Regulation of ERK/histone acetylation in plasticity of the visual system

The extracellular-signal regulated kinase (ERK) pathway mediates experience-dependent gene transcription in neurons; several studies have identified its pivotal role in long-term memory formation and experience dependent cortical plasticity. ERK seems to exert part of its action by influencing epigenetic mechanisms. The involvement of the ERK pathway in visual recognition memory and in the synaptic plasticity of the neural structures thought to implement this type of memory is still unclear. We have investigated these issues by studying recognition memory in ko mice with genetic deletion of Ras-GRF1, which have a deficient activation of ERK by neuronal activity. We also use a pharmacological approach blocking ERK activation by MEK inhibitor U0126 in a spatial and temporal selective manner. We found that ERK activation by Ras-GRF1 is a necessary component of the processes leading to consolidation and reconsolidation of visual recognition memory and that ERK activity in the perirhinal cortex is necessary for recognition memory consolidation. In mammals the development of the visual system may be altered during a sensitive period by modifying the visual input to one or both eyes. These plastic processes are reduced after the end of the sensitive period. Reduced levels of plasticity has been proposed to be at the basis of the lack of recovery from early visual deprivation observed in adult animals. A developmental downregulation of experience dependent regulation of histone acetylation has been recently involved in closing the sensitive period. Therefore, we tested whether pharmacological epigenetic treatments increasing histone acetylation could be used to reverse visual acuity deficits induced by long term monocular deprivation initiated during the sensitive period. We found that chronic intraperitoneal administration of valproic acid or sodium butyrate (two different histone deacetylases inhibitors) to long-term monocularly deprived adult rats coupled with reverse lid-suturing caused a complete recovery of visual acuity, tested electrophysiologically and behaviorally. Thus, manipulations of the epigenetic machinery can be used to promote functional recovery from early alterations of sensory input in the adult cortex.