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SummaryDuring early development, even before the senses are active, bursts of activity travel across the nervous system. This spontaneously generated activity drives the refinement of synaptic connections, preparing young networks for patterned sensory input. Synaptic fine-tuning relies not only on the presence of spontaneous activity, but also on the specific characteristics of these activity patterns, such as their frequency, amplitude and synchronicity. Here, we provide evidence that these crucial characteristics are shaped by the relative balance of excitation and inhibition, where patterns with distinct characteristics have different excitatory/inhibitory ratios. Inhibition can control whether cells participate during a spontaneous event, as pharmacogenetic suppression of the somatostatin (SST) expressing subtype of inhibitory interneurons increased cell recruitment and lateral spread of events.

© 2021 The Author(s)During early development, before the eyes open, synaptic refinement of sensory networks depends on activity generated by developing neurons themselves. In the mouse visual system, retinal cells spontaneously depolarize and recruit downstream neurons to bursts of activity, where the number of recruited cells determines the resolution of synaptic retinotopic refinement. Here we show that during the second post-natal week in mouse visual cortex, somatostatin (SST)-expressing interneurons control the recruitment of cells to retinally driven spontaneous activity. Suppressing SST interneurons increases cell participation and allows events to spread farther along the cortex. During the same developmental period, a second type of high-participation, retina-independent event occurs. During these events, cells receive such large excitatory charge that inhibition is overwhelmed and large parts of the cortex participate in each burst. These results reveal a role of SST interneurons in restricting retinally driven activity in the visual cortex, which may contribute to the refinement of retinotopy.

Summary Spontaneous network activity shapes emerging neuronal circuits during early brain development prior to sensory perception. However, how neuromodulation influences this activity is not fully understood. Here, we report that the neuromodulator oxytocin differentially shapes spontaneous activity patterns across sensory cortices. In vivo, oxytocin strongly decreased the frequency and pairwise correlations of spontaneous activity events in the primary visual cortex (V1), but it did not affect the frequency of spontaneous network events in the somatosensory cortex (S1). Patch-clamp recordings in slices and RNAscope showed that oxytocin affects S1 excitatory and inhibitory neurons similarly, whereas in V1, oxytocin targets only inhibitory neurons. Somatostatin-positive (SST+) interneurons expressed the oxytocin receptor and were activated by oxytocin in V1. Accordingly, pharmacogenetic silencing of V1 SST+ interneurons fully blocked oxytocin’s effect on inhibition in vitro as well its effect on spontaneous activity patterns in vivo. Thus, oxytocin decreases the excitatory/inhibitory (E/I) ratio by recruiting SST+ interneurons and modulates specific features of V1 spontaneous activity patterns that are crucial for the wiring and refining of developing sensory circuits., Graphical Abstract, Highlights • Oxytocin modulates spontaneous activity event patterns in the developing V1 • Oxytocin increases inhibition by activating somatostatin+ interneurons • SST+ neuron activity reduces event frequency and correlations, but not amplitude • In S1, oxytocin increases excitation and inhibition and does not modulate frequency, Maldonado et al. uncover oxytocin’s role in developing sensory cortices. In vivo, they show that oxytocin decreases the frequency and correlations of spontaneous activity patterns in V1 by specifically activating somatostatin+ interneurons. In S1, oxytocin increases both excitation and inhibition and does not affect spontaneous activity frequency.

Synaptic currents display a large degree of heterogeneity of their temporal characteristics, but the functional role of such heterogeneities remains unknown. We investigated in rat cerebellar slices synaptic currents in Unipolar Brush Cells (UBCs), which generate intrinsic mossy fibers relaying vestibular inputs to the cerebellar cortex. We show that UBCs respond to sinusoidal modulations of their sensory input with heterogeneous amplitudes and phase shifts. Experiments and modeling indicate that this variability results both from the kinetics of synaptic glutamate transients and from the diversity of postsynaptic receptors. While phase inversion is produced by an mGluR2-activated outward conductance in OFF-UBCs, the phase delay of ON UBCs is caused by a late rebound current resulting from AMPAR recovery from desensitization. Granular layer network modeling indicates that phase dispersion of UBC responses generates diverse phase coding in the granule cell population, allowing climbing-fiber-driven Purkinje cell learning at arbitrary phases of the vestibular input. DOI: http://dx.doi.org/10.7554/eLife.15872.001, eLife digest Whether walking, riding a bicycle or simply standing still, we continually adjust our posture in small ways to prevent ourselves from falling. Our sense of balance depends on a set of structures inside the inner ear called the vestibular system. These structures detect movements of the head and relay this information to the brain in the form of electrical signals. A brain area called the vestibulo-cerebellum then combines these signals with sensory input from the eyes and muscles, before sending out further signals to trigger any adjustments necessary for balance. One of the main cell types within the vestibulo-cerebellum is the unipolar brush cell (or UBC for short). UBCs pass on signals to another type of neuron called Purkinje cells, which support the learning of motor skills such as adjusting posture. Zampini, Liu et al. set out to test the idea that UBCs transform inputs from the vestibular system into a format that makes it easier for cerebellar Purkinje cells to drive this kind of learning. First, recordings from slices of rodent brain revealed that UBCs respond in highly variable ways to vestibular input, with both the size and timing of responses varying between cells. This is because vestibular signals trigger the release of a chemical messenger called glutamate onto UBCs, but UBCs possess a variety of different types of glutamate receptors. Vestibular input therefore activates distinct signaling cascades from one UBC to the next. According to a computer model, this variability in UBC responses ensures that a subset of UBCs will always be active at any point during vestibular input. This in turn means that Purkinje cells can fire at any stage of a movement, which boosts the learning of motor skills. The next steps will be to test this hypothesis using mutant mice that lack specific receptor subtypes in UBCs or UBCs completely. A further challenge for the future will be to build a computer model of the vestibulo-cerebellar system that includes all of its component cell types. DOI: http://dx.doi.org/10.7554/eLife.15872.002

NG2-expressing glial cells (NG2 cells) represent a major pool of progenitors able to generate myelinating oligodendrocytes, and perhaps astrocytes and neurones, in the postnatal brain. In the last decade, it has been demonstrated that NG2 cells receive functional glutamatergic and GABAergic synapses mediating fast synaptic transmission in different brain regions. However, several controversies exist in this field. While two classes of NG2 cells have been defined by the presence or absence of Na(+) channels, action potential firing and neuronal input, other studies suggest that all NG2 cells possess Na(+) conductances and are the target of quantal neuronal release, but are unable to trigger action potential firing. Here we bring new evidence supporting the idea that the level of expression of Na(+) conductances is not a criterion to discriminate NG2 cell subpopulations in the somatosensory cortex. Surprisingly, recent reports demonstrated that NG2 cells detect quantal glutamate release from unmyelinated axons in white matter regions. Yet, it is difficult from these studies to establish whether axonal vesicular release in white matter occurs at genuine synaptic junctions or at ectopic release sites. In addition, we recently reported a new mode of extrasynaptic communication between neurones and NG2 cells that relies on pure GABA spillover and does not require GABAergic synaptic input. This review discusses the properties of quantal neuronal release onto NG2 cells and gives an extended overview of potential extrasynaptic modes of transmission, from ectopic to diffuse volume transmission, between neurones and NG2 cells in the brain.

The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron–OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron–OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders.

NG2 cells, oligodendrocyte progenitors, receive a major synaptic input from interneurons in the developing neocortex. It is presumed that these precursors integrate cortical networks where they act as sensors of neuronal activity. We show that NG2 cells of the developing somatosensory cortex form a transient and structured synaptic network with interneurons that follows its own rules of connectivity. Fast-spiking interneurons, highly connected to NG2 cells, target proximal subcellular domains containing GABAA receptors with γ2 subunits. Conversely, non-fast-spiking interneurons, poorly connected with these progenitors, target distal sites lacking this subunit. In the network, interneuron-NG2 cell connectivity maps exhibit a local spatial arrangement reflecting innervation only by the nearest interneurons. This microcircuit architecture shows a connectivity peak at PN10, coinciding with a switch to massive oligodendrocyte differentiation. Hence, GABAergic innervation of NG2 cells is temporally and spatially regulated from the subcellular to the network level in coordination with the onset of oligodendrogenesis. DOI: http://dx.doi.org/10.7554/eLife.06953.001, eLife digest Neurons are outnumbered in the brain by cells called glial cells. The brain contains various types of glial cells that perform a range of different jobs, including the supply of nutrients and the removal of dead neurons. The role of glial cells called oligodendrocytes is to produce a material called myelin: this is an electrical insulator that, when wrapped around a neuron, increases the speed at which electrical impulses can travel through the nervous system. Neurons communicate with one another through specialized junctions called synapses, and at one time it was thought that only neurons could form synapses in the brain. However, this view had to be revised when researchers discovered synapses between neurons and glial cells called NG2 cells, which go on to become oligodendrocytes. These neuron-NG2 cell synapses have a lot in common with neuron–neuron synapses, but much less is known about them. Orduz, Maldonado et al. have now examined these synapses in unprecedented detail by analyzing individual synapses between a type of neuron called an interneuron and an NG2 cell in mice aged only a few weeks. Interneurons can be divided into two major classes based on how quickly they fire, and Orduz, Maldonado et al. show that both types of interneuron form synapses with NG2 cells. However, these two types of interneuron establish synapses on different parts of the NG2 cell, and these synapses involve different receptor proteins. Together, the synapses give rise to a local interneuron-NG2 cell network that reaches a peak of activity roughly two weeks after birth, after which the network is disassembled. This period of peak activity is accompanied by a sudden increase in the maturation of NG2 cells into oligodendrocytes. Further experiments are needed to test the possibility that activity in the interneuron-NG2 cell network acts as the trigger for the NG2 cells to turn into oligodendrocytes, which then supply myelin for the developing brain. DOI: http://dx.doi.org/10.7554/eLife.06953.002

Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders.

Oligodendrocyte precursor cells (OPCs) are the major source of myelinating oligodendrocytes during development. These progenitors are highly abundant at birth and persist in the adult where they are distributed throughout the brain. The large abundance of OPCs after completion of myelination challenges their unique role as progenitors in the healthy adult brain. Here we show that adult OPCs of the barrel cortex sense fine extracellular K+increases generated by neuronal activity, a property commonly assigned to differentiated astrocytes rather than to progenitors. Biophysical, pharmacological, and single-cell RT-PCR analyses demonstrate that this ability of OPCs establishes itself progressively through the postnatal upregulation of Kir4.1 K+channels. In animals with advanced cortical myelination, extracellular stimulation of layer V axons induces slow K+currents in OPCs, which amplitude correlates with presynaptic action potential rate. Moreover, using paired recordings, we demonstrate that the discharge of a single neuron can be detected by nearby adult OPCs, indicating that these cells are strategically located to detect local changes in extracellular K+concentration during physiological neuronal activity. These results identify a novel unitary neuron–OPC connection, which transmission does not rely on neurotransmitter release and appears late in development. Beyond their abundance in the mature brain, the postnatal emergence of a physiological response of OPCs to neuronal network activity supports the view that in the adult these cells are not progenitors only.

NG2 cells, oligodendrocyte precursors, play a critical role in myelination during postnatal brain maturation, but a pool of these precursors is maintained in the adult and recruited to lesions in demyelinating diseases. NG2 cells in immature animals have recently been shown to receive synaptic inputs from neurons, and these have been assumed to persist in the adult. Here, we investigated the GABAergic synaptic activity of NG2 cells in acute slices of the barrel cortex of NG2-DsRed transgenic mice during the first postnatal month, which corresponds to the period of active myelination in the neocortex. Our data demonstrated that the frequency of spontaneous and miniature GABAergic synaptic activity of cortical NG2 cells dramatically decreases after the second postnatal week, indicating a decrease in the number of synaptic inputs onto NG2 cells during development. However, NG2 cells still receive GABAergic inputs from interneurons in the adult cortex. These inputs do not rely on the presence of functional synapses but involve a form of GABA spillover. This GABA volume transmission allows interneurons to induce phasic responses in target NG2 cells through the activation of extrasynaptic GABAAreceptors. Hence, after development is complete, volume transmission allows NG2 cells to integrate neuronal activity patterns at frequencies occurring duringin vivosensory stimulation.