Rem2 stabilizes intrinsic excitability and spontaneous firing in visual circuits

Abstract

Sensory experience plays an important role in shaping neural circuitry by affecting the synaptic connectivity and intrinsic properties of individual neurons. Identifying the molecular players responsible for converting external stimuli into altered neuronal output remains a crucial step in understanding experience-dependent plasticity and circuit function. Here, we investigate the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in visual circuit plasticity. We demonstrate that Rem2-/- mice fail to exhibit normal ocular dominance plasticity during the critical period. At the cellular level, our data establish a cell-autonomous role for Rem2 in regulating intrinsic excitability of layer 2/3 pyramidal neurons, prior to changes in synaptic function. Consistent with these findings, both in vitro and in vivo recordings reveal increased spontaneous firing rates in the absence of Rem2. Taken together, our data demonstrate that Rem2 is a key molecule that regulates neuronal excitability and circuit function in the context of changing sensory experience.

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].…”

“…While much experimentation remains to be done in order to explore a possible connection between synaptic and dendritic stability in the context of Rem2 function, some of our recent work may provide a hint. When Rem2 is deleted during the critical period, the same time period in which we observe dendritic instability here, changes in miniature excitatory post-synaptic current (mEPSC) frequency and amplitude were unchanged 4 days after Rem2 deletion, but by 10 days post-deletion a 25% decrease in mEPSC frequency was observed [76]. Here, we observed arbor changes as early as 5 days post-infection, suggesting that arbor changes may lead synaptic changes or occur simultaneously.…”

“…Previous work has established that Rem2 plays a multi-faceted role in regulating cortical development, including functioning as a positive regulator of synapse formation [51, 55, 76–78], a negative regulator of intrinsic excitability [76], and as a required molecule for complete expression of juvenile ocular dominance plasticity in the mouse [76]. Here, we have added to these findings evidence that Rem2 is an age- and experience-dependent regulator of dendritic complexity and promotes basal dendrite directionality.…”

Experience-Dependent Development of Dendritic Arbors in Mouse Visual Cortex

“…Rem2 is an experience-dependent negative regulator of segment number Rem2 function has previously been shown to be regulated by neuronal activity and sensory experience (Ghiretti et al, 2013Kenny et al, 2017;Moore et al, 2018). Therefore, we investigated whether visual experience was required for Rem2-dependent regulation of segment number.…”

The Ras-like GTPase Rem2 is a potent inhibitor of calcium/calmodulin-dependent kinase II activity

“…We previously showed that Rem2 is an activity-regulated gene as its mRNA expression is up-regulated by neuronal depolarization both in vitro and in vivo (13,14), and the Rem2 protein is also subject to activity-dependent post-translational modification (15). Moreover, we demonstrated using gene knockdown approaches in cultured rodent neurons and Xenopus laevis optic tectum that Rem2 regulates dendritic branching (13,16) in conjunction with CaMKII signaling.…”