Normal brain function requires proper targeting of synaptic-vesicle (SV) and active-zone components for presynaptic assembly and function. Whether and how synaptogenic signals (e.g., adhesion) at axo-dendritic contact sites promote axonal transport of presynaptic components for synapse formation, however, remain unclear. In this study, we show that Borderless (Bdl), a member of the conserved IgSF9-family trans-synaptic cell adhesion molecules, plays a novel and specific role in regulating axonal transport of SV components. Loss of bdl disrupts axonal transport of SV components in photoreceptor R8 axons, but does not affect the transport of mitochondria. Genetic mosaic analysis, transgene rescue and cell-type-specific knockdown indicate that Bdl is required both presynaptically and postsynaptically for delivering SV components in R8 axons. Consistent with a role for Bdl in R8 axons, loss of bdl causes a failure of R8-dependent phototaxis response to green light. bdl interacts genetically with imac encoding for a member of the UNC-104/Imac/KIF1A-family motor proteins, and is required for proper localization of Imac in R8 presynaptic terminals. Our results support a model in which Bdl mediates specific axo-dendritic interactions in a homophilic manner, which upregulates the Imac motor in promoting axonal transport of SV components for R8 presynaptic assembly and function.SIGNIFICANCE STATEMENT Whether and how synaptogenic adhesion at axo-dendritic contact sites regulates axonal transport of presynaptic components remain unknown. Here we show for the first time that a trans-synaptic adhesion molecule mediates specific interactions at axo-dendritic contact sites, which is required for upregulating the UNC-104/Imac/KIF1A motor in promoting axonal transport of synaptic-vesicle components for presynaptic assembly and function.

Reward-related activity in the dopaminergic midbrain is thought to guide animal behavior, in part by boosting the perceptual and attentional processing of reward-predictive environmental stimuli. In line with this incentive salience hypothesis, studies of human visual search have shown that simple synthetic stimuli, such as lines, shapes, or Gabor patches, capture attention to their location when they are characterized by reward-associated visual features, such as color. In the real world, however, we commonly search for members of a category of visually heterogeneous objects, such as people, cars, or trees, where category examples do not share low-level features. Is attention captured to examples of a reward-associated real-world object category? Here, we have human participants search for targets in photographs of city and landscapes that contain task-irrelevant examples of a reward-associated category. We use the temporal precision of EEG machine learning and ERPs to show that these distractors acquire incentive salience and draw attention, but do not capture it. Instead, we find evidence of rapid, stimulus-triggered attentional suppression, such that the neural encoding of these objects is degraded relative to neutral objects. Humans appear able to suppress the incentive salience of reward-associated objects when they know these objects will be irrelevant, supporting the rapid deployment of attention to other objects that might be more useful. Incentive salience is thought to underlie key behaviors in eating disorders and addiction, among other conditions, and the kind of suppression identified here likely plays a role in mediating the attentional biases that emerge in these circumstances.Significance Statement Like other animals, humans are prone to notice and interact with environmental objects that have proven rewarding in earlier experience. However, it is common that such objects have no immediate strategic use and are therefore distracting. Do these reward-associated real-world objects capture our attention, despite our strategic efforts otherwise? Or are we able to strategically control the impulse to notice them? Here we use machine learning classification of human electrical brain activity to show that we can establish strategic control over the salience of naturalistic reward-associated objects. These objects draw our attention, but do not necessarily capture it, and this kind of control may play an important role in mediating conditions like eating disorder and addiction.

Attention can facilitate the selection of elementary object features such as color, orientation, or motion. This is referred to as feature-based attention and it is commonly attributed to a modulation of the gain and tuning of feature-selective units in visual cortex. Although gain mechanisms are well characterized, little is known about the cortical processes underlying the sharpening of feature selectivity. Here, we show with high-resolution magnetoencephalography in human observers (men and women) that sharpened selectivity for a particular color arises from feedback processing in the human visual cortex hierarchy. To assess color selectivity, we analyze the response to a color probe that varies in color distance from an attended color target. We find that attention causes an initial gain enhancement in anterior ventral extrastriate cortex that is coarsely selective for the target color and transitions within ∼100 ms into a sharper tuned profile in more posterior ventral occipital cortex. We conclude that attention sharpens selectivity over time by attenuating the response at lower levels of the cortical hierarchy to color values neighboring the target in color space. These observations support computational models proposing that attention tunes feature selectivity in visual cortex through backward-propagating attenuation of units less tuned to the target.SIGNIFICANCE STATEMENT Whether searching for your car, a particular item of clothing, or just obeying traffic lights, in everyday life, we must select items based on color. But how does attention allow us to select a specific color? Here, we use high spatiotemporal resolution neuromagnetic recordings to examine how color selectivity emerges in the human brain. We find that color selectivity evolves as a coarse to fine process from higher to lower levels within the visual cortex hierarchy. Our observations support computational models proposing that feature selectivity increases over time by attenuating the responses of less-selective cells in lower-level brain areas. These data emphasize that color perception involves multiple areas across a hierarchy of regions, interacting with each other in a complex, recursive manner.

Animals use vision to perform such diverse behaviors as finding food, interacting socially with other animals, choosing a mate, and avoiding predators. These behaviors are complex and the visual system must process color, motion, and pattern cues efficiently so that animals can respond to relevant stimuli. The visual system achieves this by dividing visual information into separate pathways, but to what extent are these parallel streams separated in the brain? To answer this question, we recorded intracellularly in vivo from 105 morphologically identified neurons in the lobula, a major visual processing structure of bumblebees (Bombus impatiens). We found that these cells have anatomically segregated dendritic inputs confined to one or two of six lobula layers. Lobula neurons exhibit physiological characteristics common to their respective input layer. Cells with arborizations in layers 1-4 are generally indifferent to color but sensitive to motion, whereas layer 5-6 neurons often respond to both color and motion cues. Furthermore, the temporal characteristics of these responses differ systematically with dendritic branching pattern. Some layers are more temporally precise, whereas others are less precise but more reliable across trials. Because different layers send projections to different regions of the central brain, we hypothesize that the anatomical layers of the lobula are the structural basis for the segregation of visual information into color, motion, and stimulus timing.

Gap junctions are ubiquitous throughout the nervous system, mediating critical signal transmission and integration, as well as emergent network properties. In mammalian retina, gap junctions within the Aii amacrine cell-ON cone bipolar cell (CBC) network are essential for night vision, modulation of day vision, and contribute to visual impairment in retinal degenerations, yet neither the extended network topology nor its conservation is well established. Here, we map the network contribution of gap junctions using a high-resolution connectomics dataset of an adult female rabbit retina. Gap junctions are prominent synaptic components of ON CBC classes, constituting 5%-25% of all axonal synaptic contacts. Many of these mediate canonical transfer of rod signals from Aii cells to ON CBCs for night vision, and we find that the uneven distribution of Aii signals to ON CBCs is conserved in rabbit, including one class entirely lacking direct Aii coupling. However, the majority of gap junctions formed by ON CBCs unexpectedly occur between ON CBCs, rather than with Aii cells. Such coupling is extensive, creating an interconnected network with numerous lateral paths both within, and particularly across, these parallel processing streams. Coupling patterns are precise with ON CBCs accepting and rejecting unique combinations of partnerships according to robust rulesets. Coupling specificity extends to both size and spatial topologies, thereby rivaling the synaptic specificity of chemical synapses. These ON CBC coupling motifs dramatically extend the coupled Aii-ON CBC network, with implications for signal flow in both scotopic and photopic retinal networks during visual processing and disease.SIGNIFICANCE STATEMENT Electrical synapses mediated by gap junctions are fundamental components of neural networks. In retina, coupling within the Aii-ON CBC network shapes visual processing in both the scotopic and photopic networks. In retinal degenerations, these same gap junctions mediate oscillatory activity that contributes to visual impairment. Here, we use high-resolution connectomics strategies to identify gap junctions and cellular partnerships. We describe novel, pervasive motifs both within and across classes of ON CBCs that dramatically extend the Aii-ON CBC network. These motifs are highly specific with implications for both signal processing within the retina and therapeutic interventions for blinding conditions. These findings highlight the underappreciated contribution of coupling motifs in retinal circuitry and the necessity of their detection in connectomics studies.

Photoreceptor-specific transcription of individual genes collectively constitutes the transcriptional profile that orchestrates the structural and functional characteristics of each photoreceptor type. It is challenging, however, to study the transcriptional specificity of individual photoreceptor genes because each gene's distinct spatiotemporal transcription patterns are determined by the unique interactions between a specific set of transcription factors and the gene's own cis-regulatory elements (CREs), which remain unknown for most of the genes. For example, it is unknown what CREs underlie the zebrafish mpp5bponli (ponli) and crumbs2b (crb2b) apical polarity genes' restrictive transcription in the red, green, and blue (RGB) cones in the retina, but not in other retinal cell types. Here we show that the intronic enhancers of both the ponli and crb2b genes are conserved among teleost species and that they share sequence motifs that are critical for RGB cone-specific transcription. Given their similarities in sequences and functions, we name the ponli and crb2b enhancers collectively rainbow enhancers. Rainbow enhancers may represent a cis-regulatory mechanism to turn on a group of genes that are commonly and restrictively expressed in RGB cones, which largely define the beginning of the color vision pathway.SIGNIFICANCE STATEMENT Dim-light achromatic vision and bright-light color vision are initiated in rod and several types of cone photoreceptors, respectively; these photoreceptors are structurally distinct from each other. In zebrafish, although quite different from rods and UV cones, RGB cones (red, green, and blue cones) are structurally similar and unite into mirror-symmetric pentamers (G-R-B-R-G) by adhesion. This structural commonality and unity suggest that a set of genes is commonly expressed only in RGB cones but not in other cells. Here, we report that the rainbow enhancers activate RGB cone-specific transcription of the ponli and crb2b genes. This study provides a starting point to study how RGB cone-specific transcription defines RGB cones' distinct functions for color vision.

Search for target objects in visual scenes is guided by mental representations of target features (attentional templates). However, it is unknown when such templates are activated during each search episode and whether this can be controlled by temporal expectations. We used electrophysiological measures to track search template activation processes in real time. In three experiments, female and male humans searched for a color-defined target object in search displays where targets were accompanied by distractors in different nontarget colors. Brief task-irrelevant color singleton probes that matched the target template were flashed rapidly (every 200 ms) throughout each block. Probes presented at times when the target template is active should capture attention, whereas probes presented at other times should not. To assess this, N2pc components were measured as markers of attentional capture, separately for probes at each successive temporal position between two search displays. Results demonstrated that search templates were active from ∼1000 ms before the arrival of the next search display, and were deactivated after each search episode, even when the preceding search display did not contain a target object. Templates were activated later when the predictable interval between search displays was increased. Results demonstrate that search templates are not continuously active but are transiently activated during the preparation for each new search episode. These activation states are regulated in a top-down fashion by temporal expectations about when an attentional template will become task-relevant.SIGNIFICANCE STATEMENT It is often assumed that observers prepare for a visual search task by activating mental representations of search target objects (attentional templates). However, the time course of such template activation processes is completely unknown. By using a new sequential probe presentation technique and electrophysiological measures of attentional processing, we demonstrate that target templates are rapidly activated and deactivated before and after each successive search display, and that these template activation states are tuned to observers' temporal expectations. These results provide novel insights into the temporal dynamics of cognitive control processes in visual attention. They show that attentional templates for visual search are preparatory states that are activated in a transient fashion before each new search episode.

cAMP signaling is known to be critical in neuronal survival and axon growth. Increasingly the subcellular compartmentation of cAMP signaling has been appreciated, but outside of dendritic synaptic regulation, few cAMP compartments have been defined in terms of molecular composition or function in neurons. Specificity in cAMP signaling is conferred in large part by A-kinase anchoring proteins (AKAPs) that localize protein kinase A and other signaling enzymes to discrete intracellular compartments. We now reveal that cAMP signaling within a perinuclear neuronal compartment organized by the large multivalent scaffold protein mAKAPα promotes neuronal survival and axon growth. mAKAPα signalosome function is explored using new molecular tools designed to specifically alter local cAMP levels as studied by live-cell FRET imaging. In addition, enhancement of mAKAPα-associated cAMP signaling by isoform-specific displacement of bound phosphodiesterase is demonstrated to increase retinal ganglion cell survival in vivo in mice of both sexes following optic nerve crush injury. These findings define a novel neuronal compartment that confers cAMP regulation of neuroprotection and axon growth and that may be therapeutically targeted in disease.SIGNIFICANCE STATEMENT cAMP is a second messenger responsible for the regulation of diverse cellular processes including neuronal neurite extension and survival following injury. Signal transduction by cAMP is highly compartmentalized in large part because of the formation of discrete, localized multimolecular signaling complexes by A-kinase anchoring proteins. Although the concept of cAMP compartmentation is well established, the function and identity of these compartments remain poorly understood in neurons. In this study, we provide evidence for a neuronal perinuclear cAMP compartment organized by the scaffold protein mAKAPα that is necessary and sufficient for the induction of neurite outgrowth in vitro and for the survival of retinal ganglion cells in vivo following optic nerve injury.

Two main subcortical pathways serving conscious visual perception are the midget-parvocellular (P), and the parasol-magnocellular (M) pathways. It is generally accepted that the P pathway serves red-green color vision, but the relative contribution of P and M pathways to spatial vision is a long-standing and unresolved issue. Here, we mapped the spatial sampling properties of P and M pathways across the human retina. Data were obtained from immunolabeled vertical sections of six postmortem male and female human donor retinas and imaged using high-resolution microscopy. Cone photoreceptors, OFF-midget bipolar cells (P pathway), OFF-diffuse bipolar (DB) types DB3a and DB3b (M pathway), and ganglion cells were counted along the temporal horizontal meridian, taking foveal spatial distortions (postreceptoral displacements) into account. We found that the density of OFF-midget bipolar and OFF-midget ganglion cells can support one-to-one connections to 1.05-mm (3.6°) eccentricity. One-to-one connections of cones to OFF-midget bipolar cells are present to at least 10-mm (35°) eccentricity. The OFF-midget ganglion cell array acuity is well-matched to photopic spatial acuity measures throughout the central 35°, but the OFF-parasol array acuity is well below photopic spatial acuity, supporting the view that the P pathway underlies high-acuity spatial vision. Outside the fovea, array acuity of both OFF-midget and OFF-DB cells exceeds psychophysical measures of photopic spatial acuity. We conclude that parasol and midget pathway bipolar cells deliver high-acuity spatial signals to the inner plexiform layer, but outside the fovea, this spatial resolution is lost at the level of ganglion cells.SIGNIFICANCE STATEMENT We make accurate maps of the spatial density and distribution of neurons in the human retina to aid in understanding human spatial vision, interpretation of diagnostic tests, and the implementation of therapies for retinal diseases. Here, we map neurons involved with the midget-parvocellular (P pathway) and parasol-magnocellular (M pathway) through human retina. We find that P-type bipolar cells outnumber M-type bipolar cells at all eccentricities. We show that cone photoreceptors and P-type pathway bipolar cells are tightly connected throughout the retina, but that spatial resolution is lost at the level of the ganglion cells. Overall, the results support the view that the P pathway is specialized to serve both high acuity vision and red-green color vision.

The cornea has the densest sensory innervation of the body, originating primarily from neurons in the trigeminal ganglion. The basic principles of cornea nerve patterning have been established many years ago using classic neuroanatomical methods, such as immunocytochemistry and electrophysiology. Our understanding of the morphology and distribution of the sensory nerves in the skin has considerably progressed over the past few years through the generation and analysis of a variety of genetically modified mouse lines. Surprisingly, these lines were not used to study corneal axons. Here, we have screened a collection of transgenic and knockin mice (of both sexes) to select lines allowing the visualization and genetic manipulation of corneal nerves. We identified multiple lines, including some in which different types of corneal axons can be simultaneously observed with fluorescent proteins expressed in a combinatorial manner. We also provide the first description of the morphology and arborization of single corneal axons and identify three main types of branching pattern. We applied this genetic strategy to the analysis of corneal nerve development and plasticity. We provide direct evidence for a progressive reduction of the density of corneal innervation during aging. We also show that the semaphorin receptor neuropilin-1 acts cell-autonomously to control the development of corneal axons and that early axon guidance defects have long-term consequences on corneal innervation.SIGNIFICANCE STATEMENT We have screened a collection of transgenic and knockin mice and identify lines allowing the visualization and genetic manipulation of corneal nerves. We provide the first description of the arborization pattern of single corneal axons. We also present applications of this genetic strategy to the analysis of corneal nerve development and remodeling during aging.

Most of our knowledge about vision comes from experiments in which stimuli are presented to immobile human subjects or animals. In the case of human subjects, movement during psychophysical, electrophysiological, or neuroimaging experiments is considered to be a source of noise to be eliminated. Animals used in visual neuroscience experiments are typically restrained and, in many cases, anesthetized. In reality, however, vision is often used to guide the motion of awake, ambulating organisms. Recent work in mice has shown that locomotion elevates visual neuronal response amplitudes (Niell and Stryker, 2010; Erisken et al., 2014; Fu et al., 2014; Lee et al., 2014; Mineault et al., 2016) and reduces long-range gain control (Ayaz et al., 2013). Here, we used both psychophysics and steady-state electrophysiology to investigate whether similar effects of locomotion on early visual processing can be measured in humans. Our psychophysical results show that brisk walking has little effect on subjects' ability to detect briefly presented contrast changes and that co-oriented flankers are, if anything, more effective masks when subjects are walking. Our electrophysiological data were consistent with the psychophysics indicating no increase in stimulus-driven neuronal responses while walking and no reduction in surround suppression. In summary, we have found evidence that early contrast processing is altered by locomotion in humans but in a manner that differs from that reported in mice. The effects of locomotion on very low-level visual processing may differ on a species-by-species basis and may reflect important differences in the levels of arousal associated with locomotion.SIGNIFICANCE STATEMENT Mice are the current model of choice for studying low-level visual processing. Recent studies have shown that mouse visual cortex is modulated by behavioral state: primary visual cortex neurons in locomoting mice tend to be more sensitive and less influenced by long-range gain control. Here, we tested these effects in humans by measuring psychophysical detection thresholds and electroencephalography (EEG) responses while subjects walked on a treadmill. We found no evidence of increased contrast sensitivity or reduced surround suppression in walking humans. Our data show that fundamental measurements of early visual processing differ between humans and mice and this has important implications for recent work on the links among arousal, behavior, and vision in these two species.

Experience seems continuous and detailed despite saccadic eye movements changing retinal input several times per second. There is debate whether neural signals related to updating across saccades contain information about stimulus features, or only location pointers without visual details. We investigated the time course of low-level visual information processing across saccades by decoding the spatial frequency of a stationary stimulus that changed from one visual hemifield to the other because of a horizontal saccadic eye movement. We recorded magnetoencephalography while human subjects (both sexes) monitored the orientation of a grating stimulus, making spatial frequency task irrelevant. Separate trials, in which subjects maintained fixation, were used to train a classifier, whose performance was then tested on saccade trials. Decoding performance showed that spatial frequency information of the presaccadic stimulus remained present for ∼200 ms after the saccade, transcending retinotopic specificity. Postsaccadic information ramped up rapidly after saccade offset. There was an overlap of over 100 ms during which decoding was significant from both presaccadic and postsaccadic processing areas. This suggests that the apparent richness of perception across saccades may be supported by the continuous availability of low-level information with a "soft handoff" of information during the initial processing sweep of the new fixation.SIGNIFICANCE STATEMENT Saccades create frequent discontinuities in visual input, yet perception appears stable and continuous. How is this discontinuous input processed resulting in visual stability? Previous studies have focused on presaccadic remapping. Here we examined the time course of processing of low-level visual information (spatial frequency) across saccades with magnetoencephalography. The results suggest that spatial frequency information is not predictively remapped but also is not discarded. Instead, they suggest a soft handoff over time between different visual areas, making this information continuously available across the saccade. Information about the presaccadic stimulus remains available, while the information about the postsaccadic stimulus has also become available. The simultaneous availability of both the presaccadic and postsaccadic information could enable rich and continuous perception across saccades.

Neonatal hindpaw incision primes developing spinal nociceptive circuitry, resulting in enhanced hyperalgesia following reinjury in adulthood. Spinal microglia contribute to this persistent effect, and microglial inhibition at the time of adult reincision blocks the enhanced hyperalgesia. Here, we pharmacologically inhibited microglial function with systemic minocycline or intrathecal SB203580 at the time of neonatal incision and evaluated sex-dependent differences following adult reincision. Incision in adult male and female rats induced equivalent hyperalgesia and spinal dorsal horn expression of genes associated with microglial proliferation (Emr1) and transformation to a reactive phenotype (Irf8). In control adults with prior neonatal incision, the enhanced degree and duration of incision-induced hyperalgesia and spinal microglial responses to reincision were equivalent in males and females. However, microglial inhibition at the time of the neonatal incision revealed sex-dependent effects: the persistent mechanical and thermal hyperalgesia following reincision in adulthood was prevented in males but unaffected in females. Similarly, reincision induced Emr1 and Irf8 gene expression was downregulated in males, but not in females, following neonatal incision with minocycline. To evaluate the distribution of reincision hyperalgesia, prior neonatal incision was performed at different body sites. Hyperalgesia was maximal when the same paw was reincised, and was increased following prior incision at ipsilateral, but not contralateral, sites, supporting a segmentally restricted spinal mechanism. These data highlight the contribution of spinal microglial mechanisms to persistent effects of early-life injury in males, and sex-dependent differences in the ability of microglial inhibition to prevent the transition to a persistent pain state span developmental stages.SIGNIFICANCE STATEMENT Following the same surgery, some patients develop persistent pain. Contributory mechanisms are not fully understood, but early-life experience and sex/gender may influence the transition to chronic pain. Surgery and painful procedural interventions in vulnerable preterm neonates are associated with long-term alterations in somatosensory function and pain that differ in males and females. Surgical injury in neonatal rodents primes the developing nociceptive system and enhances reinjury response in adulthood. Neuroimmune interactions are critical mediators of persistent pain, but sex-dependent differences in spinal neuroglial signaling influence the efficacy of microglial inhibitors following adult injury. Neonatal microglial inhibition has beneficial long-term effects on reinjury response in adult males only, emphasizing the importance of evaluating sex-dependent differences at all ages in preclinical studies.

Stroke-induced immunodepression (SIDS) is an essential cause of poststroke infections. Pharmacological inhibition of SIDS appears promising in preventing life-threatening infections in stroke patients. However, SIDS might represent an adaptive mechanism preventing autoreactive immune responses after stroke. To address this, we used myelin oligodendrocyte glycoprotein (MOG) T-cell receptor transgenic (2D2) mice where >80% of peripheral CD4(+) T cells express a functional receptor for MOG. We investigated in a murine model of middle cerebral artery occlusion the effect of blocking SIDS by inhibiting body's main stress axes, the sympathetic nervous system (SNS) with propranolol and the hypothalamic-pituitary-adrenal axis (HPA) with mifepristone. Blockade of both stress axes robustly reduced infarct volumes, decreased infection rate, and increased long-term survival of 2D2 and C57BL/6J wild-type mice. Despite these protective effects, blockade of SIDS increased CNS antigen-specific Type1 T helper cell (Th1) responses in the brains of 2D2 mice 14 d after middle cerebral artery occlusion. One month after experimental stroke, 2D2 mice developed signs of polyradiculitis, which were diminished by SIDS blockade. Adoptive transfer of CD4(+) T cells, isolated from 2D2 mice, into lymphocyte-deficient Rag-1KO mice did not reveal differences between SIDS blockade and vehicle treatment in functional long-term outcome after stroke. In conclusion, inhibiting SIDS by pharmacological blockade of body's stress axes increases autoreactive CNS antigen-specific T-cell responses in the brain but does not worsen functional long-term outcome after experimental stroke, even in a mouse model where CNS antigen-specific autoreactive T-cell responses are boosted.

Mutations in the synaptic scaffolding protein SHANK3 are a major cause of autism and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher-order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in adult male mice, here we show that loss of Shank3 (Shank3B-/-) results in disrupted local and long-range prefrontal and frontostriatal functional connectivity. We document that prefrontal hypoconnectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.SIGNIFICANCE STATEMENT Mutations in the synaptic scaffolding protein SHANK3 are commonly associated with autism, intellectual, and language deficits. Previous research has linked SHANK3 deficiency to basal ganglia dysfunction, motor stereotypies, and social deficits. However, the neural mechanism whereby Shank3 gene mutations affects cortical functional connectivity and higher-order socio-communicative functions remain unclear. Here we show that loss of SHANK3 in mice results in largely disrupted functional connectivity and abnormal gray matter anatomy in prefrontal areas. We also show that prefrontal connectivity disruption is tightly linked to socio-communicative deficits. Our findings suggest that SHANK3 is a critical orchestrator of frontocortical function, and that disrupted connectivity of prefrontal areas may underpin socio-communicative impairments observed in SHANK3 mutation carriers.