• plasticity

During brain development there are periods, called critical or sensitive period, in which specific regions are highly plastic and learning occurs more readily and more permanently than during adulthood. If during this period abnormal stimulation causes altered circuits development, there are permanent damage to the brain as is the case of amblyopia. Understanding the molecular and genetic mechanisms underlying sensitive period plasticity could lead to clinical therapies for such disorders through reopening sensitive periods and allowing plasticity to reoccur. Ocular dominance plasticity is the most used paradigm of experience-dependent plasticity and occurs in primary visual cortex, when one eye is closed (monocular deprivation) for several days during critical period. Since the first investigation of critical period by Hubel and Wiesel, much work has been done to discover which factors are involved.
A flurry of studies demonstrate that experience-dependent plasticity is initiated when neuronal activation triggers intracellular signalling pathways, from the synapse to the nucleus, that modulate gene expression. The gene expression products modelling the neuronal circuits. But how is the gene expression molecular modulates?
Recent evidence suggests that the dynamic regulation of gene expression through epigenetic mechanisms is at the interface between environmental stimuli and long lasting molecular, cellular and complex behavioral phenotypes acquired during periods of developmental plasticity. Understanding these mechanisms may give insight into the regulation of critical periods and provide new strategies for increasing plasticity and adaptive change in adulthood.
In this work, I analyzed whether, similarly to the establishment of cellular identity during development, epigenetic DNA modifications are used by experience-dependent plasticity to permanently modulate the neuronal gene expression and neuronal circuit formation.
I first analyzed DNA methyltransferases (DNMTs) expression after 3 days of monocular deprivation, a protocol resulting in a reduction of neurons responding to the deprived eye in the binocular visual cortex . I found that monocular deprivation induced a significant increase of all the three DNMTs. The block of these enzymes with a pharmacological inhibitor (RG108) prevented the effects of monocular deprivation as demonstrated by using electrophysiological recordings.
At molecular level, I analyzed the promoters of two plasticity genes previously known to be downregulated during monocular deprivation containing CpG sites, Bdnf exIV and miR132-212. I found that methylation at CpG sites upstream Bdnf exIV and some in the locus miR212-132 was significant increased during monocular deprivation and RG108 contrasted the downregulation of Bdnf exIV and mR132-212 genes.
I showed that visual experience regulation of plasticity-related genes involves mechanisms of DNA methylation. These mechanisms are indispensable for cortical plasticity tested using a classical model of developmental plasticity i.e. ocular dominance plasticity in monocularly deprived juvenile mice.