The visual cortex is organized into retinotopic maps that preserve an orderly representation of the visual world, achieved by topographically precise inputs from the lateral geniculate nucleus. We show here that geniculocortical mapping is imprecise when the waves of spontaneous activity in the retina during the first postnatal week are disrupted genetically. This anatomical mapping defect is present by postnatal day 8 and has functional consequences, as revealed by optical imaging and microelectrode recording in adults. Pharmacological disruption of these retinal waves during the first week phenocopies the mapping defect, confirming both the site and the timing of the disruption in neural activity responsible for the defect. Analysis shows that the geniculocortical miswiring is not a trivial or necessary consequence of the retinogeniculate defect. Our findings demonstrate that disrupting early spontaneous activity in the eye alters thalamic connections to the cortex.

Sustained increase in intraocular pressure represents a major risk factor for eye disease yet the cellular mechanisms of pressure transduction in the posterior eye are essentially unknown. Here we show that the mouse retina expresses mRNA and protein for the polymodal TRPV4 cation channel known to mediate osmo- and mechanotransduction. TRPV4 antibodies labeled perikarya, axons and dendrites of retinal ganglion cells (RGCs) and intensely immunostained the optic nerve head. Müller glial cells, but not retinal astrocytes or microglia, also expressed TRPV4 immunoreactivity. The selective TRPV4 agonists 4α-PDD and GSK1016790A elevated [Ca2+]i in dissociated RGCs in a dose-dependent manner whereas the TRPV1 agonist capsaicin had no effect on [Ca2+]RGC. Exposure to hypotonic stimulation evoked robust increases in [Ca2+]RGC. RGC responses to TRPV4-selective agonists and hypotonic stimulation were absent in Ca2+-free saline and were antagonized by the nonselective TRP channel antagonists Ruthenium Red and gadolinium, but were unaffected by the TRPV1 antagonist capsazepine. TRPV4-selective agonists increased the spiking frequency recorded from intact retinas recorded with multielectrode arrays. Sustained exposure to TRPV4 agonists evoked dose-dependent apoptosis of RGCs. Our results demonstrate functional TRPV4 expression in RGCs and suggest that its activation mediates response to membrane stretch leading to elevated [Ca2+]i and augmented excitability. Excessive Ca2+ influx through TRPV4 predisposes RGCs to activation of Ca2+-dependent pro-apoptotic signaling pathways, indicating that TRPV4 is a component of the response mechanism to pathological elevations of intraocular pressure.

In mammals, retinal ganglion cell projections initially intermingle and then segregate into a stereotyped pattern of eye-specific layers in the dorsal lateral geniculate nucleus (dLGN). We show here that, in mice deficient for ephrin-A2, ephrin-A3, and ephrin-A5, eye-specific inputs segregate but the shape and location of eye-specific layers is profoundly disrupted. In contrast, mice that lack correlated retinal activity do not segregate eye-specific inputs. Inhibiting correlated neural activity in ephrin mutants leads to overlapping retinal projections located in inappropriate regions of the dLGN. Thus, ephrin-As and neural activity act together to control patterning of eye-specific retinogeniculate layers.In the mammalian visual system, retinal ganglion cells (RGCs) project to their main forebrain target, the dLGN of the thalamus, in an orderly and stereotypical manner. This order is established during development and can be described by two main components. First, the projection pattern from each eye is topographic, with neighboring RGCs connecting to neighboring positions in the dLGN. The Eph family of receptor tyrosine kinases and their cell surface-bound ligands, the ephrins, have been shown to act as graded labels that are required for topographic mapping in multiple areas in the CNS, including the two main targets of RGCs: the dLGN and the superior colliculus (SC) 1-5 .The second organizing feature of visual connectivity is the segregation of projections from each eye, a phenomenon thought to depend mechanistically on neural activity. Early in development the retinogeniculate projections of the two eyes overlap but then segregate and form eye-specific layers postnatally 6,7 . Inhibiting activity in the retina or in the whole brain prevents the segregation of RGC axons 8-10 . Neural activity has been theorized to drive axonaxon competition for dLGN territory between the two eyes, and indeed, when the balance of activity levels in the two eyes is altered, inputs from the more active eye occupy a larger area within the dLGN 10-14 . It is thought that activity-based competition relies on the ability of inputs from each eye to cooperate with one another to strengthen synaptic connections in a Hebbian manner, although exactly how activity functions in this context remains controversial 15,16 . While activity-dependent models can account for how eye-specific inputs segregate, they cannot explain the stereotypical placement of the layers within the dLGN. Segregation models based solely on neural activity predict that layer placement should be stochastic, such that in some animals a given layer of the dLGN would be innervated from the left eye while in other animals it would be innervated by the right eye, or alternatively, that axons from each eye would segregate in a "salt and pepper" pattern 17,18 . Multiple theories have been proposed to explain the stereotypical placement of the eye-specific layers, including temporal differences between ipsi-and contralateral ingrowth into the dLGN, layer-specific m...

Neuronal pentraxins (NPs) define a family of proteins that are homologous to C-reactive and acutephase proteins in the immune system and have been hypothesized to be involved in activity-dependent synaptic plasticity. To investigate the role of NPs in vivo, we generated mice that lack one, two, or all three NPs. NP1/2 knock-out mice exhibited defects in the segregation of eye-specific retinal ganglion cell (RGC) projections to the dorsal lateral geniculate nucleus, a process that involves activity-dependent synapse formation and elimination. Retinas from mice lacking NP1 and NP2 had cholinergically driven waves of activity that occurred at a frequency similar to that of wild-type mice, but several other parameters of retinal activity were altered. RGCs cultured from these mice exhibited a significant delay in functional maturation of glutamatergic synapses. Other developmental processes, such as pathfinding of RGCs at the optic chiasm and hippocampal long-term potentiation and long-term depression, appeared normal in NP-deficient mice. These data indicate that NPs are necessary for early synaptic refinements in the mammalian retina and dorsal lateral geniculate nucleus. We speculate that NPs exert their effects through mechanisms that parallel the known role of short pentraxins outside the CNS.