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Key Points Molecular diversification of surface molecules has long been postulated to impart specific surface identities on neuronal cell types. Such unique surface identities would allow cells to distinguish one another and connect with their appropriate target cells, thus contributing to the highly precise patterns of connectivity in the nervous system. Several families of cell surface receptors have been identified that display substantial molecular diversity, either because they belong to large gene families or because diversity is generated from a limited number of genes through alternative splicing. Their specific modes of interaction with binding partners generate additional diversity in cell surface interactions. Large-scale extracellular interactome studies are accelerating the characterization of surface molecule–ligand interactions. For some organisms, such as Drosophila melanogaster , a complete characterization of the extracellular interactome is within reach. Advances in single-cell profiling are beginning to support the existence of cell type-specific surface molecule repertoires. Cell type-specific diversity of neurexins and neurexin ligands does not seem to specify connectivity with target cells but may be part of an adhesion code that specifies the synaptic properties of those cell types. Limited in vivo evidence supports the idea that cell type-specific surface molecule repertoires specify connectivity. Protocadherin diversity is important for self-recognition in certain cell types, indirectly contributing to wiring specificity. Cell type-specific expression of type II cadherins, immunoglobulin superfamily proteins and leucine-rich repeat proteins has been shown to contribute to laminar, cellular and subcellular specificity in select instances. Many of the genes encoding cell surface molecules described in this Review have been linked to neurodevelopmental and psychiatric disorders. A deeper understanding of the molecular mechanisms controlling precise connectivity in neural circuits will therefore be essential to develop and realize future treatments for cognitive disorders. Cell surface molecule diversification has been proposed to confer specific surface identities on neuronal cell types, enabling the precise pattern of connectivity that is observed between CNS neurons. In this Review, de Wit and Ghosh explore the role of various protein superfamilies in the specification of such connectivity. The molecular diversification of cell surface molecules has long been postulated to impart specific surface identities on neuronal cell types. The existence of unique cell surface identities would allow neurons to distinguish one another and connect with their appropriate target cells. Although progress has been made in identifying cell type-specific surface molecule repertoires and in characterizing their extracellular interactions, determining how this molecular diversity contributes to the precise wiring of neural circuitry has proven challenging. Here, we review the role of the cadherin, neurexin, immunoglobulin and leucine-rich repeat protein superfamilies in the specification of connectivity. The emerging evidence suggests that the concerted actions of these proteins may critically contribute to the assembly of neural circuits.

Although synaptic transmission may be unidirectional, the establishment of synaptic connections with specific properties can involve bidirectional signaling. Pyramidal neurons in the hippocampus form functionally distinct synapses onto two types of interneurons. Excitatory synapses onto oriens-lacunosum moleculare (O-LM) interneurons are facilitating and have a low release probability, whereas synapses onto parvalbumin interneurons are depressing and have a high release probability. Here, we show that the extracellular leucine-rich repeat fibronectin containing 1 (Elfn1) protein is selectively expressed by O-LM interneurons and regulates presynaptic release probability to direct the formation of highly facilitating pyramidal-O-LM synapses. Thus, postsynaptic expression of Elfn1 in O-LM interneurons regulates presynaptic release probability, which confers target-specific synaptic properties to pyramidal cell axons.

Gene editing in the mouse brain is achieved by injection of Cas9 ribonucleoprotein complexes. We demonstrate editing of post-mitotic neurons in the adult mouse brain following injection of Cas9 ribonucleoprotein (RNP) complexes in the hippocampus, striatum and cortex. Engineered variants of Cas9 with multiple SV40 nuclear localization sequences enabled a tenfold increase in the efficiency of neuronal editing in vivo . These advances indicate the potential of genome editing in the brain to correct or inactivate the underlying genetic causes of neurological diseases.

Light mechanical stimulation of hairy skin can induce a form of itch known as mechanical itch. This itch sensation is normally suppressed by inputs from mechanoreceptors; however, in many forms of chronic itch, including alloknesis, this gating mechanism is lost. Here we demonstrate that a population of spinal inhibitory interneurons that are defined by the expression of neuropeptide Y::Cre (NPY::Cre) act to gate mechanical itch. Mice in which dorsal NPY::Cre-derived neurons are selectively ablated or silenced develop mechanical itch without an increase in sensitivity to chemical itch or pain. This chronic itch state is histamine-independent and is transmitted independently of neurons that express the gastrin-releasing peptide receptor. Thus, our studies reveal a dedicated spinal cord inhibitory pathway that gates the transmission of mechanical itch.

Compromised vascular endothelial barrier function is a salient feature of diabetic complications such as sight-threatening diabetic macular edema (DME). Current standards of care for DME manage aspects of the disease, but require frequent intravitreal administration and are poorly effective in large subsets of patients. Here we provide evidence that an elevated burden of senescent cells in the retina triggers cardinal features of DME pathology and conduct an initial test of senolytic therapy in patients with DME. In cell culture models, sustained hyperglycemia provoked cellular senescence in subsets of vascular endothelial cells displaying perturbed transendothelial junctions associated with poor barrier function and leading to micro-inflammation. Pharmacological elimination of senescent cells in a mouse model of DME reduces diabetes-induced retinal vascular leakage and preserves retinal function. We then conducted a phase 1 single ascending dose safety study of UBX1325 (foselutoclax), a senolytic small-molecule inhibitor of BCL-xL, in patients with advanced DME for whom anti-vascular endothelial growth factor therapy was no longer considered beneficial. The primary objective of assessment of safety and tolerability of UBX1325 was achieved. Collectively, our data suggest that therapeutic targeting of senescent cells in the diabetic retina with a BCL-xL inhibitor may provide a long-lasting, disease-modifying intervention for DME. This hypothesis will need to be verified in larger clinical trials. ClinicalTrials.gov identifier: NCT04537884 . Small-molecule senolytic compounds targeting BCL-xL were beneficial in a mouse model of diabetic edema and well tolerated when tested in a phase 1 trial involving eight patients with diabetic macular edema.

Key Points The current prevalence rates of autism spectrum disorder (ASD) are about 1 in a 100, with a greater incidence in boys. ASD has a strong genetic component, and new sequencing methods have allowed the identification of many rare and de novo mutations that can contribute to the condition. Many of the genes associated with ASD encode for proteins that act at the synapse, which suggests that these might be potential points of intervention and therapeutic targets. Induced pluripotent stem cells derived from individuals with ASD and animal models with construct and face validity provide an opportunity to identify cellular and molecular phenotypes associated with the condition. Clinical development of therapeutics for ASD poses particular challenges with regard to identification of suitable end points, treatment of paediatric populations, lack of biomarkers for progression, and regulatory considerations. Ongoing clinical trials for genetically defined neurodevelopmental disorders such as fragile X syndrome offer a valuable opportunity to learn about considerations for clinical development for ASD and related disorders. The development of drugs for autism spectrum disorder (ASD) is hampered by the limited understanding of its pathophysiology, the heterogeneity of its symptoms, a dearth of experimental models, and the lack of experience in clinical development. In this Review, Ghosh and colleagues present recent insights into the molecular underpinnings of ASD and how these have translated into new tools for drug development, and also new approaches to overcome the particular challenges in this field. The rising rates of autism spectrum disorder (ASD) and the lack of effective medications to treat its core symptoms have led to an increased sense of urgency to identify therapies for this group of neurodevelopmental conditions. Developing drugs for ASD, however, has been challenging because of a limited understanding of its pathophysiology, difficulties in modelling the disease in vitro and in vivo , the heterogeneity of symptoms, and the dearth of prior experience in clinical development. In the past few years these challenges have been mitigated by considerable advances in our understanding of forms of ASD caused by single-gene alterations, such as fragile X syndrome and tuberous sclerosis. In these cases we have gained insights into the pathophysiological mechanisms underlying these conditions. In addition, they have aided in the development of animal models and compounds with the potential for disease modification in clinical development. Moreover, genetic studies are illuminating the molecular pathophysiology of ASD, and new tools such as induced pluripotent stem cells offer novel possibilities for drug screening and disease diagnostics. Finally, large-scale collaborations between academia and industry are starting to address some of the key barriers to developing drugs for ASD. Here, we propose a conceptual framework for drug discovery in ASD encompassing target identification, drug profiling and considerations for clinical trials in this novel area.

Using a combination of viral-tracing and in vivo imaging techniques, the authors show that there are several parallel pathways in the mouse visual system and that directional and orientation selectivity in the cortex may arise from the specialized tuning of retinal circuits. How the eye observes directional change The motion-detecting cells of the retina, called direction-selective ganglion cells (DSGCs), have been known about and studied for more than half a century but their precise role in visual processing has remained unclear. Using a combination of genetic, anatomical and imaging techniques, Andrew Huberman and colleagues investigate the connections made by DSGCs in the mouse brain and find that they link specifically to neurons in the superficial layers of primary visual cortex. Inputs from several different DSGC types are combined to convey both directional and orientation information to the cortex. In addition, non-direction-tuned information from the retina is sent to deeper layers of cortex. This reveals that the mouse visual system contains several functionally distinct parallel pathways and that directional and orientation selectivity in the cortex may arise from the earliest stages of visual processing involving motion-detecting cells in the retina. How specific features in the environment are represented within the brain is an important unanswered question in neuroscience. A subset of retinal neurons, called direction-selective ganglion cells (DSGCs), are specialized for detecting motion along specific axes of the visual field 1 . Despite extensive study of the retinal circuitry that endows DSGCs with their unique tuning properties 2 , 3 , their downstream circuitry in the brain and thus their contribution to visual processing has remained unclear. In mice, several different types of DSGCs connect to the dorsal lateral geniculate nucleus (dLGN) 4 , 5 , 6 , the visual thalamic structure that harbours cortical relay neurons. Whether direction-selective information computed at the level of the retina is routed to cortical circuits and integrated with other visual channels, however, is unknown. Here we show that there is a di-synaptic circuit linking DSGCs with the superficial layers of the primary visual cortex (V1) by using viral trans-synaptic circuit mapping 7 , 8 and functional imaging of visually driven calcium signals in thalamocortical axons. This circuit pools information from several types of DSGCs, converges in a specialized subdivision of the dLGN, and delivers direction-tuned and orientation-tuned signals to superficial V1. Notably, this circuit is anatomically segregated from the retino-geniculo-cortical pathway carrying non-direction-tuned visual information to deeper layers of V1, such as layer 4. Thus, the mouse harbours several functionally specialized, parallel retino-geniculo-cortical pathways, one of which originates with retinal DSGCs and delivers direction- and orientation-tuned information specifically to the superficial layers of the primary visual cortex. These data provide evidence that direction and orientation selectivity of some V1 neurons may be influenced by the activation of DSGCs.

Autism spectrum disorder comprises several neurodevelopmental conditions presenting symptoms in social communication and restricted, repetitive behaviors. A major roadblock for drug development for autism is the lack of robust behavioral signatures predictive of clinical efficacy. To address this issue, we further characterized, in a uniform and rigorous way, mouse models of autism that are of interest because of their construct validity and wide availability to the scientific community. We implemented a broad behavioral battery that included but was not restricted to core autism domains, with the goal of identifying robust, reliable phenotypes amenable for further testing. Here we describe comprehensive findings from two known mouse models of autism, obtained at different developmental stages, using a systematic behavioral test battery combining standard tests as well as novel, quantitative, computer-vision based systems. The first mouse model recapitulates a deletion in human chromosome 16p11.2, found in 1% of individuals with autism. The second mouse model harbors homozygous null mutations in Cntnap2, associated with autism and Pitt-Hopkins-like syndrome. Consistent with previous results, 16p11.2 heterozygous null mice, also known as Del(7Slx1b-Sept1)4Aam weighed less than wild type littermates displayed hyperactivity and no social deficits. Cntnap2 homozygous null mice were also hyperactive, froze less during testing, showed a mild gait phenotype and deficits in the three-chamber social preference test, although less robust than previously published. In the open field test with exposure to urine of an estrous female, however, the Cntnap2 null mice showed reduced vocalizations. In addition, Cntnap2 null mice performed slightly better in a cognitive procedural learning test. Although finding and replicating robust behavioral phenotypes in animal models is a challenging task, such functional readouts remain important in the development of therapeutics and we anticipate both our positive and negative findings will be utilized as a resource for the broader scientific community.

Key Points Recent studies indicate that transcription factors have a crucial role in regulating axon guidance and synapse formation. Many of these factors act by regulating the response of neurons to guidance and synaptogenic cues. Islet 2 (ISL2), ZIC2, chick brain factor 1 (CBF1) and CBF2 are transcription factors that have been implicated in retinotectal patterning. ISL2 and ZIC2 appear to exert their effects by regulating EphB2 expression. CBF1 and CBF2 seem to exert their effects by regulating ephrin A–EphA signalling. ISL1, LIM1, LHX3 and LMX1B are LIM homeobox transcription factors that are implicated in the development of motor neuron projections. These factors are likely to affect axonal trajectories by influencing signalling by ephrins, semaphorins and fibroblast growth factors. Neurogenin 2, LIM domain only 4 (LMO4) and neurodifferentiation D2 (NeuroD2) have an important role in patterning thalamocortical axons. LMO4 and NeuroD2 are expressed in the postnatal cortex and mediate the activity-dependent refinement of thalamocortical axon terminals. Many of the transcription factors that affect axon guidance act by regulating the expression of ephrin and Eph receptor genes. Several transcription factors have been implicated in synapse formation, maturation and elimination. Cyclic AMP-response element binding protein (CREB) and NeuroD2 are involved in synapse formation and maturation. Myocyte enhancer factor 2 (MEF2) and neurogenin 3 appear to be involved in synapse elimination. These factors act in part by regulating the responsiveness of neurons to neurotransmitters. The formation of complex neuronal circuitry requires precise spatial, temporal and cell-type-specific regulation of the responses of neurons to extracellular guidance and synaptogenic cues. Ghosh and colleagues discuss the key roles of transcription factors in regulating connectivity in the nervous system. The establishment of functional neural connections requires the growth of axons to specific target areas and the formation of synapses with appropriate synaptic partners. Several molecules that regulate axon guidance and synapse formation have been identified in the past decade, but it is unclear how a relatively limited number of factors can specify a large number of connections. Recent evidence indicates that transcription factors make a crucial contribution to the specification of connections in the nervous system by coordinating the response of neurons to guidance molecules and neurotransmitters.

BackgroundWnt proteins comprise a large class of signaling molecules that regulate a variety of developmental processes, including synapse formation. Previous studies have shown Wnts to be involved in both the induction and prevention of synapses in a number of different organisms. However, it is not clear whether the influence of Wnts on synapses is a result of Wnts' behavior in different organisms or differences in the activity of different Wnt ligands.ResultsWe used in situ hybridization to show that several Wnt ligands (Wnt3, Wnt5a, Wnt7a, and Wnt7b) and their receptors, Frizzled, are expressed in the developing hippocampus during the period of synapse formation in rodents. We used recombinant Wnt protein or Wnt conditioned media to explore the effects of Wnts on synapses in hippocampal cultures. We found that Wnt7a and Wnt7b activate canonical signaling, whereas Wnt5a activates a noncanonical pathway. The activation of the canonical pathway, either through pathway manipulations or through Wnt stimulation, increases presynaptic inputs. In contrast, exposure to Wnt5a, which activates a noncanonical signaling pathway, decreases the number of presynaptic terminals.ConclusionOur observations suggest that the pro- and antisynaptogenic effects of Wnt proteins are associated with the activation of the canonical and noncanonical Wnt signaling pathways.