Homeostatic plasticity bidirectionally constrains neuronal activity to a target firing range, allowing stable neuronal and network function throughout development. In rodent visual cortex, monocular deprivation causes the firing rate of neurons responding to the deprived eye to initially decrease before gradually rebounding to within 15% of the baseline firing rate, even in the face of continued deprivation. This homeostatic activity rebound occurs in neurons with baseline firing rates spanning three orders of magnitude, demonstrating that each neuron has a firing rate set point maintained by cell-autonomous homeostatic mechanisms. However, nothing is known about the molecular mechanisms that control this firing rate set point in vivo. CaMKIV, a Ca2+/calmodulin-dependent kinase, plays a critical role in Ca2+-dependent gene transcription and has been implicated in multiple forms of homeostatic plasticity. I have designed a series of experiments to test the hypothesis that CaMKIV signaling coordinates different forms of homeostatic plasticity in vivo in response to changes in activity, shifting firing rate towards a target rate influenced by CaMKIV protein levels. First, I will measure the relationship between neuronal activity and CaMKIV protein levels in cortical slices and test the effect of prolonged activity deprivation in vivo on CaMKIV protein levels. Then, by manipulating CaMKIV protein levels in vivo, I will test the role of CaMKIV signaling in coordinating different types of homeostatic plasticity ex vivo and establishing the firing rate set point in vivo. These experiments will provide fundamental mechanistic insight into how neurons and networks maintain stable function despite varying inputs. The ability to adjust firing rate set points in vivo could lead to conceptually novel treatment approaches for neurological disorders characterized by dysregulated neuronal activity, such as autism spectrum disorders and epilepsy.
Health Relevance During prolonged changes in input activity, the output activity of individual neurons homeostatically adjusts to remain at a target level, enabling stable neuronal and network function across development. The experiments proposed here will provide the first molecular characterization of this output target, and will shed light into the coordination of different homeostatic mechanisms used to achieve this target. This work has the potential to provide conceptually novel treatment approaches for neurological disorders that arise from dysregulated neuronal activity, such as autism spectrum disorders and epilepsy.
| Moeyaert, Benjamien; Holt, Graham; Madangopal, Rajtarun et al. (2018) Improved methods for marking active neuron populations. Nat Commun 9:4440 |
