Activity-regulated gene expression and circuit function

Surprisingly little is known about the molecular mechanisms by which changes in neuronal activity are translated into changes in neuronal morphology and synaptic connections. Using mouse strains generated in our lab, we discovered that the activity-regulated GTPase Rem2 regulates dendritic arborization in an activity-dependent manner (Ghiretti et al., 2014) and that significant Rem2-dependent dendritic remodeling persists in adulthood in the intact visual cortex in rodents (Richards et al., 2020). These findings indicate that the genetic programs that regulate structural plasticity are still accessible in the mature nervous system.

Ocular dominance (OD) plasticity in the mammalian visual system is a readily inducible, well-characterized form of plasticity that includes Hebbian and homeostatic components. Homeostatic plasticity in the form of the synaptic scaling up of excitatory postsynaptic currents and increased neuronal intrinsic excitability is thought to contribute to the increased responsiveness to monocular deprivation (MD) which characterizes OD plasticity during the critical period. However, the molecular underpinnings of these homeostatic plasticity mechanisms are poorly understood.

In collaboration with the lab of Dr. Steve Van Hooser at Brandeis, we sought to determine if Rem2 deletion affected neural plasticity mechanisms using OD plasticity as a paradigm. Using our transgenic Rem2 knockout mice, we also demonstrated that Rem2 regulates both the neuronal intrinsic excitability set-point and neuronal changes in intrinsic excitability in response to sensory deprivation in visual cortex (Moore et al., 2018). To uncover the molecular mechanisms of this particular Rem2 function, we employed an RNAseq approach and found that Rem2 regulates the expression of genes encoding neuronal ion channels and regulators of synapse formation (Kenny et al., 2017). We posit that Rem2 acts a “sensor” molecule whose main function is to assess cell-wide activity levels and implement downstream signaling mechanisms, which regulate both structural and homeostatic plasticity.

We also employed a proteomic analysis, in collaboration with Dr. Mike Marr at Brandeis, to identify relevant Rem2-dependent signaling networks which led us to the unexpected discovery that Rem2 is a direct, endogenous inhibitor of CaMKII enzymatic activity (Royer et al., 2018). CaMKII is a well-characterized, abundant protein kinase that subserves many important functions in neurons including regulation of activity-dependent dendritic remodeling and Long Term Potentiation (LTP), which is the biological correlate of learning and memory. This discovery is important because Rem2 is one of very few protein factors have been described thus far that inhibit CaMKII signaling. Thus, our findings suggest that Rem2 modulation of CaMKII function plays a previously unsuspected role in CaMKII-dependent neuronal functions. Further, we identified two amino acid residues in the Rem2 N-terminus that are required for Rem2 inhibition of CaMKII. This molecular insight will now enable the development of novel strategies to inhibit CaMKII and thus provide new key reagents for our experiments (Royer et al., 2018). Our current and future experiments seek to determine the cellular consequences of Rem2 inhibition of CaMKII.