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The developing visual thalamus and cortex extract positional information encoded in the correlated activity of retinal ganglion cells by synaptic plasticity, allowing for the refinement of connectivity. Here, we use a biophysical model of the visual thalamus during the initial visual circuit refinement period to explore the role of synaptic and circuit properties in the regulation of such neural correlations. We find that the NMDA receptor dominance, combined with weak recurrent excitation and inhibition characteristic of this age, prevents the emergence of spike-correlations between thalamocortical neurons on the millisecond timescale. Such precise correlations, which would emerge due to the broad, unrefined connections from the retina to the thalamus, reduce the spatial information contained by thalamic spikes, and therefore we term them 'parasitic' correlations. Our results suggest that developing synapses and circuits evolved mechanisms to compensate for such detrimental parasitic correlations arising from the unrefined and immature circuit., Competing Interests: RT, GG, WG, MC No competing interests declared, (© 2023, Tikidji-Hamburyan et al.)

Intracortical inhibition plays a critical role in shaping activity patterns in the mature cortex. However, little is known about the structure of inhibition in early development prior to the onset of sensory experience, a time when spontaneous activity exhibits long-range correlations predictive of mature functional networks. Here, using calcium imaging of GABAergic neurons in the ferret visual cortex, we show that spontaneous activity in inhibitory neurons is already highly organized into distributed modular networks before visual experience. Inhibitory neurons exhibit spatially modular activity with long-range correlations and precise local organization that is in quantitative agreement with excitatory networks. Furthermore, excitatory and inhibitory networks are strongly co-aligned at both millimeter and cellular scales. These results demonstrate a remarkable degree of organization in inhibitory networks early in the developing cortex, providing support for computational models of self-organizing networks and suggesting a mechanism for the emergence of distributed functional networks during development., Competing Interests: HM, BH, MK, GS No competing interests declared, (© 2021, Mulholland et al.)

Astrocytes regulate the formation and function of neuronal synapses via multiple signals; however, what controls regional and temporal expression of these signals during development is unknown. We determined the expression profile of astrocyte synapse-regulating genes in the developing mouse visual cortex, identifying astrocyte signals that show differential temporal and layer-enriched expression. These patterns are not intrinsic to astrocytes, but regulated by visually evoked neuronal activity, as they are absent in mice lacking glutamate release from thalamocortical terminals. Consequently, synapses remain immature. Expression of synapse-regulating genes and synaptic development is also altered when astrocyte signaling is blunted by diminishing calcium release from astrocyte stores. Single-nucleus RNA sequencing identified groups of astrocytic genes regulated by neuronal and astrocyte activity, and a cassette of genes that show layer-specific enrichment. Thus, the development of cortical circuits requires coordinated signaling between astrocytes and neurons, highlighting astrocytes as a target to manipulate in neurodevelopmental disorders., Competing Interests: IF, MB, HL, CD, GE, EB, CF, MS, JE, NA No competing interests declared, (© 2021, Farhy-Tselnicker et al.)

Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 may also lead to neurodevelopmental disorders (ND). Here, we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed in Xenopus tadpoles after early exposure to valproic acid (VPA), a known teratogen associated with ND in humans. In Xenopus tadpoles, VPA exposure results in excess local synaptic connectivity, disrupted social behavior and increased seizure susceptibility. We found that overexpressing MMP-9 in the brain copies effects of VPA on synaptic connectivity, and blocking MMP-9 activity pharmacologically or genetically reverses effects of VPA on physiology and behavior. We further show that during normal neurodevelopment MMP-9 levels are tightly regulated by neuronal activity and required for structural plasticity. These studies show a critical role for MMP-9 in both normal and abnormal development., Competing Interests: SG, EJ, LH, JP, AB, AT, HC, CA No competing interests declared, (© 2021, Gore et al.)

Modifications of synaptic inputs and cell-intrinsic properties both contribute to neuronal plasticity and development. To better understand these mechanisms, we undertook an intracellular analysis of the development of direction selectivity in the ferret visual cortex, which occurs rapidly over a few days after eye opening. We found strong evidence of developmental changes in linear spatiotemporal receptive fields of simple cells, implying alterations in circuit inputs. Further, this receptive field plasticity was accompanied by increases in near-spike-threshold excitability and input-output gain that resulted in dramatically increased spiking responses in the experienced state. Increases in subthreshold membrane responses induced by the receptive field plasticity and the increased input-output spiking gain were both necessary to explain the elevated firing rates in experienced ferrets. These results demonstrate that cortical direction selectivity develops through a combination of plasticity in inputs and in cell-intrinsic properties., Competing Interests: AR, JO, BM, WA, DL, SV No competing interests declared, (© 2020, Roy et al.)

The Deleted in Colorectal Carcinoma (Dcc) receptor plays a critical role in optic nerve development. Whilst Dcc is expressed postnatally in the eye, its function remains unknown as Dcc knockouts die at birth. To circumvent this drawback, we generated an eye-specific Dcc mutant. To study the organization of the retina and visual projections in these mice, we also established EyeDISCO, a novel tissue clearing protocol that removes melanin allowing 3D imaging of whole eyes and visual pathways. We show that in the absence of Dcc , some ganglion cell axons stalled at the optic disc, whereas others perforated the retina, separating photoreceptors from the retinal pigment epithelium. A subset of visual axons entered the CNS, but these projections are perturbed. Moreover, Dcc -deficient retinas displayed a massive postnatal loss of retinal ganglion cells and a large fraction of photoreceptors. Thus, Dcc is essential for the development and maintenance of the retina., Competing Interests: RV, QC, AC, KN No competing interests declared, (© 2020, Vigouroux et al.)

The adult primate visual system comprises a series of hierarchically organized areas. Each cortical area contains a topographic map of visual space, with different areas extracting different kinds of information from the retinal input. Here we asked to what extent the newborn visual system resembles the adult organization. We find that hierarchical, topographic organization is present at birth and therefore constitutes a proto-organization for the entire primate visual system. Even within inferior temporal cortex, this proto-organization was already present, prior to the emergence of category selectivity (e.g., faces or scenes). We propose that this topographic organization provides the scaffolding for the subsequent development of visual cortex that commences at the onset of visual experience.

To build a coherent view of the external world, an organism needs to integrate multiple types of sensory information from different sources, a process known as multisensory integration (MSI). Previously, we showed that the temporal dependence of MSI in the optic tectum of Xenopus laevis tadpoles is mediated by the network dynamics of the recruitment of local inhibition by sensory input (Felch et al., 2016). This was one of the first cellular-level mechanisms described for MSI. Here, we expand this cellular level view of MSI by focusing on the principle of inverse effectiveness, another central feature of MSI stating that the amount of multisensory enhancement observed inversely depends on the size of unisensory responses. We show that non-linear summation of crossmodal synaptic responses, mediated by NMDA-type glutamate receptor (NMDARs) activation, form the cellular basis for inverse effectiveness, both at the cellular and behavioral levels.

Multisensory integration (MSI) is the process that allows the brain to bind together spatiotemporally congruent inputs from different sensory modalities to produce single salient representations. While the phenomenology of MSI in vertebrate brains is well described, relatively little is known about cellular and synaptic mechanisms underlying this phenomenon. Here we use an isolated brain preparation to describe cellular mechanisms underlying development of MSI between visual and mechanosensory inputs in the optic tectum of Xenopus tadpoles. We find MSI is highly dependent on the temporal interval between crossmodal stimulus pairs. Over a key developmental period, the temporal window for MSI significantly narrows and is selectively tuned to specific interstimulus intervals. These changes in MSI correlate with developmental increases in evoked synaptic inhibition, and inhibitory blockade reverses observed developmental changes in MSI. We propose a model in which development of recurrent inhibition mediates development of temporal aspects of MSI in the tectum.

Biophysical properties of neurons become increasingly diverse over development, but mechanisms underlying and constraining this diversity are not fully understood. Here we investigate electrophysiological characteristics of Xenopus tadpole midbrain neurons across development and during homeostatic plasticity induced by patterned visual stimulation. We show that in development tectal neuron properties not only change on average, but also become increasingly diverse. After sensory stimulation, both electrophysiological diversity and functional differentiation of cells are reduced. At the same time, the amount of cross-correlations between cell properties increase after patterned stimulation as a result of homeostatic plasticity. We show that tectal neurons with similar spiking profiles often have strikingly different electrophysiological properties, and demonstrate that changes in intrinsic excitability during development and in response to sensory stimulation are mediated by different underlying mechanisms. Overall, this analysis and the accompanying dataset provide a unique framework for further studies of network maturation in Xenopus tadpoles.