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Neurofibromatosis type 1 (NF1) is a common monogenic neurodevelopmental disorder associated with physical and cognitive problems. The cognitive issues are thought to arise from increased release of the neurotransmitter GABA. Modulating the signaling pathways causing increased GABA release in a mouse model of NF1 reverts deficits in hippocampal learning. However, clinical trials based on these approaches have so far been unsuccessful. We therefore used a combination of slice electrophysiology, in vivo two-photon calcium imaging, and optical imaging of intrinsic signal in a mouse model of NF1 to investigate whether cortical development is affected in NF1, possibly causing lifelong consequences that cannot be rescued by reducing inhibition later in life. We find that, in NF1 mice of both sexes, inhibition increases strongly during the development of the visual cortex and remains high. While this increase in cortical inhibition does not affect spontaneous cortical activity patterns during early cortical development, the critical period for ocular dominance plasticity is shortened in NF1 mice due to its early closure but unaltered onset. Notably, after environmental enrichment, differences in inhibitory innervation and ocular dominance plasticity between NF1 mice and WT littermates disappear. These results provide the first evidence for critical period dysregulation in NF1 and suggest that treatments aimed at normalizing levels of inhibition will need to start at early stages of development. SIGNIFICANCE STATEMENT Neurofibromatosis type 1 is associated with cognitive problems for which no treatment is currently available. This study shows that, in a mouse model of neurofibromatosis type 1, cortical inhibition is increased during development and critical period regulation is disturbed. Rearing the mice in an environment that stimulates cognitive function overcomes these deficits. These results uncover critical period dysregulation as a novel mechanism in the pathogenesis of neurofibromatosis type 1. This suggests that targeting the affected signaling pathways in neurofibromatosis type 1 for the treatment of cognitive disabilities may have to start at a much younger age than has so far been tested in clinical trials., (Copyright © 2020 the authors.)

The firing rates of neurons in primary visual cortex (V1) are suppressed by large stimuli, an effect known as surround suppression. In cats and monkeys, the strength of suppression is sensitive to orientation; responses to regions containing uniform orientations are more suppressed than those containing orientation contrast. This effect is thought to be important for scene segmentation, but the underlying neural mechanisms are poorly understood. We asked whether it is possible to study these mechanisms in the visual cortex of mice, because of recent advances in technology for studying the cortical circuitry in mice. It is unknown whether neurons in mouse V1 are sensitive to orientation contrast. We measured the orientation selectivity of surround suppression in the different layers of mouse V1. We found strong surround suppression in layer 4 and the superficial layers, part of which was orientation tuned: iso-oriented surrounds caused more suppression than cross-oriented surrounds. Surround suppression was delayed relative to the visual response and orientation-tuned suppression was delayed further, suggesting two separate suppressive mechanisms. Previous studies proposed that surround suppression depends on the activity of inhibitory somatostatin-positive interneurons in the superficial layers. To test the involvement of the superficial layers we topically applied lidocaine. Silencing of the superficial layers did not prevent orientation-tuned suppression in layer 4. These results show that neurons in mouse V1, which lacks orientation columns, show orientation-dependent surround suppression in layer 4 and the superficial layers and that surround suppression in layer 4 does not require contributions from neurons in the superficial layers., (Copyright © 2014 the authors 0270-6474/14/349290-15$15.00/0.)

On bipolar cells are connected to photoreceptors via a sign-inverting synapse. At this synapse, glutamate binds to a metabotropic receptor which couples to the closure of a cation-selective transduction channel. The molecular identity of both the receptor and the G protein are known, but the identity of the transduction channel has remained elusive. Here, we show that the transduction channel in mouse rod bipolar cells, a subtype of On bipolar cell, is likely to be a member of the TRP family of channels. To evoke a transduction current, the metabotropic receptor antagonist LY341495 was applied to the dendrites of cells that were bathed in a solution containing the mGluR6 agonists L-AP4 or glutamate. The transduction current was suppressed by ruthenium red and the TRPV1 antagonists capsazepine and SB-366791. Furthermore, focal application of the TRPV1 agonists capsaicin and anandamide evoked a transduction-like current. The capsaicin-evoked and endogenous transduction current displayed prominent outward rectification, a property of the TRPV1 channel. To test the possibility that the transduction channel is TRPV1, we measured rod bipolar cell function in the TRPV1(-/-) mouse. The ERG b-wave, a measure of On bipolar cell function, as well as the transduction current and the response to TRPV1 agonists were normal, arguing against a role for TRPV1. However, ERG measurements from mice lacking TRPM1 receptors, another TRP channel implicated in retinal function, revealed the absence of a b-wave. Our results suggest that a TRP-like channel, possibly TRPM1, is essential for synaptic function in On bipolar cells.

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.

In the cerebral cortex of mammals, horizontal connections link cells up to several millimeters apart. In primary visual cortex (V1) of mammals with orientation maps, horizontal connections ramify in periodic patches across the cortical surface, connecting cells with similar orientation preferences. Rodents have orientation-selective cells but lack orientation maps, raising questions about relationships of horizontal connections to functional maps and receptive field properties. To address these questions, we studied anatomy of horizontal connections and characterized horizontal functional interactions in V1 of the gray squirrel, a highly visual rodent. Long-range intrinsic connections in squirrel V1 extended 1-2 mm but were not patchy or periodic. This result suggests that periodic and patchy connectivity is not a universal organizing principle of cortex, and the existence of patchy and periodic connectivity and functional maps may be linked. In multielectrode and intracellular recordings, we found evidence of unselective local interactions among cells, similar to pinwheel centers of carnivores. These data suggest that, in mammals with and without orientation maps, local connections link near neighbors without regard to orientation selectivity. In single-unit recordings, we found length-summing and end-stopped cells that were similar to those in other mammals. Length-summing cell surrounds were orientation selective, whereas surrounds of end-stopped cells were not. Receptive field response classes are quite similar across mammals, and therefore patchy and columnar connectivity may not be essential for these properties.

In mammalian neocortex, the orderly arrangement of columns of neurons is thought to be a fundamental organizing principle. In primary visual cortex (V1), neurons respond preferentially to bars of a particular orientation, and, in many mammals, these orientation-selective cells are arranged in a semiregular, smoothly varying map across the cortical surface. Curiously, orientation maps have not been found in rodents or lagomorphs. To explore whether this lack of organization in previously studied rodents could be attributable to low visual acuity, poorly differentiated visual brain areas, or small absolute V1 size, we examined V1 organization of a larger, highly visual rodent, the gray squirrel. Using intrinsic signal optical imaging and single-cell recordings, we found no evidence of an orientation map, suggesting that formation of orientation maps depends on mechanisms not found in rodents. We did find robust orientation tuning of single cells, and this tuning was invariant to stimulus contrast. Therefore, it seems unlikely that orientation maps are important for orientation tuning or its contrast invariance in V1. In vertical electrode penetrations, we found little evidence for columnar organization of orientation-selective neurons and little evidence for local anisotropy of orientation preferences. We conclude that an orderly and columnar arrangement of functional response properties is not a universal characteristic of cortical architecture.