cAMP/Ca²⁺Response Element-Binding Protein Function Is Essential for Ocular Dominance Plasticity

Abstract

The monocular deprivation model of amblyopia is characterized by a reduction in cortical responses to stimulation of the deprived eye. Although the effects of monocular deprivation on the primary visual cortex have been well characterized physiologically and anatomically, the molecular mechanisms underlying ocular dominance plasticity remain unknown. Previous studies have indicated that the transcription factor adenosine cAMP/Ca(2+) response element-binding protein (CREB) is activated during monocular deprivation. However, it remains unknown whether CREB function is required for the loss of cortical responses to the deprived eye. To address this issue, we used the herpes simplex virus (HSV) to express a dominant negative form of CREB (HSV-mCREB) containing a single point mutation that prevents its activation. Quantitative single-unit electrophysiology showed that cortical expression of this mutated form of CREB during monocular deprivation prevented the loss of responses to the deprived eye. This effect was specific and not related to viral toxicity, because overexpression of functional CREB or expression of beta-galactosidase using HSV injections did not prevent the ocular dominance shift during monocular deprivation. Additional evidence for specificity was provided by the finding that blockade of ocular dominance plasticity was reversible; animals treated with HSV-mCREB recovered ocular dominance plasticity when mCREB expression declined. Moreover, this effect did not result from a suppression of sensory responses caused by the viral infection because neurons in infected cortex responded normally to visual stimulation. These findings demonstrate that CREB function is essential for ocular dominance plasticity.

Acceleration of Visual System Development by Environmental Enrichment

“…It is indeed known that CREB/CRE participates in the modulation of plasticity and development of the mouse visual cortex and is also developmentally regulated in the LGN (Huang et al, 1999;Pham et al, 1999;Mower et al, 2002). CREB is activated by neuronal activity (West et al, 2002), and environmental enrichment increases immunoreactivity to CREB in the hippocampus (Williams et al, 2001).…”

“…An important hub in the development and plasticity of sensory systems and in particular of the visual system is the cAMP/ CREB pathway (Impey et al, 1996;Pham et al, 1999;Barth et al, 2000;Mower et al, 2002;Cancedda et al, 2003). To investigate the involvement of this system in mediating the effects of environmental enrichment on visual system development, we used transgenic mice that carry the LacZ reporter gene under the control of the CRE promoter (Impey et al, 1996).…”

Nurturing brain plasticity: impact of environmental enrichment

“…90 Another way by which EE can regulate gene expression might be the activation of specific transcription factors. One possibility is that BDNF intracellular signalling stimulates CREB phosphorylation and activation, [91][92][93] which has a pivotal role in various forms of plasticity in the visual cortex [94][95][96] and other brain structures. 97 In line with this hypothesis, it has been shown that EE in adulthood increases immunoreactivity to CREB in the hippocampus as well 98 (Figure 3b).…”

Different Mechanisms for Loss and Recovery of Binocularity in the Visual Cortex

“…A common mechanism through which these molecules might act in ocular dominance plasticity is phosphorylation of the cAMP/ Ca 2ϩ response element-binding protein (CREB), which in turn regulates the transcription of plasticity-related genes (Gonzalez and Montminy, 1989;Deisseroth et al, 1996;Finkbeiner et al, 1997). More recent experiments have indeed shown that CREB function is necessary for the occurrence of an ocular dominance shift during monocular deprivation (Mower et al, 2002).…”

“…Vectors expressing CREB and LacZ were used as controls. This methodology is advantageous in that it allows temporally and spatially restricted expression of transgenes while preserving normal visual cortical responses (Mower et al, 2002). Quantitative in vivo recording techniques were then used to assess recovery.…”