Interaction of an α-synuclein epitope with HLA-DRB115:01 triggers enteric features in mice reminiscent of prodromal Parkinson's disease.

Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein (α-syn)-derived epitopes. One epitope, α-syn, binds with strong affinity to the HLA-DRB115:01 allele implicated in autoimmune diseases.

Distinct Th17 effector cytokines differentially promote microglial and blood-brain barrier inflammatory responses during post-infectious encephalitis.

Group A (GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown.

Mural Wnt/β-catenin signaling regulates Lama2 expression to promote neurovascular unit maturation.

Neurovascular unit and barrier maturation rely on vascular basement membrane (vBM) composition. Laminins, a major vBM component, are crucial for these processes, yet the signaling pathway(s) that regulate their expression remain unknown. Here, we show that mural cells have active Wnt/β-catenin signaling during central nervous system development in mice.

Th17 lymphocytes drive vascular and neuronal deficits in a mouse model of postinfectious autoimmune encephalitis.

Antibodies against neuronal receptors and synaptic proteins are associated with a group of ill-defined central nervous system (CNS) autoimmune diseases termed autoimmune encephalitides (AE), which are characterized by abrupt onset of seizures and/or movement and psychiatric symptoms. Basal ganglia encephalitis (BGE), representing a subset of AE syndromes, is triggered in children by repeated group A (GAS) infections that lead to neuropsychiatric symptoms. We have previously shown that multiple GAS infections of mice induce migration of Th17 lymphocytes from the nose into the brain, causing blood-brain barrier (BBB) breakdown, extravasation of autoantibodies into the CNS, and loss of excitatory synapses within the olfactory bulb (OB).

The Wnt Inhibitor Apcdd1 Coordinates Vascular Remodeling and Barrier Maturation of Retinal Blood Vessels.

Coordinating angiogenesis with acquisition of tissue-specific properties in endothelial cells is essential for vascular function. In the retina, endothelial cells form a blood-retina barrier by virtue of tight junctions and low transcytosis. While the canonical Norrin/Fz4/Lrp5/6 pathway is essential for angiogenesis, vascular remodeling, and barrier maturation, how these diverse processes are coordinated remains poorly understood.

Hello from the Other Side: How Autoantibodies Circumvent the Blood-Brain Barrier in Autoimmune Encephalitis.

Antibodies against neuronal receptors and synaptic proteins are associated with autoimmune encephalitides (AE) that produce movement and psychiatric disorders. In order to exert their pathological effects on neural circuits, autoantibodies against central nervous system (CNS) targets must gain access to the brain and spinal cord by crossing the blood-brain barrier (BBB), a tightly regulated gateway formed by endothelial cells lining CNS blood vessels. To date, the pathogenic mechanisms that underlie autoantibody-triggered encephalitic syndromes are poorly understood, and how autoantibodies breach the barrier remains obscure for almost all AE syndromes.

Increased Excitatory Synaptic Transmission of Dentate Granule Neurons in Mice Lacking PSD-95-Interacting Adhesion Molecule Neph2/Kirrel3 during the Early Postnatal Period.

Copy number variants and point mutations of (also called ) gene encoding an immunoglobulin (Ig) superfamily adhesion molecule have been linked to autism spectrum disorders, intellectual disability and neurocognitive delay associated with Jacobsen syndrome, but the physiological roles of Neph2 in the mammalian brain remain largely unknown. Neph2 is highly expressed in the dentate granule (DG) neurons of the hippocampus and is localized in both dendrites and axons. It was recently shown that Neph2 is required for the formation of mossy fiber filopodia, the axon terminal structure of DG neurons forming synapses with GABAergic neurons of CA3.

CNS autoimmune disease after infections: animal models, cellular mechanisms and genetic factors.

infections have been associated with two autoimmune diseases of the CNS: Sydenham's chorea (SC) and Pediatric Autoimmune Neuropsychiatric Disorders Associated with infections (PANDAS). Despite the high frequency of pharyngeal streptococcus infections among children, only a small fraction develops SC or PANDAS. This suggests that several factors in combination are necessary to trigger autoimmune complications: specific strains that induce a strong immune response toward the host nervous system; genetic susceptibility that predispose children toward an autoimmune response involving movement or tic symptoms; and multiple infections of the throat or tonsils that lead to a robust T17 cellular and humoral immune response when untreated.

The intellectual disability gene Kirrel3 regulates target-specific mossy fiber synapse development in the hippocampus.

Synaptic target specificity, whereby neurons make distinct types of synapses with different target cells, is critical for brain function, yet the mechanisms driving it are poorly understood. In this study, we demonstrate Kirrel3 regulates target-specific synapse formation at hippocampal mossy fiber (MF) synapses, which connect dentate granule (DG) neurons to both CA3 and GABAergic neurons. Here, we show Kirrel3 is required for formation of MF filopodia; the structures that give rise to DG-GABA synapses and that regulate feed-forward inhibition of CA3 neurons.

Mice lacking the synaptic adhesion molecule Neph2/Kirrel3 display moderate hyperactivity and defective novel object preference.

Synaptic adhesion molecules regulate diverse aspects of neuronal synapse development, including synapse specificity, formation, and maturation. Neph2, also known as Kirrel3, is an immunoglobulin superfamily adhesion molecule implicated in intellectual disability, neurocognitive delay associated with Jacobsen syndrome, and autism spectrum disorders. We here report mice lacking Neph2 (Neph2(-/-) mice) display moderate hyperactivity in a familiar, but not novel, environment and defective novel object recognition with normal performances in Morris water maze spatial learning and memory, contextual fear conditioning and extinction, and pattern separation tests.

Dissecting the Role of Smooth Muscle Cells versus Pericytes in Regulating Cerebral Blood Flow Using In Vivo Optical Imaging.

The brain regulates blood flow to match energy demand to nutrient supply. In this issue of Neuron, using in vivo optical imaging and optogenetics, Hill et al. (2015) report that arteriolar smooth muscle cells are key players in regulating cerebral blood flow in the healthy state and contribute to the "no reflow" phenomenon after ischemic stroke.

The role of angiogenesis in the pathology of multiple sclerosis.

Angiogenesis, or the growth of new blood vessels from existing vasculature, is critical for the proper development of many organs. This process is inhibited and tightly regulated in adults, once endothelial cells have acquired organ-specific properties. Within the central nervous system (CNS), angiogenesis and acquisition of blood-brain barrier (BBB) properties by endothelial cells is essential for CNS function.

Kirrel3 is required for the coalescence of vomeronasal sensory neuron axons into glomeruli and for male-male aggression.

The accessory olfactory system controls social and sexual interactions in mice that are crucial for survival. Vomeronasal sensory neurons (VSNs) form synapses with dendrites of second order neurons in glomeruli of the accessory olfactory bulb (AOB). Axons of VSNs expressing the same vomeronasal receptor coalesce into multiple glomeruli within spatially conserved regions of the AOB.

Learned recognition of maternal signature odors mediates the first suckling episode in mice.

Background: Soon after birth, all mammals must initiate milk suckling to survive. In rodents, this innate behavior is critically dependent on uncharacterized maternally derived chemosensory ligands. Recently, the first pheromone sufficient to initiate suckling was isolated from the rabbit.

The pattern of glomerular map formation defines responsiveness to aversive odorants in mice.

In many species, the detection and recognition of odors is critical to regulate behaviors that are essential for survival, such as foraging for food and avoidance of predators. The formation of complex stereotypic connections between olfactory sensory neurons (OSNs) and second-order neurons in the olfactory bulb (OB) is believed to be important for accurate odorant information processing. In mice, ablation of OSNs that innervate the dorsal region of the OB leads to a loss of avoidance behavior in response to aversive and predator odorants (Kobayakawa et al.

Distinct representations of olfactory information in different cortical centres.

Sensory information is transmitted to the brain where it must be processed to translate stimulus features into appropriate behavioural output. In the olfactory system, distributed neural activity in the nose is converted into a segregated map in the olfactory bulb. Here we investigate how this ordered representation is transformed in higher olfactory centres in mice.

Sensory maps in the olfactory cortex defined by long-range viral tracing of single neurons.

Sensory information may be represented in the brain by stereotyped mapping of axonal inputs or by patterning that varies between individuals. In olfaction, a stereotyped map is evident in the first sensory processing centre, the olfactory bulb (OB), where different odours elicit activity in unique combinatorial patterns of spatially invariant glomeruli. Activation of each glomerulus is relayed to higher cortical processing centres by a set of ∼20-50 'homotypic' mitral and tufted (MT) neurons.

Robo-2 controls the segregation of a portion of basal vomeronasal sensory neuron axons to the posterior region of the accessory olfactory bulb.

The ability of sensory systems to detect and process information from the environment relies on the elaboration of precise connections between sensory neurons in the periphery and second order neurons in the CNS. In mice, the accessory olfactory system is thought to regulate a wide variety of social and sexual behaviors. The expression of the Slit receptors Robo-1 and Robo-2 in vomeronasal sensory neurons (VSNs) suggests they may direct the stereotypic targeting of their axons to the accessory olfactory bulb (AOB).

Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping.

In mammals, retinal ganglion cell (RGC) projections initially intermingle and then segregate into a stereotyped pattern of eye-specific layers in the dorsal lateral geniculate nucleus (dLGN). Here we found that in mice deficient for ephrin-A2, ephrin-A3 and ephrin-A5, eye-specific inputs segregated but the shape and location of eye-specific layers were profoundly disrupted. In contrast, mice that lacked correlated retinal activity did not segregate eye-specific inputs.

Axonal ephrin-As and odorant receptors: coordinate determination of the olfactory sensory map.

Olfactory sensory neurons expressing a given odorant receptor (OR) project with precision to specific glomeruli in the olfactory bulb, generating a topographic map. In this study, we demonstrate that neurons expressing different ORs express different levels of ephrin-A protein on their axons. Moreover, alterations in the level of ephrin-A alter the glomerular map.

Ephs and ephrins close ranks.

The past decade has seen remarkable advances in identification of the proteins regulating axon guidance and synapse formation. Understanding the structural and molecular basis of their signaling properties is now the task at hand. The recently characterized crystal structure of the complex formed between the ligand-binding domain of EphB2 and the ectodomain of its binding partner ephrin-B2 provides an insight into the recognition and signal transduction mechanisms of this large multifunctional family of surface receptors.

Sequence analysis of mouse vomeronasal receptor gene clusters reveals common promoter motifs and a history of recent expansion.

We have analyzed the organization and sequence of 73 V1R genes encoding putative pheromone receptors to identify regulatory features and characterize the evolutionary history of the V1R family. The 73 V1Rs arose from seven ancestral genes around the time of mouse-rat speciation through large local duplications, and this expansion may contribute to speciation events. Orthologous V1R genes appear to have been lost during primate evolution.