Rem2 regulates distinct homeostatic mechanisms in visual circuit plasticity

Abstract

SUMMARYActivity-regulated genes sculpt neural circuits in response to sensory experience. These calciumsensitive genes generally fall into two categories: transcription factors and proteins that function at synapses. Yet little is known about activity-regulated, cytosolic proteins that transduce signals between the neuronal membrane and the nucleus. Using the visual system as a model, we investigated the role of the activity-regulated, non-canonical Ras-like GTPase Rem2 in vivo. We demonstrate that Rem2 -/-mice fail to exhibit normal ocular dominance plasticity during the critical period. At the circuit level, cortical layer 2/3 neurons in Rem2 -/-mice show deficits in both postsynaptic scaling up of excitatory synapses and misregulation of intrinsic excitability. Further, we reveal that Rem2 plays a novel, cell-autonomous role in regulating neuronal intrinsic excitability. Thus, Rem2 is a critical regulator of neural circuit function and distinct homeostatic plasticity mechanisms in vivo.

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

“…First, a previously published electrophysiological study from our lab [17, 62] and others [17, 62] using verified RNAi reagents to knock down Rem2 in cultured neurons, failed to uncover a role for Rem2 loss of function in modulation of calcium currents. In addition, we found no difference in the resting Ca 2+ levels of cortical neurons obtained from Rem2 −/− mice compared to WT controls using ratiometric Ca 2+ imaging [25]. The Ikeda lab also reports a similar result using an electrophysiological approach: no change in calcium currents in dissociated cultures of striatal medium spiny neurons in which Rem2 was deleted [63].…”

“…To perform these studies, we took advantage of a Cre-dependent conditional allele of Rem2, Rem2 flx/flx , that was generated in our laboratory [25]. In brief, exons 2 and 3 of the Rem2 allele, which encode the GTP-binding domain, were flanked by LoxP sites.…”

“…In brief, exons 2 and 3 of the Rem2 allele, which encode the GTP-binding domain, were flanked by LoxP sites. Therefore, when Cre recombinase is expressed, exons 2 and 3 are excised, resulting in a Rem2 null allele [25]. …”