Homeostatic plasticity in mouse visual cortex

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The primary visual cortex (V1) is one of the most extensively studied areas of the mammalian brain, not only because it is crucial for our understanding of human vision but also because it has become a model system for studying cellular processes underlying plasticity, learning and memory. Visual experience during a so-called critical period in early childhood shapes the way neurons in V1 respond to visual stimuli throughout life, and any conditions that put one eye at a disadvantage (such as cross-eyes or a cataract) can cause amblyopia ('lazy eye') if not corrected in time. Up to 4% of the population suffer from this condition. In recent years research (including in our own labs) has increasingly employed mice in an effort to discover the cellular and molecular mechanisms of the underlying processes, using monocular eyelid suture ('monocular deprivation') as the standard paradigm to challenge visual cortex plasticity. Studies have identified the involvement of different mechanisms for different lengths of monocular deprivation and at different ages. One of these is 'homeostatic plasticity', an important ability of neurons to regulate their excitability in order to maintain stable network activity, balancing the effects of long-term synaptic potentiation and depression. This is thought to be mediated by a process called synaptic scaling. We have previously discovered evidence for the operation of this mechanism following monocular deprivation in juvenile but not adult mouse visual cortex. We also showed that the GluA1 subunit of the AMPA receptor which is the main mediator of excitatory transmission in the visual cortex is important for homeostatic plasticity.In addition to monocular deprivation, homeostatic plasticity can be triggered by placing animals in complete darkness, presumably because this depresses overall cortical activity dramatically. Dark exposure has recently been shown to promote recovery from monocular deprivation in adolescent rats and cats and may therefore present an opportunity to treat amblyopia beyond the end of the critical period. The latest work in our lab demonstrates that just a few days of dark exposure restore plasticity in V1 of mice which have been monocular deprived beyond the end of the critical period.Here we address key questions regarding the cellular mechanisms of homeostatic plasticity in juvenile and adult mice, as well as of the effects of dark exposure on plasticity. We shall investigate,1) By which mechanism does dark exposure promote plasticity in the adult visual cortex? Does it enable the GluA1 dependent homeostatic plasticity that operates in the juvenile cortex, or does it simply enhance existing mechanisms of adult plasticity (such as long-term potentiation)? 2) Is the restoration of visual cortex plasticity in adult mice by means of dark exposure behaviourally significant? In other words, do mice perform better on visually guided tasks, using the previously deprived eye, after a period of dark exposure?3) Which of the cells in V1 mediate the GluA1 dependent plasticity? Using molecular biology techniques we shall inhibit the production of GluA1 in each of 3 main classes of cells (excitatory pyramidal neurons, parvalbumin positive inhibitory neurons and astrocytes) in turn to assess whether plasticity in response to monocular deprivation in young mice is affected.4) Does homeostatic plasticity occur at all in adult visual cortex, and if not through synaptic scaling then through which alternative mechanism?