The synaptic proteome during development and plasticity of the mouse visual cortex.

During brain development, the neocortex shows periods of enhanced plasticity, which enables the acquisition of knowledge and skills that we use and build on in adult life. Key to persistent modifications of neuronal connectivity and plasticity of the neocortex are molecular changes occurring at the synapse. Here we used isobaric tag for relative and absolute quantification to measure levels of 467 synaptic proteins in a well-established model of plasticity in the mouse visual cortex and the regulation of its critical period. We found that inducing visual cortex plasticity by monocular deprivation during the critical period increased levels of kinases and proteins regulating the actin-cytoskeleton and endocytosis. Upon closure of the critical period with age, proteins associated with transmitter vesicle release and the tubulin- and septin-cytoskeletons increased, whereas actin-regulators decreased in line with augmented synapse stability and efficacy. Maintaining the visual cortex in a plastic state by dark rearing mice into adulthood only partially prevented these changes and increased levels of G-proteins and protein kinase A subunits. This suggests that in contrast to the general belief, dark rearing does not simply delay cortical development but may activate signaling pathways that specifically maintain or increase the plasticity potential of the visual cortex. Altogether, this study identified many novel candidate plasticity proteins and signaling pathways that mediate synaptic plasticity during critical developmental periods or restrict it in adulthood.

Contrast gain control and cortical TrkB signaling shape visual acuity.

During development and aging and in amblyopia, visual acuity is far below the limitations set by the retina. Expression of brain-derived neurotrophic factor (BDNF) in the visual cortex is reduced in these situations. We asked whether neurotrophic tyrosine kinase receptor, type 2 (TrkB) regulates cortical visual acuity in adult mice. We found that genetically interfering with TrkB/BDNF signaling in pyramidal cells in the mature visual cortex reduced synaptic strength and resulted in a loss of neural responses to high spatial-frequency stimuli. Responses to low spatial-frequency stimuli were unaffected. This selective loss was not accompanied by a change in receptive field sizes or plasticity, but apparent contrast was reduced. Our results indicate that a dependence on spatial frequency in the Heeger normalization model explains this selective effect of contrast reduction on high-resolution vision and suggest that it involves contrast gain control operating in the visual cortex.

Notch1 signaling in pyramidal neurons regulates synaptic connectivity and experience-dependent modifications of acuity in the visual cortex.

How the visual cortex responds to specific stimuli is strongly influenced by visual experience during development. Monocular deprivation, for example, changes the likelihood of neurons in the visual cortex to respond to input from the deprived eye and reduces its visual acuity. Because these functional changes are accompanied by extensive reorganization of neurite morphology and dendritic spine turnover, genes regulating neuronal morphology are likely to be involved in visual plasticity. In recent years, Notch1 has been shown to mediate contact inhibition of neurite outgrowth in postmitotic neurons and implicated in the pathogenesis of various degenerative diseases of the CNS. Here, we provide the first evidence for the involvement of neuronal Notch1 signaling in synaptic morphology and plasticity in the visual cortex. By making use of the Cre/Lox system, we expressed an active form of Notch1 in cortical pyramidal neurons several weeks after birth. We show that neuronal Notch1 signals reduce dendritic spine and filopodia densities in a cell-autonomous manner and limit long-term potentiation in the visual cortex. After monocular deprivation, these effects of Notch1 activity predominantly affect responses to visual stimuli with higher spatial frequencies. This results in an enhanced effect of monocular deprivation on visual acuity.

Screening mouse vision with intrinsic signal optical imaging.

The introduction of forward genetic screens in the mouse asks for techniques that make rapid screening of visual function possible. Transcranial imaging of intrinsic signal is suitable for this purpose and could detect the effects of retinal degeneration, and the increased predominance of the contralateral eye in albino animals. We quantified visual response properties of the cortex by introducing a normalization method to reduce the impact of biological noise. In addition, the presentation of a 'reset'-stimulus shortly after the probing stimulus at a different visual location could reduce the interstimulus time necessary for the decay of the response. Applying these novel methods, we found that acuity of C57Bl/6J mice rises from 0.35 cycles per degree (cpd) at postnatal day 25 to 0.56 cpd in adults. Temporal resolution was lower in adults than in juvenile animals. There was no patchy organization of spatial or temporal frequency preference at the intrinsic signal resolution. Monocular deprivation, a model for amblyopia and critical period plasticity, led to a loss in acuity and a shift towards the nondeprived eye in juvenile animals. Short deprivation did not lead to increased acuity of the nondeprived eye. In adults, a small ocular dominance shift was detectable with urethane anaesthesia. This was not observed when the combination of the opiate fentanyl, fluanisone with a benzodiazepine was used, adding evidence to the hypothesis that enhancing GABA(A)-receptor function masks an adult shift. Together, these novel applications confirm that noninvasive screening of many functional properties of the visual cortex is possible.

Kinetics of inhibition of sperm beta-acrosin activity by suramin.

Sperm beta-acrosin activity is inhibited by suramin, a polysulfonated naphthylurea compound with therapeutic potential as a combined antifertility agent and microbicide. A kinetic analysis of enzyme inhibition suggests that three and four molecules of suramin bind to one molecule of ram and boar beta-acrosins respectively. Surface charge distribution models of boar beta-acrosin based on its crystal structure indicate several positively charged exosites that represent potential 'docking' regions for suramin. It is hypothesised that the spatial arrangement and distance between these exosites determines the capacity of beta-acrosin to bind suramin.