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In humans, a quantifiable number of cortical synapses appears early in fetal life. In this paper, we present a bridge across different scales of resolution and the distribution of synapses across the transient cytoarchitectonic compartments: marginal zone (MZ), cortical plate (CP), subplate (SP), and in vivo MR images. The tissue of somatosensory cortex (7-26 postconceptional weeks (PCW)) was prepared for electron microscopy, and classified synapses with a determined subpial depth were used for creating histograms matched to the histological sections immunoreacted for synaptic markers and aligned to in vivo MR images (1.5 T) of corresponding fetal ages (maternal indication). Two time periods and laminar patterns of synaptogenesis were identified: an early and midfetal two-compartmental distribution (MZ and SP) and a late fetal three-compartmental distribution (CP synaptogenesis). During both periods, a voluminous, synapse-rich SP was visualized on the in vivo MR. Another novel finding concerns the phase of secondary expansion of the SP (13 PCW), where a quantifiable number of synapses appears in the upper SP. This lamina shows a T2 intermediate signal intensity below the low signal CP. In conclusion, the early fetal appearance of synapses shows early differentiation of putative genetic mechanisms underlying the synthesis, transport and assembly of synaptic proteins. "Pioneering" synapses are likely to play a morphogenetic role in constructing of fundamental circuitry architecture due to interaction between neurons. They underlie spontaneous, evoked, and resting state activity prior to ex utero experience. Synapses can also mediate genetic and environmental triggers, adversely altering the development of cortical circuitry and leading to neurodevelopmental disorders., Competing Interests: Declarations. Conflict of interest: The author have no relevant financial or non-financial interests to disclose. Ethical approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by Ethics Committee of School of Medicine University of Zagreb (19.11.2015./protocol number 380–59-10,106–15-168/314)., (© 2024. The Author(s).)

Spike timing-dependent plasticity (STDP) is a learning rule important for synaptic refinement and for learning and memory during development. While different forms of presynaptic t-LTD have been deeply investigated, little is known about the mechanisms of somatosensory cortex postsynaptic t-LTD. In the present work, we investigated the requirements and mechanisms for induction of developmental spike timing-dependent long-term depression (t-LTD) at L2/3-L2/3 synapses in the juvenile mouse somatosensory cortex. We found that postnatal day (P) 13-21 mice of either sex show t-LTD at L2/3-L2/3 synapses induced by pairing single presynaptic activity with single postsynaptic action potentials at low stimulation frequency (0.2 Hz) that is expressed postsynaptically and requires the activation of ionotropic postsynaptic NMDA-type glutamate receptors containing GluN2B subunits. In addition, it requires postsynaptic Ca 2+ , Ca 2+ release from internal stores, calcineurin, postsynaptic endocannabinoid synthesis, activation of CB 1 receptors, and astrocytic signaling to release the gliotransmitter d-serine to activate postsynaptic NMDARs to induce t-LTD. These results show direct evidence of the mechanism involved in developmental postsynaptic t-LTD at L2/3-L2/3 synapses, revealing a central role of astrocytes and their release of d-serine in its induction., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Experience- and activity-dependent transcription is a candidate mechanism to mediate development and refinement of specific cortical circuits. Here, we demonstrate that the activity-dependent transcription factor myocyte enhancer factor 2C (MEF2C) is required in both presynaptic layer (L) 4 and postsynaptic L2/3 mouse (male and female) somatosensory (S1) cortical neurons for development of this specific synaptic connection. While postsynaptic deletion of Mef2c weakens L4 synaptic inputs, it has no effect on inputs from local L2/3, contralateral S1, or the ipsilateral frontal/motor cortex. Similarly, homozygous or heterozygous deletion of Mef2c in presynaptic L4 neurons weakens L4 to L2/3 excitatory synaptic inputs by decreasing presynaptic release probability. Postsynaptic MEF2C is specifically required during an early postnatal, experience-dependent, period for L4 to L2/3 synapse function, and expression of transcriptionally active MEF2C (MEF2C-VP16) rescues weak L4 to L2/3 synaptic strength in sensory-deprived mice. Together, these results suggest that experience- and/or activity-dependent transcriptional activation of MEF2C promotes development of L4 to L2/3 synapses. Additionally, MEF2C regulates the expression of many pre- and postsynaptic genes in postnatal cortical neurons. Interestingly, MEF2C was necessary for activity-dependent expression of many presynaptic genes, including those that function in transsynaptic adhesion and neurotransmitter release. This work provides mechanistic insight into the experience-dependent development of specific cortical circuits., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Early life experiences shape physical and behavioral outcomes throughout lifetime. Sensory circuits are especially susceptible to environmental and physiological changes during development. However, the impact of different types of early life experience are often evaluated in isolation. In this mini review, we discuss the specific effects of postnatal sensory experience, sleep, social isolation, and substance exposure on barrel cortex development. Considering these concurrent factors will improve understanding of the etiology of atypical sensory perception in many neuropsychiatric and neurodevelopmental disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nwabudike and Che.)

Sense of touch is essential for our interactions with external objects and fine control of hand actions. Despite extensive research on human somatosensory processing, it is still elusive how involved brain regions interact as a dynamic network in processing tactile information. Few studies probed temporal dynamics of somatosensory information flow and reported inconsistent results. Here, we examined cortical somatosensory processing through magnetic source imaging and cortico-cortical coupling dynamics. We recorded magnetoencephalography signals from typically developing children during unilateral pneumatic stimulation. Neural activities underlying somatosensory evoked fields were mapped with dynamic statistical parametric mapping, assessed with spatiotemporal activation analysis, and modeled by Granger causality. Unilateral pneumatic stimulation evoked prominent and consistent activations in the contralateral primary and secondary somatosensory areas but weaker and less consistent activations in the ipsilateral primary and secondary somatosensory areas. Activations in the contralateral primary motor cortex and supramarginal gyrus were also consistently observed. Spatiotemporal activation and Granger causality analysis revealed initial serial information flow from contralateral primary to supramarginal gyrus, contralateral primary motor cortex, and contralateral secondary and later dynamic and parallel information flows between the consistently activated contralateral cortical areas. Our study reveals the spatiotemporal dynamics of cortical somatosensory processing in the normal developing brain., (© The Author(s) 2024. Published by Oxford University Press.)

During the first and second stages of postnatal development, neocortical neurons exhibit a wide range of spontaneous synchronous activity (SSA). Towards the end of the second postnatal week, the SSA is replaced by a more sparse and desynchronized firing pattern. The developmental desynchronization of neocortical spontaneous neuronal activity is thought to be intrinsically generated, since sensory deprivation from the periphery does not affect the time course of this transition. The extracellular protein reelin controls various aspects of neuronal development through multimodular signaling. However, so far it is unclear whether reelin contributes to the developmental desynchronization transition of neocortical neurons. The present study aims to investigate the role of reelin in postnatal cortical developmental desynchronization using a conditional reelin knockout (Reln cKO ) mouse model. Conditional reelin deficiency was induced during early postnatal development, and Ca 2+ recordings were conducted from organotypic cultures (OTCs) of the somatosensory cortex. Our results show that both wild type (wt) and Reln cKO exhibited an SSA pattern during the early postnatal week. However, at the end of the second postnatal week, wt OTCs underwent a transition to a desynchronized network activity pattern, while Reln cKO activity remained synchronous. This changing activity pattern suggests that reelin is involved in regulating the developmental desynchronization of cortical neuronal network activity. Moreover, the developmental desynchronization impairment observed in Reln cKO was rescued when Reln cKO OTCs were co-cultured with wt OTCs. Finally, we show that the developmental transition to a desynchronized state at the end of the second postnatal week is not dependent on glutamatergic signaling. Instead, the transition is dependent on GABA A R and GABA B R signaling. The results suggest that reelin controls developmental desynchronization through GABA A R and GABA B R signaling.

For neural circuit construction in the brain, coarse neuronal connections are assembled prenatally following genetic programs, being reorganized postnatally by activity-dependent mechanisms to implement area-specific computational functions. Activity-dependent dendrite patterning is a critical component of neural circuit reorganization, whereby individual neurons rearrange and optimize their presynaptic partners. In the rodent primary somatosensory cortex (barrel cortex), driven by thalamocortical inputs, layer 4 (L4) excitatory neurons extensively remodel their basal dendrites at neonatal stages to ensure specific responses of barrels to the corresponding individual whiskers. This feature of barrel cortex L4 neurons makes them an excellent model, significantly contributing to unveiling the activity-dependent nature of dendrite patterning and circuit reorganization. In this review, we summarize recent advances in our understanding of the activity-dependent mechanisms underlying dendrite patterning. Our focus lays on the mechanisms revealed by in vivo time-lapse imaging, and the role of activity-dependent Golgi apparatus polarity regulation in dendrite patterning. We also discuss the type of neuronal activity that could contribute to dendrite patterning and hence connectivity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Nakagawa and Iwasato.)

Nasal chemosensation is considered the evolutionarily oldest mammalian sense and, together with somatosensation, is crucial for neonatal well-being before auditory and visual pathways start engaging the brain. Using anatomical and functional approaches in mice, we reveal that odor-driven activity propagates to a large part of the cortex during the first postnatal week and enhances whisker-evoked activation of primary whisker somatosensory cortex (wS1). This effect disappears in adult animals, in line with the loss of excitatory connectivity from olfactory cortex to wS1. By performing neonatal odor deprivation, followed by electrophysiological and behavioral work in adult animals, we identify a key transient regulation of nasal chemosensory information necessary for the development of wS1 sensory-driven dynamics and somatosensation. Our work uncovers a cross-modal critical window for nasal chemosensation-dependent somatosensory functional maturation.

Columnar structure is one of the most fundamental morphological features of the cerebral cortex and is thought to be the basis of information processing in higher animals. Yet, how such a topographically precise structure is formed is largely unknown. Formation of columnar projection of layer 4 (L4) axons is preceded by thalamocortical formation, in which type 1 cannabinoid receptors (CB1R) play an important role in shaping barrel-specific targeted projection by operating spike timing-dependent plasticity during development (Itami et al. , J. Neurosci. 36, 7039-7054 [2016]; Kimura & Itami, J. Neurosci. 39, 3784-3791 [2019]). Right after the formation of thalamocortical projections, CB1Rs start to function at L4 axon terminals (Itami & Kimura, J. Neurosci. 32, 15000-15011 [2012]), which coincides with the timing of columnar shaping of L4 axons. Here, we show that the endocannabinoid 2-arachidonoylglycerol (2-AG) plays a crucial role in columnar shaping. We found that L4 axon projections were less organized until P12 and then became columnar after CB1Rs became functional. By contrast, the columnar organization of L4 axons was collapsed in mice genetically lacking diacylglycerol lipase α, the major enzyme for 2-AG synthesis. Intraperitoneally administered CB1R agonists shortened axon length, whereas knockout of CB1R in L4 neurons impaired columnar projection of their axons. Our results suggest that endocannabinoid signaling is crucial for shaping columnar axonal projection in the cerebral cortex.

One consequence of the opioid epidemic are lasting neurodevelopmental sequelae afflicting adolescents exposed to opioids in the womb. A translationally relevant and developmentally accurate preclinical model is needed to understand the behavioral, circuit, network, and molecular abnormalities resulting from this exposure. By employing a novel preclinical model of perinatal fentanyl exposure, our data reveal that fentanyl has several dose-dependent, developmental consequences to somatosensory function and behavior. Newborn male and female mice exhibit signs of withdrawal and sensory-related deficits that extend at least to adolescence. As fentanyl exposure does not affect dams' health or maternal behavior, these effects result from the direct actions of perinatal fentanyl on the pups' developing brain. At adolescence, exposed mice exhibit reduced adaptation to sensory stimuli, and a corresponding impairment in primary somatosensory (S1) function. In vitro electrophysiology demonstrates a long-lasting reduction in S1 synaptic excitation, evidenced by decreases in release probability, NMDA receptor-mediated postsynaptic currents, and frequency of miniature excitatory postsynaptic currents (mEPSCs), as well as increased frequency of miniature inhibitory postsynaptic currents (mIPSCs). In contrast, anterior cingulate cortical neurons exhibit an opposite phenotype, with increased synaptic excitation. Consistent with these changes, electrocorticograms (ECoGs) reveal suppressed ketamine-evoked γ oscillations. Morphologic analysis of S1 pyramidal neurons indicate reduced dendritic complexity, dendritic length, and soma size. Further, exposed mice exhibited abnormal cortical mRNA expression of key receptors involved in synaptic transmission and neuronal growth and development, changes that were consistent with the electrophysiological and morphologic changes. These findings demonstrate the lasting sequelae of perinatal fentanyl exposure on sensory processing and function. SIGNIFICANCE STATEMENT This is the first study to show that exposure to fentanyl in the womb results in behavioral, circuitry, and synaptic effects that last at least to adolescence. We also show, for the first time, that this exposure has different, lasting effects on synapses in different cortical areas., (Copyright © 2021 the authors.)

It is generally supposed that primary motor cortex (M1) receives somatosensory input predominantly via primary somatosensory cortex (S1). However, a growing body of evidence indicates that M1 also receives direct sensory input from the thalamus, independent of S1; such direct input is particularly evident at early ages before M1 contributes to motor control. Here, recording extracellularly from the forelimb regions of S1 and M1 in unanesthetized rats at postnatal day (P)8 and P12, we compared S1 and M1 responses to self-generated (i.e., reafferent) forelimb movements during active sleep and wake, and to other-generated (i.e., exafferent) forelimb movements. At both ages, reafferent responses were processed in parallel by S1 and M1; in contrast, exafferent responses were processed in parallel at P8 but serially, from S1 to M1, at P12. To further assess this developmental difference in processing, we compared exafferent responses to proprioceptive and tactile stimulation. At both P8 and P12, proprioceptive stimulation evoked parallel responses in S1 and M1, whereas tactile stimulation evoked parallel responses at P8 and serial responses at P12. Independent of the submodality of exafferent stimulation, pairs of S1-M1 units exhibited greater coactivation during active sleep than wake. These results indicate that S1 and M1 independently develop somatotopy before establishing the interactive relationship that typifies their functionality in adults. SIGNIFICANCE STATEMENT Learning any new motor task depends on the ability to use sensory information to update motor outflow. Thus, to understand motor learning, we must also understand how animals process sensory input. Primary somatosensory cortex (S1) and primary motor cortex (M1) are two interdependent structures that process sensory input throughout life. In adults, the functional relationship between S1 and M1 is well established; however, little is known about how S1 and M1 begin to transmit or process sensory information in early life. In this study, we investigate the early development of S1 and M1 as a sensory processing unit. Our findings provide new insights into the fundamental principles of sensory processing and the development of functional connectivity between these important sensorimotor structures., (Copyright © 2021 the authors.)

Synapses are able to form in the absence of neuronal activity, but how is their subsequent maturation affected in the absence of regulated vesicular release? We explored this question using 3D electron microscopy and immunoelectron microscopy analyses in the large, complex synapses formed between cortical sensory efferent axons and dendrites in the posterior thalamic nucleus. Using a Synaptosome-associated protein 25 conditional knockout (Snap25 cKO), we found that during the first 2 postnatal weeks the axonal boutons emerge and increase in the size similar to the control animals. However, by P18, when an adult-like architecture should normally be established, axons were significantly smaller with 3D reconstructions, showing that each Snap25 cKO bouton only forms a single synapse with the connecting dendritic shaft. No excrescences from the dendrites were formed, and none of the normally large glomerular axon endings were seen. These results show that activity mediated through regulated vesicular release from the presynaptic terminal is not necessary for the formation of synapses, but it is required for the maturation of the specialized synaptic structures between layer 5 corticothalamic projections in the posterior thalamic nucleus., (© The Author(s) 2020. Published by Oxford University Press.)

Callosal projections from primary somatosensory cortex (S1) are key for processing somatosensory inputs and integrating sensory-motor information. How the callosal innervation pattern in S1 is formed during early postnatal development is not clear. We found that the normal termination pattern of these callosal projections is disrupted in cortex specific NMDAR mutants. Rather than projecting selectively to the primary/secondary somatosensory cortex (S1/S2) border, axons were uniformly distributed throughout S1. In addition, the density of this projection increased over postnatal life until the mice died by P30. By combining genetic and antibody-mediated loss of function, we demonstrated that it is GluN2B-containing NMDA receptors in target S1 that mediate this guidance phenotype, thus playing a central role in interhemispheric connectivity. Furthermore, we found that this function of NMDA receptors in callosal circuit formation is independent of ion channel function and works with the EPHRIN-B/EPHB system. Thus, NMDAR in target S1 cortex regulates the formation callosal circuits perhaps by modulating EPH-dependent repulsion., Competing Interests: JZ, YL, TH, HN, JB, SP No competing interests declared, (© 2021, Zhou et al.)

Brain circuits in the neocortex develop from diverse types of neurons that migrate and form synapses. Here we quantify the circuit patterns of synaptogenesis for inhibitory interneurons in the developing mouse somatosensory cortex. We studied synaptic innervation of cell bodies, apical dendrites, and axon initial segments using three-dimensional electron microscopy focusing on the first 4 weeks postnatally (postnatal days P5 to P28). We found that innervation of apical dendrites occurs early and specifically: Target preference is already almost at adult levels at P5. Axons innervating cell bodies, on the other hand, gradually acquire specificity from P5 to P9, likely via synaptic overabundance followed by antispecific synapse removal. Chandelier axons show first target preference by P14 but develop full target specificity almost completely by P28, which is consistent with a combination of axon outgrowth and off-target synapse removal. This connectomic developmental profile reveals how inhibitory axons in the mouse cortex establish brain circuitry during development., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Mutations in the Euchromatic Histone Methyltransferase 1 (EHMT1) gene cause Kleefstra syndrome, a rare form of intellectual disability (ID) with strong autistic traits and sensory processing deficits. Proper development of inhibitory interneurons is crucial for sensory function. Here we report a timeline of Parvalbumin-positive (PV + ) interneuron development in the three most important sensory cortical areas in the Ehmt1 +/- mouse. We find a hitherto unreported delay of PV + neuron maturation early in sensory development, with layer- and region-specific variability later in development. The delayed PV + maturation is also reflected in a delayed maturation of GABAergic transmission in Ehmt1 +/- auditory cortex, where we find a reduced GABA release probability specifically in putative PV + synapses. Together with earlier reports of excitatory impairments in Ehmt1 +/- neurons, we propose a shift in excitatory-inhibitory balance towards overexcitability in Ehmt1 +/- sensory cortices as a consequence of early deficits in inhibitory maturation.

Astrocytes have been shown to modulate synaptic transmission and plasticity in specific cortical synapses, but our understanding of the underlying molecular and cellular mechanisms remains limited. Here we present a new biophysicochemical model of a somatosensory cortical layer 4 to layer 2/3 synapse to study the role of astrocytes in spike-timing-dependent long-term depression (t-LTD) in vivo. By applying the synapse model and electrophysiological data recorded from rodent somatosensory cortex, we show that a signal from a postsynaptic neuron, orchestrated by endocannabinoids, astrocytic calcium signaling, and presynaptic N-methyl-D-aspartate receptors coupled with calcineurin signaling, induces t-LTD which is sensitive to the temporal difference between post- and presynaptic firing. We predict for the first time the dynamics of astrocyte-mediated molecular mechanisms underlying t-LTD and link complex biochemical networks at presynaptic, postsynaptic, and astrocytic sites to the time window of t-LTD induction. During t-LTD a single astrocyte acts as a delay factor for fast neuronal activity and integrates fast neuronal sensory processing with slow non-neuronal processing to modulate synaptic properties in the brain. Our results suggest that astrocytes play a critical role in synaptic computation during postnatal development and are of paramount importance in guiding the development of brain circuit functions, learning and memory., Competing Interests: The authors have declared that no competing interests exist.

The formation of functional cortical maps in the cerebral cortex results from a timely regulated interaction between intrinsic genetic mechanisms and electrical activity. To understand how transcriptional regulation influences network activity and neuronal excitability within the neocortex, we used mice deficient for Nr2f1 (also known as COUP-TFI), a key determinant of primary somatosensory (S1) area specification during development. We found that the cortical loss of Nr2f1 impacts on spontaneous network activity and synchronization of S1 cortex at perinatal stages. In addition, we observed alterations in the intrinsic excitability and morphological features of layer V pyramidal neurons. Accordingly, we identified distinct voltage-gated ion channels regulated by Nr2f1 that might directly influence intrinsic bioelectrical properties during critical time windows of S1 cortex specification. Altogether, our data suggest a tight link between Nr2f1 and neuronal excitability in the developmental sequence that ultimately sculpts the emergence of cortical network activity within the immature neocortex., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Higher brain function in mammals primarily relies on complex yet sophisticated neuronal circuits in the neocortex. In early developmental stages, neocortical circuits are coarse. Mostly postnatally, the circuits are reorganized to establish mature precise connectivity, in an activity-dependent manner. These connections underlie adult brain function. The rodent somatosensory cortex (barrel cortex) contains a barrel map in layer 4 (L4) and has been considered an ideal model for the study of postnatal neuronal circuit formation since the first report of barrels in 1970. Recently, two-photon microscopy has been used for analyses of neuronal circuit formation in the mammalian brain during early postnatal development. These studies have further highlighted the mouse barrel cortex as an ideal model. In particular, the unique dendritic projection pattern of barrel cortex L4 spiny stellate neurons (barrel neurons) is key for the precise one-to-one functional relationship between whiskers and barrels and thus an important target of studies. In this article, I will review the morphological aspects of postnatal development of neocortical circuits revealed by recent two-photon in vivo imaging studies of the mouse barrel cortex and other related works. The focus of this review will be on barrel neuron dendritic refinement during neonatal development., (© 2020 Japanese Society of Developmental Biologists.)

The sexual characteristics of the vertebrate body change under the control of sex hormones. In mammals, genitals undergo major changes in puberty. While such bodily changes have been well documented, the associated changes in the nervous system are poorly understood. To address this issue, we studied the growth and innervation of the mouse penis throughout puberty. To this end, we measured length and thickness of the mouse penis in prepubertal (3-4 week old) and adult (8-10 week old) mice and performed fiber counts of the dorsal penile nerve. We obtained such counts with confocal imaging of proximal sections of the mouse penis after paraffin embedding and antibody staining against Protein-Gene-Product-9.5 or Neurofilament-H in combination with antigen retrieval procedures. We find that the mouse penis grows roughly 1.4 times in both thickness and length. Fiber counts in the dorsal penile nerve were not different in prepubertal (1,620 ± 165 fibers per penis) and adult (1,572 ± 383 fibers per penis) mice, however. Antibody staining along with myelin staining by Luxol-Fast-Blue suggested about 57% of penile nerve fibers were myelinated. Quantification of the area of mouse somatosensory penis cortex allowed us to compare cortical magnification of the penile cortex and the whisker-barrel-cortex systems. This comparison suggested that 2 to 4 times less cortical area is devoted to a penile-nerve-fiber than to a whisker-nerve-fiber. The constant innervation of mouse penis through puberty suggests that the pubertal increase of cortical magnification of the penis is not simply a reflection of peripheral change., (© 2020 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.)

For half a century now, the barrel cortex of common laboratory rodents has been an exceptionally useful model for studying the formation of topographically organized maps, neural patterning, and plasticity, both in development and in maturity. We present a historical perspective on how barrels were discovered, and how thereafter, they became a workhorse for developmental neuroscientists and for studies on brain plasticity and activity-dependent modeling of brain circuits. What is particularly remarkable about this sensory system is a cellular patterning that is induced by signals derived from the sensory receptors surrounding the snout whiskers and transmitted centrally to the brainstem (barrelettes), the thalamus (barreloids), and the neocortex (barrels). Injury to the sensory receptors shortly after birth leads to predictable pattern alterations at all levels of the system. Mouse genetics have increased our understanding of how barrels are constructed and revealed the interplay of the molecular programs that direct axon growth and cell specification, with activity-dependent mechanisms. There is an ever-rising interest in this sensory system as a neurobiological model to study development of somatotopy, patterning, and plasticity at both the morphologic and physiological levels. This article is part of a group of articles commemorating the 50th anniversary of the Society for Neuroscience., (Copyright © 2020 the authors.)

There is growing interest in developing and using novel measures to assess how the body is represented in human infancy. Various lines of evidence with adults and older children show that tactile perception is modulated by a high-level representation of the body. For instance, the distance between two points of tactile stimulation is perceived as being greater when these points cross a joint boundary than when they are within a body part, suggesting that the representation of the body is structured with joints acting as categorical boundaries between body parts. Investigating the developmental origins of this categorical effect has been constrained by infants' inability to verbally report on the properties of tactile stimulation. Here we made novel use of an infant brain measure, the somatosensory mismatch negativity (sMMN), to explore categorical aspects of tactile body processing in infants aged 6-7 months. Amplitude of the sMMN elicited by tactile stimuli across the wrist boundary was significantly greater than for stimuli of equal distance that were within the boundary, suggesting a categorical effect in body processing in infants. We suggest that an early-appearing, structured representation of the body into 'parts' may play a role in mapping correspondences between self and other., Competing Interests: Declaration of Competing Interest The reported study does not involve any conflict of interest., (Copyright © 2020. Published by Elsevier Ltd.)

This review and synthesis discusses recent work that has utilized brain imaging methods, such as the electroencephalogram (EEG) and magnetoencephalogram, to provide insights into the ways that the body is represented in the infant brain. One aspect of body representation concerns somatotopic maps of the body surface in somatosensory cortex. A good deal is known about the properties of these maps in adults, but there has been relatively little developmental work. Recent studies have provided new insights into the organization of infant neural body maps and have laid the foundations for examining their plasticity in relation to behavioral development. Other work has suggested that neural body maps may be involved in the registration of correspondences between self and other, with implications for early social development. Here, body representations are discussed in the context of preterm birth and autism spectrum disorder, providing novel perspectives relevant to developmental medicine and child neurology. WHAT THIS PAPER ADDS: ●Somatotopic body maps develop prenatally through intrinsic and activity-dependent mechanisms. ●There is increasing interest in understanding postnatal plasticity in body maps. ●Body representations may be involved in the registration of preverbal, interpersonal relationships., (© 2020 Mac Keith Press.)

In recent years, numerous studies have shown that astrocytes play an important role in neuronal processing of information. One of the most interesting findings is the existence of bidirectional interactions between neurons and astrocytes at synapses, which has given rise to the concept of "tripartite synapses" from a functional point of view. We used focused ion beam milling and scanning electron microscopy (FIB/SEM) to examine in 3D the relationship of synapses with astrocytes that were previously labeled by intracellular injections in the rat somatosensory cortex. We observed that a large number of synapses (32%) had no contact with astrocytic processes. The remaining synapses (68%) were in contact with astrocytic processes, either at the level of the synaptic cleft (44%) or with the pre- and/or post-synaptic elements (24%). Regarding synaptic morphology, larger synapses with more complex shapes were most frequently found within the population that had the synaptic cleft in contact with astrocytic processes. Furthermore, we observed that although synapses were randomly distributed in space, synapses that were free of astrocytic processes tended to form clusters. Overall, at least in the developing rat neocortex, the concept of tripartite synapse only seems to be applicable to a subset of synapses., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The activity-dependent rules that govern the wiring of GABAergic interneurons are not well understood. Chandelier cells (ChCs) are a type of GABAergic interneuron that control pyramidal cell output through axo-axonic synapses that target the axon initial segment. In vivo imaging of ChCs during development uncovered a narrow window (P12-P18) over which axons arborized and formed connections. We found that increases in the activity of either pyramidal cells or individual ChCs during this temporal window result in a reversible decrease in axo-axonic connections. Voltage imaging of GABAergic transmission at the axon initial segment (AIS) showed that axo-axonic synapses were depolarizing during this period. Identical manipulations of network activity in older mice (P40-P46), when ChC synapses are inhibitory, resulted instead in an increase in axo-axonic synapses. We propose that the direction of ChC synaptic plasticity follows homeostatic rules that depend on the polarity of axo-axonic synapses., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Sensory experience regulates the structural and functional wiring of sensory cortices. In previous work, we showed that whisker deprivation (WD) from birth not only reduced excitatory synaptic transmission of layer (L) 2/3 pyramidal neurons of the correspondent barrel cortex in mice, but also cross-modally reduced synaptic transmission of L2/3 pyramidal neurons in other sensory cortices. Here, we used in utero electroporation, in combination with optical clearing, to examine the main morphological components regulating neural circuit wiring, namely presynaptic bouton density, spine density, as well as dendrite and axon arbor lengths. We found that WD from P0 to P14 reduced presynaptic bouton density in both L4 and L2/3 inputs to L2/3 pyramidal neurons, as well as spine density across the dendritic tree of L2/3 pyramidal neurons, in the barrel field of the primary somatosensory cortex. The cross-modal effects in the primary auditory cortex were manifested mostly as reduced dendrite and axon arbor size, as well as reduced bouton density of L2/3 inputs. Increasing sensory experience by rearing mice in an enriched environment rescued the effects of WD. Together, these results demonstrate that multiple morphological factors contribute to experience-dependent structural plasticity during early wiring of the sensory cortices., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The multiplex role of cadherin-based adhesion complexes during development of pallial excitatory neurons has been thoroughly characterized. In contrast, much less is known about their function during interneuron development. Here, we report that conditional removal of N-cadherin (Cdh2) from postmitotic neuroblasts of the subpallium results in a decreased number of Gad65-GFP-positive interneurons in the adult cortex. We also found that interneuron precursor migration into the pallium was already delayed at E14. Using immunohistochemistry and TUNEL assay in the embryonic subpallium, we excluded decreased mitosis and elevated cell death as possible sources of this defect. Moreover, by analyzing the interneuron composition of the adult somatosensory cortex, we uncovered an unexpected interneuron-type-specific defect caused by Cdh2-loss. This was not due to a fate-switch between interneuron populations or altered target selection during migration. Instead, potentially due to the migration delay, part of the precursors failed to enter the cortical plate and consequently got eliminated at early postnatal stages. In summary, our results indicate that Cdh2-mediated interactions are necessary for migration and survival during the postmitotic phase of interneuron development. Furthermore, we also propose that unlike in pallial glutamatergic cells, Cdh2 is not universal, rather a cell type-specific factor during this process., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The barrel cortex is within the primary somatosensory cortex of the rodent, and processes signals from the vibrissae. Much focus has been devoted to the function of neurons, more recently, the role of glial cells in the processing of sensory input has gained increasing interest. Microglia are the principal immune cells of the nervous system that survey and regulate the cellular constituents of the dynamic nervous system. We investigated the normal and disrupted development of microglia in barrel cortex by chronically depriving sensory signals via whisker trimming for the animals' first postnatal month. Using immunohistochemistry to label microglia, we performed morphological reconstructions as well as densitometry analyses as a function of developmental age and sensory experience. Findings suggest that both developmental age and sensory experience has profound impact on microglia morphology. Following chronic sensory deprivation, microglia undergo a morphological transition from a monitoring or resting state to an altered morphological state, by exhibiting expanded cell body size and retracted processes. Sensory restoration via whisker regrowth returns these morphological alterations back to age-matched control values. Our results indicate that microglia may be recruited to participate in the modulation of neuronal structural remodeling during developmental critical periods and in response to alteration in sensory input., (© 2019 Wiley Periodicals, Inc.)

During neonatal development, sensory cortices generate spontaneous activity patterns shaped by both sensory experience and intrinsic influences. How these patterns contribute to the assembly of neuronal circuits is not clearly understood. Using longitudinal in vivo calcium imaging in un-anesthetized mouse pups, we show that spatially segregated functional assemblies composed of interneurons and pyramidal cells are prominent in the somatosensory cortex by postnatal day (P) 7. Both reduction of GABA release and synaptic inputs onto pyramidal cells erode the emergence of functional topography, leading to increased network synchrony. This aberrant pattern effectively blocks interneuron apoptosis, causing increased survival of parvalbumin and somatostatin interneurons. Furthermore, the effect of GABA on apoptosis is mediated by inputs from medial ganglionic eminence (MGE)-derived but not caudal ganglionic eminence (CGE)-derived interneurons. These findings indicate that immature MGE interneurons are fundamental for shaping GABA-driven activity patterns that balance the number of interneurons integrating into maturing cortical networks., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The developmental journey of cortical interneurons encounters several activity-dependent milestones. During the early postnatal period in developing mice, GABAergic neurons are transient preferential recipients of thalamic inputs and undergo activity-dependent migration arrest, wiring, and programmed cell-death. Despite their importance for the emergence of sensory experience and the role of activity in their integration into cortical networks, the collective dynamics of GABAergic neurons during that neonatal period remain unknown. Here, we study coordinated activity in GABAergic cells of the mouse barrel cortex using in vivo calcium imaging. We uncover a transient structure in GABAergic population dynamics that disappears in a sensory-dependent process. Its building blocks are anatomically clustered GABAergic assemblies mostly composed by prospective parvalbumin-expressing cells. These progressively widen their territories until forming a uniform perisomatic GABAergic network. Such transient patterning of GABAergic activity is a functional scaffold that links the cortex to the external world prior to active exploration. VIDEO ABSTRACT., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Topographic sensory maps are a prominent feature of the adult primate brain. Here, we asked whether topographic representations of the body are present at birth. Using functional MRI (fMRI), we find that the newborn somatomotor system, spanning frontoparietal cortex and subcortex, comprises multiple topographic representations of the body. The organization of these large-scale body maps was indistinguishable from those in older monkeys. Finer-scale differentiation of individual fingers increased over the first 2 y, suggesting that topographic representations are refined during early development. Last, we found that somatomotor representations were unchanged in 2 visually impaired monkeys who relied on touch for interacting with their environment, demonstrating that massive shifts in early sensory experience in an otherwise anatomically intact brain are insufficient for driving cross-modal plasticity. We propose that a topographic scaffolding is present at birth that both directs and constrains experience-driven modifications throughout somatosensory and motor systems., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Spontaneous correlated activity in cortical columns is critical for postnatal circuit refinement. We used spatial discrimination techniques to explore the late maturation of synaptic pathways through the laminar distribution of the field potential (FP) generators underlying spontaneous and evoked activities of the S1HL cortex in juvenile (P14-P16) and adult anesthetized rats. Juveniles exhibit an intermittent FP pattern resembling Up/Down states in adults, but with much reduced power and different laminar distribution. Whereas FPs in active periods are dominated by a layer VI generator in juveniles, in adults a developing multipart generator takes over, displaying current sinks in middle layers (III-V). The blockade of excitatory transmission in upper and middle layers of adults recovered the juvenile-like FP profiles. In addition to the layer VI generator, a gamma-specific generator in supragranular layers was the same in both age groups. While searching for dynamical coupling among generators in juveniles we found significant cross-correlation in ∼one-half of the tested pairs, whereas excessive coherence hindered their efficient separation in adults. Also, potentials evoked by tactile and electrical stimuli showed different short-latency dipoles between the two age groups, and the juveniles lacked the characteristic long latency UP state currents in middle layers. In addition, the mean firing rate of neurons was lower in juveniles. Thus, cortical FPs originate from different intra-columnar segments as they become active postnatally. We suggest that although some cortical segments are active early postnatally, a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers. SIGNIFICANCE STATEMENT Early postnatal activity in the rodent cortex is mostly endogenous, whereas it becomes driven by peripheral input at later stages. The precise schedule for the maturation of synaptic pathways is largely unknown. We explored this in the somatosensory hindlimb cortex at an age when animals begin to use their limbs by uncovering the laminar distribution of the field potential generators underlying the dominant delta waves in juveniles and adults. Our results suggest that field potentials are mostly generated by a pathway in deep layers, whereas other pathways mature later in middle layers and take over in adults. We suggest that a functional sensory-motor control relies on a delayed maturation and network integration of synaptic connections in middle layers., (Copyright © 2019 the authors.)

Early loss of vision produces dramatic changes in the functional organization and connectivity of the neocortex in cortical areas that normally process visual inputs, such as the primary and second visual area. This loss also results in alterations in the size, functional organization, and neural response properties of the primary somatosensory area, S1. However, the anatomical substrate for these functional changes in S1 has never been described. In the present investigation, we quantified the cortical and subcortical connections of S1 in animals that were bilaterally enucleated very early in development, prior to the formation of retino-geniculate and thalamocortical pathways. We found that S1 receives dense inputs from novel cortical fields, and that the density of existing cortical and thalamocortical connections was altered. Our results demonstrate that sensory systems develop in tandem and that alterations in sensory input in one system can affect the connections and organization of other sensory systems. Thus, therapeutic intervention following early loss of vision should focus not only on restoring vision, but also on augmenting the natural plasticity of the spared systems., (© 2018 Wiley Periodicals, Inc.)

A small subset of interneurons that are generated earliest as pioneer neurons are the first cohort of neurons that enter the neocortex. However, it remains largely unclear whether these early-generated interneurons (EGIns) predominantly regulate neocortical circuit formation. Using inducible genetic fate mapping to selectively label EGIns and pseudo-random interneurons (pRIns), we found that EGIns exhibited more mature electrophysiological and morphological properties and higher synaptic connectivity than pRIns in the somatosensory cortex at early postnatal stages. In addition, when stimulating one cell, the proportion of EGIns that influence spontaneous network synchronization is significantly higher than that of pRIns. Importantly, toxin-mediated ablation of EGIns after birth significantly reduce spontaneous network synchronization and decrease inhibitory synaptic formation during the first postnatal week. These results suggest that EGIns can shape developing networks and may contribute to the refinement of neuronal connectivity before the establishment of the adult neuronal circuit., Competing Interests: CW, JM, YX, SJ, TC, ZY, XM, SZ, LL, YF, YY No competing interests declared, (© 2019, Wang et al.)

Spike timing is an important factor in the modification of synaptic strength. Various forms of spike timing-dependent plasticity (STDP) occur in the brains of diverse species, from insects to humans. In unimodal STDP, only LTP or LTD occurs at the synapse, regardless of which neuron spikes first; the magnitude of potentiation or depression increases as the time between presynaptic and postsynaptic spikes decreases. This from of STDP may promote developmental strengthening or weakening of early projections. In bidirectional Hebbian STDP, the magnitude and the sign (potentiation or depression) of plasticity depend, respectively, on the timing and the order of presynaptic and postsynaptic spikes. In the rodent barrel cortex, multiple forms of STDP appear sequentially during development, and they contribute to network formation, retraction, or fine-scale functional reorganization. Hebbian STDP appears at L4-L2/3 synapses starting at postnatal day (P) 15; the synapses exhibit unimodal "all-LTP STDP" before that age. The appearance of Hebbian STDP at L4-L2/3 synapses coincides with the maturation of parvalbumin-containing GABA interneurons in L4, which contributes to the generation of L4-before-L2/3 spiking in response to thalamic input by producing fast feedforward suppression of both L4 and L2/3 cells. After P15, L4-L2/3 STDP mediates fine-scale circuit refinement, essential for the critical period in the barrel cortex. In this review, we first briefly describe the relevance of STDP to map plasticity in the barrel cortex, then look over roles of distinct forms of STDP during development. Finally, we propose a hypothesis that explains the transition from network formation to the initiation of the critical period in the barrel cortex., (Copyright © 2019 the authors.)

The effects of 15-day restriction diet (from 1 to 1.5 months of age) on some parameters of brain development were studied in rats. The immediate and delayed (15 days after transfer to normal ration) effects were evaluated. The immediate effects included a significant decrease of the absolute weights of the brain and hemispheres. The relative weight of the brain was significantly higher. The thickness of the cortex of the parietal lobe proper and its layer I decreased. The absolute weights of the brain and hemispheres were less than in the control 15 days after the rats were transferred to ad libitum feeding, while the relative weight of the brain was higher than in controls. The thickness of the parietal and anterior parietal cortex and the numerical density of neurons in layers II and V did not differ from the control. In the neurons of layers II and V of the anterior parietal and parietal lobe proper the nuclei were larger, while the nucleoli were enlarged in the neurons of these locations and the hippocampus, the shifts being significant in the anterior parietal layer V. The concentrations of RNA in the parietal, anterior parietal, and hippocampal lobe neurons in different groups were similar directly and 15 days after the diet. Changes in the gravimetric and morphometric parameters of the brain were paralleled by the development of oxidative stress.

The somatosensory system has a hierarchical organization. Information processing increases in complexity from the contralateral primary sensory cortex to bilateral association cortices and this is represented by a sequence of somatosensory-evoked potentials recorded with scalp electroencephalographies. The mammalian somatosensory system matures over the early postnatal period in a rostro-caudal progression, but little is known about the development of hierarchical information processing in the human infant brain. To investigate the normal human development of the somatosensory hierarchy, we recorded potentials evoked by mechanical stimulation of hands and feet in 34 infants between 34 and 42 weeks corrected gestational age, with median postnatal age of 3 days. We show that the shortest latency potential was evoked for both hands and feet at all ages with a contralateral somatotopic source in the primary somatosensory cortex (SI). However, the longer latency responses, localized in SI and beyond, matured with age. They gradually emerged for the foot and, although always present for the hand, showed a shift from purely contralateral to bilateral hemispheric activation. These results demonstrate the rostro-caudal development of human somatosensory hierarchy and suggest that the development of its higher tiers is complete only just before the time of normal birth., (© The Author(s) 2019. Published by Oxford University Press.)

Reduction in parvalbumin-positive (PV+) interneurons is observed in adult mice exposed to ethanol at postnatal day 7 (P7), a late gestation fetal alcohol spectrum disorder model. To evaluate whether PV+ cells are lost, or PV expression is reduced, we quantified PV+ and associated perineuronal net (PNN)+ cell densities in barrel cortex. While PNN+ cell density was not reduced by P7 ethanol, PV cell density decreased by 25% at P90 with no decrease at P14. PNN+ cells in controls were virtually all PV+, whereas more than 20% lacked PV in ethanol-treated adult animals. P7 ethanol caused immediate apoptosis in 10% of GFP+ cells in G42 mice, which express GFP in a subset of PV+ cells, and GFP+ cell density decreased by 60% at P90 without reduction at P14. The ethanol effect on PV+ cell density was attenuated by lithium treatment at P7 or at P14-28. Thus, reduced PV+ cell density may be caused by disrupted cell maturation, in addition to acute apoptosis. This effect may be regionally specific: in the dentate gyrus, P7 ethanol reduced PV+ cell density by 70% at P14 and both PV+ and PNN+ cell densities by 50% at P90, and delayed lithium did not alleviate ethanol's effect., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

How the variety of neurons that organize into neocortical layers and functional areas arises is a central question in the study of cortical development. While both intrinsic and extrinsic cues are known to influence this process, whether distinct neuronal progenitor groups contribute to neuron diversity and allocation is poorly understood. Using in vivo genetic fate-mapping combined with whole-cell patch clamp recording, we show that the firing pattern and apical dendritic morphology of excitatory neurons in layer 4 of the barrel cortex are specified in part by their neural precursor lineage. Further, we show that separate precursors contribute to unique features of barrel cortex topography including the intralaminar position and thalamic innervation of the neurons they generate. Importantly, many of these lineage-specified characteristics are different from those previously measured for pyramidal neurons in layers 2-3 of the frontal cortex. Collectively, our data elucidate a dynamic temporal program in neuronal precursors that fine-tunes the properties of their progeny according to the lamina of destination.

The complex circuitry and cell-type diversity of the cerebral cortex are required for its high-level functions. The mechanisms underlying the diversification of cortical neurons during prenatal development have received substantial attention, but understanding of neuronal heterogeneity is more limited during later periods of cortical circuit maturation. To address this knowledge gap, connectivity analysis and molecular phenotyping of cortical neuron subtypes that express the developing synapse-enriched MET receptor tyrosine kinase were performed. Experiments used a MetGFP transgenic mouse line, combined with coexpression analysis of class-specific molecular markers and retrograde connectivity mapping. The results reveal that MET is expressed by a minor subset of subcerebral and a larger number of intratelencephalic projection neurons. Remarkably, MET is excluded from most layer 6 corticothalamic neurons. These findings are particularly relevant for understanding the maturation of discrete cortical circuits, given converging evidence that MET influences dendritic elaboration and glutamatergic synapse maturation. The data suggest that classically defined cortical projection classes can be further subdivided based on molecular characteristics that likely influence synaptic maturation and circuit wiring. Additionally, given that MET is classified as a high confidence autism risk gene, the data suggest that projection neuron subpopulations may be differentially vulnerable to disorder-associated genetic variation.

Considerable evidence suggests loss-of-function mutations in the chromatin remodeler CHD2 contribute to a broad spectrum of human neurodevelopmental disorders. However, it is unknown how CHD2 mutations lead to impaired brain function. Here we report mice with heterozygous mutations in Chd2 exhibit deficits in neuron proliferation and a shift in neuronal excitability that included divergent changes in excitatory and inhibitory synaptic function. Further in vivo experiments show that Chd2 +/- mice displayed aberrant cortical rhythmogenesis and severe deficits in long-term memory, consistent with phenotypes observed in humans. We identified broad, age-dependent transcriptional changes in Chd2 +/- mice, including alterations in neurogenesis, synaptic transmission, and disease-related genes. Deficits in interneuron density and memory caused by Chd2 +/- were reproduced by Chd2 mutation restricted to a subset of inhibitory neurons and corrected by interneuron transplantation. Our results provide initial insight into how Chd2 haploinsufficiency leads to aberrant cortical network function and impaired memory., (Copyright © 2018 Elsevier Inc. All rights reserved.)

In the rodent somatosensory system, the disproportionally large whisker representation and their specialization into barrel-shaped units in the different sensory relays has offered experimentalists with an ideal tool to identify mechanisms involved in brain map formation. These combine three intertwined constraints: Firstly, fasciculation of the incoming axons; secondly, early neural activity; finally, molecular patterning. Sophisticated genetic manipulations in mice have now allowed dissecting these mechanisms with greater accuracy. Here we discuss some recent papers that provided novel insights into how these different mapping rules and constraints interact to shape the barrel map., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

This review provides an overview on the development of the rodent whisker-to-barrel cortex system from late embryonic stage to the end of the first postnatal month. During this period the system shows a remarkable transition from a mostly genetic-molecular driven generation of crude connectivity, providing the template for activity-dependent structural and functional maturation and plasticity, to the manifestation of a complex behavioral repertoire including social interactions. Spontaneous and sensory-evoked activity is present in neonatal barrel cortex and control the generation of the cortical architecture. Half a century after its first description by Woolsey and van der Loos the whisker-to-barrel cortex system with its unique and clear topographic organization still offers the exceptional opportunity to study sensory processing and complex behavior., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The retinoic acid-related orphan receptor alpha (RORα) is well-known for its role in cerebellar development and maturation as revealed in staggerer mice. However, its potential involvement in the development of other brain regions has hardly been assessed. Here, we describe a new role of RORα in the development of primary somatosensory maps. Staggerer mice showed a complete disruption of barrels in the somatosensory cortex and of barreloids in the thalamus. This phenotype results from a severe reduction of thalamocortical axon (TCA) branching and a defective maturation of layer IV cortical neurons during postnatal development. Conditional deletion of RORα was conducted in the thalamus or the cortex to determine the specific contribution of RORα in each of these structures to these phenotypes. This showed that RORα is cell-autonomously required in the thalamus for the organization of TCAs into periphery-related clusters and in the somatosensory cortex for the dendritic maturation of layer IV neurons. Microarray analyses revealed that Sema7a, Neph, and Adcy8 are RORα regulated genes that could be implicated in TCA and cortical maturation. Overall, our study outlines a new role of RORα for the coordinated maturation of the somatosensory thalamus and cortex during the assembly of columnar barrel structures.

KCC2 is the major chloride extruder in neurons. The spatiotemporal regulation of KCC2 expression orchestrates the developmental shift towards inhibitory GABAergic drive and the formation of glutamatergic synapses. Whether KCC2's role in synapse formation is similar in different brain regions is unknown. First, we found that KCC2 subcellular localization, but not overall KCC2 expression levels, differed between cortex and hippocampus during the first postnatal week. We performed site-specific in utero electroporation of KCC2 cDNA to target either hippocampal CA1 or somatosensory cortical pyramidal neurons. We found that a premature expression of KCC2 significantly decreased spine density in CA1 neurons, while it had the opposite effect in cortical neurons. These effects were cell autonomous, because single-cell biolistic overexpression of KCC2 in hippocampal and cortical organotypic cultures also induced a reduction and an increase of dendritic spine density, respectively. In addition, we found that the effects of its premature expression on spine density were dependent on BDNF levels. Finally, we showed that the effects of KCC2 on dendritic spine were dependent on its chloride transporter function in the hippocampus, contrary to what was observed in cortex. Altogether, these results demonstrate that KCC2 regulation of dendritic spine development, and its underlying mechanisms, are brain-region specific.

To understand how neurons assemble to form functional circuits, it is necessary to obtain a detailed knowledge of their diversity and to define the developmental specification programs that give rise to this diversity. Invertebrates and vertebrates appear to share common developmental principles of neuronal specification in which cascades of transcription factors temporally pattern progenitors, while spatial cues modify the outcomes of this temporal patterning. Here, we highlight these conserved mechanisms and describe how they are used in distinct neural structures. We present the questions that remain for a better understanding of neuronal specification. Single-cell RNA profiling approaches will potentially shed light on these questions, allowing not only the characterization of neuronal diversity in adult brains, but also the investigation of the developmental trajectories leading to the generation and maintenance of this diversity., (Copyright © 2018, American Association for the Advancement of Science.)

Key Points: Several behavioural studies have shown the sensory perceptions are reduced during movement; yet the neurophysiological reason for this is not clear. Participants underwent stimulation of the median nerve when either sitting quietly (i.e. passive stimulation condition) or performing haptic exploration of a ball with the left hand. Magnetoencephalographic brain imaging and advanced beamforming methods were used to identify the differences in somatosensory cortical responses. We show that the neural populations active during the passive stimulation condition were strongly gated during the haptic exploration task. These results imply that the reduced haptic perceptions might be governed by gating of certain somatosensory neural populations., Abstract: Several behavioural studies have shown that children have reduced sensory perceptions during movement; however, the neurophysiological nexus for these altered perceptions remains unknown. We used magnetoencephalographic brain imaging and advanced beamforming methods to address this knowledge gap. In our experiment, a cohort of children (aged 10-18 years) underwent stimulation of the median nerve when either sitting quietly (i.e. passive stimulation condition) or performing haptic exploration of a ball with the left hand. Our results revealed two novel observations. First, there was a relationship between the child's age and the strength of the beta (18-26 Hz) response seen within the somatosensory cortices during the passive stimulation condition. This suggests that there may be an age-dependent change in the processing of peripheral feedback by the somatosensory cortices. Second, all of the cortical regions that were active during the passive stimulation condition were almost completely gated during the haptic task. Instead, the haptic task involved neural oscillations within Brodmann area 2, which is known to convey less spatially precise tactile information but is involved in the processing of more complex somatosensations across the respective digits. These results imply that the reduced somatosensory perceptions seen during movements in healthy children may be related to the gating of certain neural generators, as well as activation of haptic-specific neural generators within the somatosensory cortices. The utilization of such haptic-specific circuits during development may lead to the enhanced somatosensory processing during haptic exploration seen in healthy adults., (© 2018 The Authors. The Journal of Physiology © 2018 The Physiological Society.)

Proper formation of laminar structures in sensory cortexes is critical for sensory information processing. Previous studies suggested that the timing of neuronal migration and the laminar position of cortical neurons differ among sensory cortexes. How they differ during postnatal development has not been systematically investigated. Here, identifying laminas using transcription factors, we examined postnatal changes in neuronal density and distribution in presumptive primary auditory (ACx), visual (VCx), and somatosensory cortexes (SCx) in a strain of mice using immunofluorescence techniques. Development of laminar thickness and its cortical proportion differed among the sensory cortexes. Layers 2-4 defined by Cut-like homeobox 1 (Cux1)-expressing neurons were narrower, and layer 5 was wider in ACx compared to those in VCx or SCx, while Forkhead-box protein P2 (Foxp2)-defined layer 6 was wider in SCx than the other two sensory cortexes throughout postnatal development. Meanwhile, thalamocortical input layers identified by Cux1-expressing neurons formed later in ACx than in the other two cortical regions. The cell densities of ETS-related protein 81-expressing neurons increased in both lower and upper layers but at distinct timing, while those of COUP-TF-interacting protein 2 expressing neurons in the lower layers changed bidirectionally (i.e., increased or decreased) both in layer- and cortical region-specific manners. Foxp2-expressing cells in layer 6 distributed differently and declined at different timing among the sensory cortexes. Overall, we demonstrate that the maturational timing of lamina differs among the sensory cortexes and that postnatal age-dependent changes in neuronal distribution are unique to each of the sensory cortexes., (© 2018 Wiley Periodicals, Inc.)

The neocortex is a 6-layered laminated structure with a precise anatomical and functional organization ensuring proper function. Laminar positioning of cortical neurons, as determined by termination of neuronal migration, is a key determinant of their ability to assemble into functional circuits. However, the exact contribution of laminar placement to dendrite morphogenesis and synapse formation remains unclear. Here we manipulated the laminar position of cortical neurons by knocking down doublecortin (Dcx), a crucial effector of migration, and show that misplaced neurons fail to properly form dendrites, spines, and functional glutamatergic and GABAergic synapses. We further show that knocking down Dcx in properly positioned neurons induces similar but milder defects, suggesting that the laminar misplacement is the primary cause of altered neuronal development. Thus, the specific laminar environment of their fated layers is crucial for the maturation of cortical neurons, and influences their functional integration into developing cortical circuits.

The neonatal mammal faces an array of sensory stimuli when diverse neuronal types have yet to form sensory maps. How these inputs interact with intrinsic neuronal activity to facilitate circuit assembly is not well understood. By using longitudinal calcium imaging in unanesthetized mouse pups, we show that layer I (LI) interneurons, delineated by co-expression of the 5HT3a serotonin receptor (5HT3aR) and reelin (Re), display spontaneous calcium transients with the highest degree of synchrony among cell types present in the superficial barrel cortex at postnatal day 6 (P6). 5HT3aR Re interneurons are activated by whisker stimulation during this period, and sensory deprivation induces decorrelation of their activity. Moreover, attenuation of thalamic inputs through knockdown of NMDA receptors (NMDARs) in these interneurons results in expansion of whisker responses, aberrant barrel map formation, and deficits in whisker-dependent behavior. These results indicate that recruitment of specific interneuron types during development is critical for adult somatosensory function. VIDEO ABSTRACT., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Neurons receive and integrate synaptic inputs at their dendrites, thus dendritic patterning shapes neural connectivity and behavior. Aberrant dendritogenesis is present in neurodevelopmental disorders such as Down's syndrome and autism. Abnormal glutamatergic signaling has been observed in these diseases, as has dysfunction of the metabotropic glutamate receptor 5 (mGluR5). Deleting mGluR5 in cortical glutamatergic neurons disrupted their coordinated dendritic outgrowth toward thalamocortical axons and perturbed somatosensory circuits. Here we show that mGluR5 loss-of-function disrupts dendritogenesis of cortical neurons by increasing mRNA levels of nerve growth factor (NGF) and fibroblast growth factor 10 (FGF10), in part through calcium-permeable AMPA receptors (CP-AMPARs), as the whisker-barrel map is forming. Postnatal NGF and FGF10 expression in cortical layer IV spiny stellate neurons differentially impacted dendritic patterns. Remarkably, NGF-expressing neurons exhibited dendritic patterns resembling mGluR5 knockout neurons: increased total dendritic length/complexity and reduced polarity. Furthermore, suppressing the kinase activity of TrkA, a major NGF receptor, prevents aberrant dendritic patterning in barrel cortex of mGluR5 knockout neurons. These results reveal novel roles for NGF-TrkA signaling and CP-AMPARs for proper dendritic development of cortical neurons. This is the first in vivo demonstration that cortical neuronal NGF expression modulates dendritic patterning during postnatal brain development.