This Week in The Journal

Regulation of Ca_V 1.2 Channels by Densin-180

Shiyi Wang, Ruslan I. Stanika, Xiaohan Wang, Jussara Hagen, Mary B. Kennedy, et al.

The postsynaptic density of excitatory synapses is packed with proteins that allow glutamate receptors to initiate signaling cascades that produce long-term changes in synapse structure and function. These proteins are organized by a variety of scaffolding molecules that contain multiple domains—often PDZ domains—that bind other proteins. One such scaffolding protein is densin-180 (densin), which interacts with the metabotropic glutamate receptor mGluR5, the actin-binding protein α-actininin, the L-type voltage-sensitive calcium channel Ca_V1.3, and the plasticity-associated signaling molecule Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), as well as other proteins. Knocking out densin causes deficits in short-term object-recognition memory and other behavioral abnormalities (Carlisle et al. 2011 J Neurosci 31:16194).

Surface expression of Ca_V1.2 channels (red) is higher in neurons overexpressing densin (bottom) than in control neurons (top). See Wang et al. for details.

Because some of the behavioral effects of densin-180 knockout are similar to those of knocking out the L-type calcium channel Ca_V1.2, Wang et al. asked if the latter also binds to densin. Indeed, densin co-immunoprecipitated with Ca_V1.2 from mouse prefrontal cortex lysates. Surprisingly, however, densin did not bind to the PDZ domain in the C-terminal region of Ca_V1.2, as it does with Ca_V1.3. Instead, densin interacted with a 10-amino-acid domain in the N-terminal region of Ca_V1.2. Moreover, densin did not promote CaMKII-dependent facilitation of calcium currents through Ca_V1.2 channels, as it does for Ca_V1.3. Instead, densin promoted delivery of Ca_V1.2 to the plasma membrane and increased channel open probability, thus increasing Ca_V1 current density. Consistent with this, knocking out densin or deleting the densin-binding domain of Ca_V1.2 reduced Ca_V1 current density and reduced the number of Ca_V1.2 channels in the plasma membrane. In addition, densin knockout reduced depolarization-induced phosphorylation of the transcription factor CREB, a major effector of the CaMKII signaling pathway activated by calcium influx through Ca_V1 channels.

These results strongly suggest that densin helps localize and regulate the function of Ca_V1.2 channels at postsynaptic sites. In so doing, densin likely enhances the ability of calcium influx through Ca_V1.2 channels to activate CaMKII, thus promoting downstream phosphorylation of CREB and CREB-dependent transcription. Therefore, modulation of densin–Ca_V1.2 binding might contribute to the regulation of synaptic plasticity and other activity-dependent processes.

How Enriched Environments Increase Newborn Neuron Numbers

Gregory W. Kirschen, Jia Shen, Mu Tian, Bryce Schroeder, Jia Wang, et al.

(see pages 4661–4678)

The addition of newborn neurons to the adult dentate gyrus is essential for normal cognitive function. The number of neurons added is regulated by neurotrophic factors, neuromodulators such as serotonin, and the activity of mature neurons, including interneurons. Exercise, environmental enrichment, diet, and stress also influence hippocampal neurogenesis (Aimone et al. 2014 Physiol Rev 94:991). Which molecular and electrophysiological processes mediate the effects of organism-level influences is poorly understood, however.

Because environmental enrichment and activating mature dentate neurons both increase the number of newborn neurons, Kirschen, Shen, et al. asked how exploring novel enriched environments affected neuronal activity in mouse dentate gyrus. To do so, they used in vivo calcium imaging to measure dentate granule cell activity. Most recorded neurons exhibited more and larger calcium transients in the enriched environment than in a standard, object-free environment. The number of transients was especially enhanced when mice were near an object. Although the number of transients decreased to control levels within an hour as mice explored the new environment, the number increased again when animals were introduced to a second novel environment.

A similar increase in the frequency of calcium transients occurred when mice explored a virtual enriched environment while walking on a treadmill. Notably, exploration of virtual environments increased the number of newborn granule cells in the dentate gyrus, and the number of newborn neurons further increased when mice were exposed to several virtual environments sequentially. Importantly, when halorhodopsin-expressing granule cells were inhibited during the first 25 min of novel environment exploration, no significant increase in newborn neurons occurred.

These results suggest that increased activity occurring in mature dentate granule cells as mice explore objects in a novel environment promotes addition or survival of newborn neurons. Remarkably, this effect occurs within a short time window lasting approximately half an hour. Future work should determine when during the development of newborn neurons—for example, before or after synaptogenesis—they are most strongly influenced by the activity of mature neurons. Determining the molecular mechanisms responsible for this influence will also be important. The ability to expose mice to numerous novel environments in rapid succession using virtual reality should help these endeavors.