ( Kenny et al, 2017 ), Figure 1A ). Acute cortical slices were then isolated either 4 days post infection (4 d.p.i., Figure 8A left) or 10–12 d.p.i.…”

“…Consistent with this model, we performed RNA-sequencing to identify downstream targets of Rem2 ( Kenny et al, 2017 ). We found that the expression of a number of ion channels, important for establishing neuronal excitability, are regulated by Rem2 signaling in an activity-dependent manner ( Kenny et al, 2017 ). We also recently demonstrated that Rem2 is a novel inhibitor of CaMKII catalytic activity ( Royer et al, 2017 ).…”

“…Further, gene knockdown approaches in cultured cortical neurons and Xenopus laevis optic tectum established that Rem2 is a positive regulator of synapse formation and a negative regulator of dendritic complexity ( Ghiretti et al, 2013 ; Ghiretti et al, 2014 ; Ghiretti and Paradis, 2011 ; Moore et al, 2013 ), suggesting Rem2 may regulate structural plasticity in an activity-dependent manner. Because Rem2 expression and signaling is sensitive to neuronal activity levels ( Ghiretti et al, 2013 ; Ghiretti et al, 2014 ), and Rem2 signaling regulates changes in gene expression ( Kenny et al, 2017 ), we hypothesized that Rem2 could be a key regulator of cortical plasticity mechanisms in the intact nervous system.…”