Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits. Südhof Thomas C Cell Synapses are specialized junctions between neurons in brain that transmit and compute information, thereby connecting neurons into millions of overlapping and interdigitated neural circuits. Here, we posit that the establishment, properties, and dynamics of synapses are governed by a molecular logic that is controlled by diverse trans-synaptic signaling molecules. Neurexins, expressed in thousands of alternatively spliced isoforms, are central components of this dynamic code. Presynaptic neurexins regulate synapse properties via differential binding to multifarious postsynaptic ligands, such as neuroligins, cerebellin/GluD complexes, and latrophilins, thereby shaping the input/output relations of their resident neural circuits. Mutations in genes encoding neurexins and their ligands are associated with diverse neuropsychiatric disorders, especially schizophrenia, autism, and Tourette syndrome. Thus, neurexins nucleate an overall trans-synaptic signaling network that controls synapse properties, which thereby determines the precise responses of synapses to spike patterns in a neuron and circuit and which is vulnerable to impairments in neuropsychiatric disorders. 10.1016/j.cell.2017.10.024
    Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease. Monday Hannah R,Younts Thomas J,Castillo Pablo E Annual review of neuroscience Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse. 10.1146/annurev-neuro-080317-062155
    Synaptic pathology: A shared mechanism in neurological disease. Henstridge Christopher M,Pickett Eleanor,Spires-Jones Tara L Ageing research reviews Synaptic proteomes have evolved a rich and complex diversity to allow the exquisite control of neuronal communication and information transfer. It is therefore not surprising that many neurological disorders are associated with alterations in synaptic function. As technology has advanced, our ability to study the anatomical and physiological function of synapses in greater detail has revealed a critical role for both central and peripheral synapses in neurodegenerative disease. Synapse loss has a devastating effect on cellular communication, leading to wide ranging effects such as network disruption within central neural systems and muscle wastage in the periphery. These devastating effects link synaptic pathology to a diverse range of neurological disorders, spanning Alzheimer's disease to multiple sclerosis. This review will highlight some of the current literature on synaptic integrity in animal models of disease and human post-mortem studies. Synaptic changes in normal brain ageing will also be discussed and finally the current and prospective treatments for neurodegenerative disorders will be summarised. 10.1016/j.arr.2016.04.005
    Parkinson's disease: convergence on synaptic homeostasis. Soukup Sandra-Fausia,Vanhauwaert Roeland,Verstreken Patrik The EMBO journal Parkinson's disease, the second most common neurodegenerative disorder, affects millions of people globally. There is no cure, and its prevalence will double by 2030. In recent years, numerous causative genes and risk factors for Parkinson's disease have been identified and more than half appear to function at the synapse. Subtle synaptic defects are thought to precede blunt neuronal death, but the mechanisms that are dysfunctional at synapses are only now being unraveled. Here, we review recent work and propose a model where different Parkinson proteins interact in a cell compartment-specific manner at the synapse where these proteins regulate endocytosis and autophagy. While this field is only recently emerging, the work suggests that the loss of synaptic homeostasis may contribute to neurodegeneration and is a key player in Parkinson's disease. 10.15252/embj.201898960
    Neuromodulation of Spike-Timing-Dependent Plasticity: Past, Present, and Future. Brzosko Zuzanna,Mierau Susanna B,Paulsen Ole Neuron Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders. 10.1016/j.neuron.2019.05.041
    The synaptic function of parkin. Sassone Jenny,Serratto GiuliaMaia,Valtorta Flavia,Silani Vincenzo,Passafaro Maria,Ciammola Andrea Brain : a journal of neurology Loss of function mutations in the gene PARK2, which encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, a neurodegenerative disease characterized by degeneration of the dopaminergic neurons localized in the substantia nigra pars compacta. No therapy is effective in slowing disease progression mostly because the pathogenesis of the disease is yet to be understood. From accruing evidence suggesting that the protein parkin directly regulates synapses it can be hypothesized that PARK2 gene mutations lead to early synaptic damage that results in dopaminergic neuron loss over time. We review evidence that supports the role of parkin in modulating excitatory and dopaminergic synapse functions. We also discuss how these findings underpin the concept that autosomal recessive juvenile parkinsonism can be primarily a synaptopathy. Investigation into the molecular interactions between parkin and synaptic proteins may yield novel targets for pharmacologic interventions. 10.1093/brain/awx006
    Synaptic vesicle cycle and amyloid β: Biting the hand that feeds. Ovsepian Saak V,O'Leary Valerie B,Zaborszky Laszlo,Ntziachristos Vasilis,Dolly J Oliver Alzheimer's & dementia : the journal of the Alzheimer's Association The synaptic vesicle cycle (SVC) holds center stage in the biology of presynaptic terminals. Through recurrent exocytosis and endocytosis, it facilitates a sequence of events enabling chemical neurotransmission between functionally related neurons. As a fundamental process that links the interior of nerve cells with their environment, the SVC is also critical for signaling and provides an entry route for a range of pathogens and toxins, enabling detrimental effects. In Alzheimer's disease, the SVC is both the prime site of amyloid β production and toxicity. In this study, we discuss the emerging evidence for physiological and pathological effects of Aβ on various stages of the SVC, from postfusion membrane recovery to trafficking, docking, and priming of vesicles for fusion and transmitter release. Understanding of the mechanisms of Aβ interaction with the SVC within the unifying calcium hypothesis of aging and Alzheimer's disease should further elucidate the fundamental biology of the presynaptic terminal and reveal novel therapeutic targets for Alzheimer's disease and other age-related dementias. 10.1016/j.jalz.2018.01.011
    Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets. Li Ying C,Kavalali Ege T Pharmacological reviews Presynaptic nerve terminals are highly specialized vesicle-trafficking machines. Neurotransmitter release from these terminals is sustained by constant local recycling of synaptic vesicles independent from the neuronal cell body. This independence places significant constraints on maintenance of synaptic protein complexes and scaffolds. Key events during the synaptic vesicle cycle-such as exocytosis and endocytosis-require formation and disassembly of protein complexes. This extremely dynamic environment poses unique challenges for proteostasis at synaptic terminals. Therefore, it is not surprising that subtle alterations in synaptic vesicle cycle-associated proteins directly or indirectly contribute to pathophysiology seen in several neurologic and psychiatric diseases. In contrast to the increasing number of examples in which presynaptic dysfunction causes neurologic symptoms or cognitive deficits associated with multiple brain disorders, synaptic vesicle-recycling machinery remains an underexplored drug target. In addition, irrespective of the involvement of presynaptic function in the disease process, presynaptic machinery may also prove to be a viable therapeutic target because subtle alterations in the neurotransmitter release may counter disease mechanisms, correct, or compensate for synaptic communication deficits without the need to interfere with postsynaptic receptor signaling. In this article, we will overview critical properties of presynaptic release machinery to help elucidate novel presynaptic avenues for the development of therapeutic strategies against neurologic and neuropsychiatric disorders. 10.1124/pr.116.013342
    Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain. Bliss Tim V P,Collingridge Graham L,Kaang Bong-Kiun,Zhuo Min Nature reviews. Neuroscience The anterior cingulate cortex (ACC) is activated in both acute and chronic pain. In this Review, we discuss increasing evidence from rodent studies that ACC activation contributes to chronic pain states and describe several forms of synaptic plasticity that may underlie this effect. In particular, one form of long-term potentiation (LTP) in the ACC, which is triggered by the activation of NMDA receptors and expressed by an increase in AMPA-receptor function, sustains the affective component of the pain state. Another form of LTP in the ACC, which is triggered by the activation of kainate receptors and expressed by an increase in glutamate release, may contribute to pain-related anxiety. 10.1038/nrn.2016.68
    A Unifying Hypothesis for Alzheimer's Disease: From Plaques to Neurodegeneration. Edwards Frances A Trends in neurosciences Evidence suggests that amyloid β is highly toxic to synapses in a phospho-Tau-dependent manner. Here, I present a hypothesis that links previous evidence from the first rise of amyloid β through to Tau tangles and neurodegeneration. In the immediate vicinity of plaques, concentrated soluble amyloid β occurs in equilibrium with deposited forms. Initially, plaques cover only a small percentage of brain volume. Microglia, by efficiently removing damaged synapses, may prevent spread of damage along the axon, restricting damage to the immediate vicinity of plaques. However, as plaque load increases, as seen in Alzheimer's disease, an individual axon may suffer multiple points of damage, leading to dissociation of Tau, formation of a tangle, and loss of the axon. As more axons suffer this fate, the network eventually degenerates. According to this hypothesis, the degree of plaque load that an individual can tolerate would depend on the efficiency of their microglia in removing amyloid-β-damaged synapses and the distribution of plaques, relative to axon trajectories, would determine the eventual cognitive symptoms. 10.1016/j.tins.2019.03.003
    Learning How Neurons Fail Inside of Networks: Nonhuman Primates Provide Critical Data for Psychiatry. Heilbronner Sarah R,Chafee Matthew V Neuron Advancing psychiatry requires understanding brain malfunction at a microscopic scale, where neurons and synapses operate under constraints imposed by behavior, cognition, and neural architecture. Nonhuman primates are unmatched in approximating the structural and computational environment of the human brain. 10.1016/j.neuron.2019.02.030
    Brain imaging: Synaptic density directly visualized in human brains. Morris Alan W J Nature reviews. Neurology 10.1038/nrneurol.2016.116
    The Molecular Basis of Drug Addiction: Linking Epigenetic to Synaptic and Circuit Mechanisms. Nestler Eric J,Lüscher Christian Neuron Addiction is a disease in which, after a period of recreational use, a subset of individuals develops compulsive use that does not stop even in light of major negative consequences. Here, we review the evidence for underlying epigenetic remodeling in brain in two settings. First, excessive dopamine signaling during drug use may modulate gene expression, altering synaptic function and circuit activity and leading over time to maladaptive behaviors in vulnerable individuals. Second, on a longer timescale, life experience can shape the epigenetic landscape in brain and thereby may contribute to an individual's vulnerability by amplifying drug-induced changes in gene expression that drive the transition to addiction. We conclude by exploring how epigenetic mechanisms might serve as therapeutic targets for addiction treatments. 10.1016/j.neuron.2019.01.016
    Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease. Nanou Evanthia,Catterall William A Neuron Voltage-gated calcium channels couple depolarization of the cell-surface membrane to entry of calcium, which triggers secretion, contraction, neurotransmission, gene expression, and other physiological responses. They are encoded by ten genes, which generate three voltage-gated calcium channel subfamilies: Ca1; Ca2; and Ca3. At synapses, Ca2 channels form large signaling complexes in the presynaptic nerve terminal, which are responsible for the calcium entry that triggers neurotransmitter release and short-term presynaptic plasticity. Ca1 channels form signaling complexes in postsynaptic dendrites and dendritic spines, where their calcium entry induces long-term potentiation. These calcium channels are the targets of mutations and polymorphisms that alter their function and/or regulation and cause neuropsychiatric diseases, including migraine headache, cerebellar ataxia, autism, schizophrenia, bipolar disorder, and depression. This article reviews the molecular properties of calcium channels, considers their multiple roles in synaptic plasticity, and discusses their potential involvement in this wide range of neuropsychiatric diseases. 10.1016/j.neuron.2018.03.017
    Autoimmune seizures and epilepsy. Geis Christian,Planagumà Jesus,Carreño Mar,Graus Francesc,Dalmau Josep The Journal of clinical investigation The rapid expansion in the number of encephalitis disorders associated with autoantibodies against neuronal proteins has led to an incremental increase in use of the term "autoimmune epilepsy," yet has occurred with limited attention to the physiopathology of each disease and genuine propensity to develop epilepsy. Indeed, most autoimmune encephalitides present with seizures, but the probability of evolving to epilepsy is relatively small. The risk of epilepsy is higher for disorders in which the antigens are intracellular (often T cell-mediated) compared with disorders in which the antigens are on the cell surface (antibody-mediated). Most autoantibodies against neuronal surface antigens show robust effects on the target proteins, resulting in hyperexcitability and impairment of synaptic function and plasticity. Here, we trace the evolution of the concept of autoimmune epilepsy and examine common inflammatory pathways that might lead to epilepsy. Then, we focus on several antibody-mediated encephalitis disorders that associate with seizures and review the synaptic alterations caused by patients' antibodies, with emphasis on those that have been modeled in animals (e.g., antibodies against NMDA, AMPA receptors, LGI1 protein) or in cultured neurons (e.g., antibodies against the GABAb receptor). 10.1172/JCI125178
    Autoimmune synaptopathies. Crisp Sarah J,Kullmann Dimitri M,Vincent Angela Nature reviews. Neuroscience Autoantibodies targeting proteins at the neuromuscular junction are known to cause several distinct myasthenic syndromes. Recently, autoantibodies targeting neurotransmitter receptors and associated proteins have also emerged as a cause of severe, but potentially treatable, diseases of the CNS. Here, we review the clinical evidence as well as in vitro and in vivo experimental evidence that autoantibodies account for myasthenic syndromes and autoimmune disorders of the CNS by disrupting the functional or structural integrity of synapses. Studying neurological and psychiatric diseases of autoimmune origin may provide new insights into the cellular and circuit mechanisms underlying a broad range of CNS disorders. 10.1038/nrn.2015.27
    Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System. Dalmau Josep,Geis Christian,Graus Francesc Physiological reviews Investigations in the last 10 years have revealed a new category of neurological diseases mediated by antibodies against cell surface and synaptic proteins. There are currently 16 such diseases all characterized by autoantibodies against neuronal proteins involved in synaptic signaling and plasticity. In clinical practice these findings have changed the diagnostic and treatment approach to potentially lethal, but now treatable, neurological and psychiatric syndromes previously considered idiopathic or not even suspected to be immune-mediated. Studies show that patients' antibodies can impair the surface dynamics of the target receptors eliminating them from synapses (e.g., NMDA receptor), block the function of the antigens without changing their synaptic density (e.g., GABAb receptor), interfere with synaptic protein-protein interactions (LGI1, Caspr2), alter synapse formation (e.g., neurexin-3α), or by unclear mechanisms associate to a new form of tauopathy (IgLON5). Here we first trace the process of discovery of these diseases, describing the triggers and symptoms related to each autoantigen, and then review in detail the structural and functional alterations caused by the autoantibodies with special emphasis in those (NMDA receptor, amphiphysin) that have been modeled in animals. 10.1152/physrev.00010.2016
    Tau-targeting therapies for Alzheimer disease. Congdon Erin E,Sigurdsson Einar M Nature reviews. Neurology Alzheimer disease (AD) is the most common form of dementia. Pathologically, AD is characterized by amyloid plaques and neurofibrillary tangles in the brain, with associated loss of synapses and neurons, resulting in cognitive deficits and eventually dementia. Amyloid-β (Aβ) peptide and tau protein are the primary components of the plaques and tangles, respectively. In the decades since Aβ and tau were identified, development of therapies for AD has primarily focused on Aβ, but tau has received more attention in recent years, in part because of the failure of various Aβ-targeting treatments in clinical trials. In this article, we review the current status of tau-targeting therapies for AD. Initially, potential anti-tau therapies were based mainly on inhibition of kinases or tau aggregation, or on stabilization of microtubules, but most of these approaches have been discontinued because of toxicity and/or lack of efficacy. Currently, the majority of tau-targeting therapies in clinical trials are immunotherapies, which have shown promise in numerous preclinical studies. Given that tau pathology correlates better with cognitive impairments than do Aβ lesions, targeting of tau is expected to be more effective than Aβ clearance once the clinical symptoms are evident. With future improvements in diagnostics, these two hallmarks of the disease might be targeted prophylactically. 10.1038/s41582-018-0013-z
    Neuromuscular Junction Formation, Aging, and Disorders. Li Lei,Xiong Wen-Cheng,Mei Lin Annual review of physiology Synapses, the fundamental unit in neuronal circuits, are critical for learning and memory, perception, thinking, and reaction. The neuromuscular junction (NMJ) is a synapse formed between motoneurons and skeletal muscle fibers that is covered by Schwann cells (SCs). It is essential for controlling muscle contraction. NMJ formation requires intimate interactions among motoneurons, muscles, and SCs. Deficits in NMJ formation and maintenance cause neuromuscular disorders, including congenital myasthenic syndrome and myasthenia gravis. NMJ decline occurs in aged animals and may appear before clinical presentation of motoneuron disorders such as amyotrophic lateral sclerosis. We review recent findings in NMJ formation, maintenance, neuromuscular disorders, and aging of the NMJ, focusing on communications among motoneurons, muscles and SCs, and underlying mechanisms. 10.1146/annurev-physiol-022516-034255
    Synaptic AMPA receptor composition in development, plasticity and disease. Henley Jeremy M,Wilkinson Kevin A Nature reviews. Neuroscience AMPA receptors (AMPARs) are assemblies of four core subunits, GluA1-4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs, and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity and in response to neuronal stress in disease. Recently, the subunit dependence of AMPAR trafficking has been questioned, leading to a reappraisal of this field. In this Review, we discuss what is known, uncertain, conjectured and unknown about the roles of the individual subunits, and how they affect AMPAR assembly, trafficking and function under both normal and pathological conditions. 10.1038/nrn.2016.37
    Early synaptic dysfunction in Parkinson's disease: Insights from animal models. Schirinzi Tommaso,Madeo Graziella,Martella Giuseppina,Maltese Marta,Picconi Barbara,Calabresi Paolo,Pisani Antonio Movement disorders : official journal of the Movement Disorder Society The appearance of motor manifestations in Parkinson's disease (PD) is invariably linked to degeneration of nigral dopaminergic neurons of the substantia nigra pars compacta. Traditional views on PD neuropathology have been grounded in the assumption that the prime event of neurodegeneration involves neuronal cell bodies with the accumulation of metabolic products. However, this view has recently been challenged by both clinical and experimental evidence. Neuropathological studies in human brain samples and both in vivo and in vitro models support the hypothesis that nigrostriatal synapses may indeed be affected at the earliest stages of the neurodegenerative process. The mechanisms leading to either structural or functional synaptic dysfunction are starting to be elucidated and include dysregulation of axonal transport, impairment of the exocytosis and endocytosis machinery, altered intracellular trafficking, and loss of corticostriatal synaptic plasticity. The aim of this review is to try to integrate different lines of evidence from both pathogenic and genetic animal models that, to different extents, suggest that early synaptic impairment may represent the key event in PD pathogenesis. Understanding the molecular and cellular events underlying such synaptopathy is a fundamental step toward developing specific biomarkers of early dopaminergic dysfunction and, more importantly, designing novel therapies targeting the synaptic apparatus of selective, vulnerable synapses. © 2016 International Parkinson and Movement Disorder Society. 10.1002/mds.26620
    Neural circuits for pain: Recent advances and current views. Peirs Cedric,Seal Rebecca P Science (New York, N.Y.) The mammalian nervous system encodes many different forms of pain, from those that arise as a result of short-term low-grade interactions with noxious thermal, chemical, or mechanical sources to more serious forms of pain induced by trauma and disease. In this Review, we highlight recent advances in our understanding of the neural circuits that encode these types of pain. Promising therapeutic strategies based on recent advances are also highlighted. 10.1126/science.aaf8933
    Membrane Lipids in Presynaptic Function and Disease. Lauwers Elsa,Goodchild Rose,Verstreken Patrik Neuron Lipids are the most abundant organic compounds in the brain. The brain has a unique lipidome, and changes in lipid concentration, organization, and metabolism are associated with many neuronal diseases. Here, we discuss recent advances in understanding presynaptic membrane lipid organization, centered on illustrative examples of how the lipids themselves regulate membrane trafficking and control protein activity. This insight highlights that presynaptic terminals are membrane-remodeling machines and that cooperation between lipid and protein molecules underlies presynaptic activity. 10.1016/j.neuron.2016.02.033
    Chloride Regulation: A Dynamic Equilibrium Crucial for Synaptic Inhibition. Doyon Nicolas,Vinay Laurent,Prescott Steven A,De Koninck Yves Neuron Fast synaptic inhibition relies on tight regulation of intracellular Cl(-). Chloride dysregulation is implicated in several neurological and psychiatric disorders. Beyond mere disinhibition, the consequences of Cl(-) dysregulation are multifaceted and best understood in terms of a dynamical system involving complex interactions between multiple processes operating on many spatiotemporal scales. This dynamical perspective helps explain many unintuitive manifestations of Cl(-) dysregulation. Here we discuss how taking into account dynamical regulation of intracellular Cl(-) is important for understanding how synaptic inhibition fails, how to best detect that failure, why Cl(-) regulation is energetically so expensive, and the overall consequences for therapeutics. 10.1016/j.neuron.2016.02.030
    Axonal transport: Driving synaptic function. Guedes-Dias Pedro,Holzbaur Erika L F Science (New York, N.Y.) The intracellular transport system in neurons is specialized to an extraordinary degree, enabling the delivery of critical cargo to sites in axons or dendrites that are far removed from the cell center. Vesicles formed in the cell body are actively transported by kinesin motors along axonal microtubules to presynaptic sites that can be located more than a meter away. Both growth factors and degradative vesicles carrying aged organelles or aggregated proteins take the opposite route, driven by dynein motors. Distance is not the only challenge; precise delivery of cargos to sites of need must also be accomplished. For example, localized delivery of presynaptic components to hundreds of thousands of "en passant" synapses distributed along the length of a single axon in some neuronal subtypes provides a layer of complexity that must be successfully navigated to maintain synaptic transmission. We review recent advances in the field of axonal transport, with a focus on conceptual developments, and highlight our growing quantitative understanding of neuronal trafficking and its role in maintaining the synaptic function that underlies higher cognitive processes such as learning and memory. 10.1126/science.aaw9997
    Adhesion G protein-coupled receptors in nervous system development and disease. Langenhan Tobias,Piao Xianhua,Monk Kelly R Nature reviews. Neuroscience Members of the adhesion G protein-coupled receptor (aGPCR) class have emerged as crucial regulators of nervous system development, with important implications for human health and disease. In this Review, we discuss the current understanding of aGPCR functions during key steps in neural development, including cortical patterning, dendrite and synapse formation, and myelination. We focus on aGPCR modulation of cell-cell and cell-matrix interactions and signalling to control these varied aspects of neural development, and we discuss how impaired aGPCR function leads to neurological disease. We further highlight the emerging hypothesis that aGPCRs can be mechanically activated and the implications of this property in the nervous system. 10.1038/nrn.2016.86
    A Synaptic Perspective of Fragile X Syndrome and Autism Spectrum Disorders. Bagni Claudia,Zukin R Suzanne Neuron Altered synaptic structure and function is a major hallmark of fragile X syndrome (FXS), autism spectrum disorders (ASDs), and other intellectual disabilities (IDs), which are therefore classified as synaptopathies. FXS and ASDs, while clinically and genetically distinct, share significant comorbidity, suggesting that there may be a common molecular and/or cellular basis, presumably at the synapse. In this article, we review brain architecture and synaptic pathways that are dysregulated in FXS and ASDs, including spine architecture, signaling in synaptic plasticity, local protein synthesis, (m)RNA modifications, and degradation. mRNA repression is a powerful mechanism for the regulation of synaptic structure and efficacy. We infer that there is no single pathway that explains most of the etiology and discuss new findings and the implications for future work directed at improving our understanding of the pathogenesis of FXS and related ASDs and the design of therapeutic strategies to ameliorate these disorders. 10.1016/j.neuron.2019.02.041
    Synaptic mechanisms underlying persistent cocaine craving. Wolf Marina E Nature reviews. Neuroscience Although it is challenging for individuals with cocaine addiction to achieve abstinence, the greatest difficulty is avoiding relapse to drug taking, which is often triggered by cues associated with prior cocaine use. This vulnerability to relapse persists for long periods (months to years) after abstinence is achieved. Here, I discuss rodent studies of cue-induced cocaine craving during abstinence, with a focus on neuronal plasticity in the reward circuitry that maintains high levels of craving. Such work has the potential to identify new therapeutic targets and to further our understanding of experience-dependent plasticity in the adult brain under normal circumstances and in the context of addiction. 10.1038/nrn.2016.39
    The Mechanisms and Functions of Synaptic Facilitation. Jackman Skyler L,Regehr Wade G Neuron The ability of the brain to store and process information relies on changing the strength of connections between neurons. Synaptic facilitation is a form of short-term plasticity that enhances synaptic transmission for less than a second. Facilitation is a ubiquitous phenomenon thought to play critical roles in information transfer and neural processing. Yet our understanding of the function of facilitation remains largely theoretical. Here we review proposed roles for facilitation and discuss how recent progress in uncovering the underlying molecular mechanisms could enable experiments that elucidate how facilitation, and short-term plasticity in general, contributes to circuit function and animal behavior. 10.1016/j.neuron.2017.02.047
    Progressive Circuit Changes during Learning and Disease. Barth Alison L,Ray Ajit Neuron A critical step toward understanding cognition, learning, and brain dysfunction will be identification of the underlying cellular computations that occur in and across discrete brain areas, as well as how they are progressively altered by experience or disease. These computations will be revealed by targeted analyses of the neurons that perform these calculations, defined not only by their firing properties but also by their molecular identity and how they are wired within the local and broad-scale network of the brain. New studies that take advantage of sophisticated genetic tools for cell-type-specific identification and control are revealing how learning and neurological disorders initiate and successively change the properties of defined neural circuits. Understanding the temporal sequence of adaptive or pathological synaptic changes across multiple synapses within a network will shed light into how small-scale neural circuits contribute to higher cognitive functions during learning and disease. 10.1016/j.neuron.2019.09.032
    Dendritic Tau in Alzheimer's Disease. Ittner Arne,Ittner Lars M Neuron The microtubule-associated protein tau and amyloid-β (Aβ) are key players in Alzheimer's disease (AD). Aβ and tau are linked in a molecular pathway at the post-synapse with tau-dependent synaptic dysfunction being a major pathomechanism in AD. Recent work on site-specific modification of dendritic and more specifically post-synaptic tau has revealed new endogenous functions of tau that limits synaptic Aβ toxicity. Thus, molecular studies opened a new perspective on tau, placing it at the center of neurotoxic and neuroprotective signaling at the post-synapse. Here, we review recent advances on tau in the dendritic compartments, with implications for understanding and treatment of AD and related neurological conditions. 10.1016/j.neuron.2018.06.003
    Integrins in synapse regulation. Park Yun Kyung,Goda Yukiko Nature reviews. Neuroscience Integrins are a large family of extracellular matrix (ECM) receptors. In the developing and adult brain, many integrins are present at high levels at synapses. The tetrapartite structure of synapses - which comprises presynaptic and postsynaptic neurons, the ECM and glial processes - places synaptic integrins in an excellent position to sense dynamic changes in the synaptic environment and use this information to coordinate further changes in synapse structure and function that will shape neural circuit properties. Recent developments in our understanding of the cellular and physiological roles of integrins, which range from control of neural process outgrowth and synapse formation to regulation of synaptic plasticity and memory, enable us to attempt a synthesis of synaptic integrin function. 10.1038/nrn.2016.138
    Towards a better diagnosis and treatment of Rett syndrome: a model synaptic disorder. Banerjee Abhishek,Miller Meghan T,Li Keji,Sur Mriganka,Kaufmann Walter E Brain : a journal of neurology With the recent 50th anniversary of the first publication on Rett syndrome, and the almost 20 years since the first report on the link between Rett syndrome and MECP2 mutations, it is important to reflect on the tremendous advances in our understanding and their implications for the diagnosis and treatment of this neurodevelopmental disorder. Rett syndrome features an interesting challenge for biologists and clinicians, as the disorder lies at the intersection of molecular mechanisms of epigenetic regulation and neurophysiological alterations in synapses and circuits that together contribute to severe pathophysiological endophenotypes. Genetic, clinical, and neurobiological evidences support the notion that Rett syndrome is primarily a synaptic disorder, and a disease model for both intellectual disability and autism spectrum disorder. This review examines major developments in both recent neurobiological and preclinical findings of Rett syndrome, and to what extent they are beginning to impact our understanding and management of the disorder. It also discusses potential applications of knowledge on synaptic plasticity abnormalities in Rett syndrome to its diagnosis and treatment. 10.1093/brain/awy323
    Cell Biology of Astrocyte-Synapse Interactions. Allen Nicola J,Eroglu Cagla Neuron Astrocytes, the most abundant glial cells in the mammalian brain, are critical regulators of brain development and physiology through dynamic and often bidirectional interactions with neuronal synapses. Despite the clear importance of astrocytes for the establishment and maintenance of proper synaptic connectivity, our understanding of their role in brain function is still in its infancy. We propose that this is at least in part due to large gaps in our knowledge of the cell biology of astrocytes and the mechanisms they use to interact with synapses. In this review, we summarize some of the seminal findings that yield important insight into the cellular and molecular basis of astrocyte-neuron communication, focusing on the role of astrocytes in the development and remodeling of synapses. Furthermore, we pose some pressing questions that need to be addressed to advance our mechanistic understanding of the role of astrocytes in regulating synaptic development. 10.1016/j.neuron.2017.09.056
    Towards an Understanding of Synapse Formation. Südhof Thomas C Neuron Synapses are intercellular junctions specialized for fast, point-to-point information transfer from a presynaptic neuron to a postsynaptic cell. At a synapse, a presynaptic terminal secretes neurotransmitters via a canonical release machinery, while a postsynaptic specialization senses neurotransmitters via diverse receptors. Synaptic junctions are likely organized by trans-synaptic cell-adhesion molecules (CAMs) that bidirectionally orchestrate synapse formation, restructuring, and elimination. Many candidate synaptic CAMs were described, but which CAMs are central actors and which are bystanders remains unclear. Moreover, multiple genes encoding synaptic CAMs were linked to neuropsychiatric disorders, but the mechanisms involved are unresolved. Here, I propose that engagement of multifarious synaptic CAMs produces parallel trans-synaptic signals that mediate the establishment, organization, and plasticity of synapses, thereby controlling information processing by neural circuits. Among others, this hypothesis implies that synapse formation can be understood in terms of inter- and intracellular signaling, and that neuropsychiatric disorders involve an impairment in such signaling. 10.1016/j.neuron.2018.09.040
    Synaptic adhesion molecules. Yamagata Masahito,Sanes Joshua R,Weiner Joshua A Current opinion in cell biology Formation, differentiation and plasticity of synapses, the specialized cell-cell contacts through which neurons communicate, all require interactions between pre- and post-synaptic partners. Several synaptically localized adhesion molecules potentially capable of mediating these interactions have been identified recently. Functional studies suggest roles for some of them in target recognition (e.g. SYG-1 and sidekicks), formation and alignment of synaptic specializations (e.g. SynCAM, neuroligin and neurexin), and regulation of synaptic structure and function (e.g. cadherins and syndecan). 10.1016/s0955-0674(03)00107-8
    Regulation of Neuronal Differentiation, Function, and Plasticity by Alternative Splicing. Furlanis Elisabetta,Scheiffele Peter Annual review of cell and developmental biology Posttranscriptional mechanisms provide powerful means to expand the coding power of genomes. In nervous systems, alternative splicing has emerged as a fundamental mechanism not only for the diversification of protein isoforms but also for the spatiotemporal control of transcripts. Thus, alternative splicing programs play instructive roles in the development of neuronal cell type-specific properties, neuronal growth, self-recognition, synapse specification, and neuronal network function. Here we discuss the most recent genome-wide efforts on mapping RNA codes and RNA-binding proteins for neuronal alternative splicing regulation. We illustrate how alternative splicing shapes key steps of neuronal development, neuronal maturation, and synaptic properties. Finally, we highlight efforts to dissect the spatiotemporal dynamics of alternative splicing and their potential contribution to neuronal plasticity and the mature nervous system. 10.1146/annurev-cellbio-100617-062826
    Cadherins communicate structural plasticity of presynaptic and postsynaptic terminals. Goda Yukiko Neuron Synapse adhesion molecules play a key role in specifying and facilitating the recognition of axodendritic contacts. New studies by and reported in this issue of Neuron reveal multiple functions for the cadherin-catenin complex. This adhesion complex regulates synaptogenesis and coordinates synaptic strength with presynaptic and postsynaptic organization, including the shape of dendritic spines.
    Glutamate receptor ion channels: structure, regulation, and function. Traynelis Stephen F,Wollmuth Lonnie P,McBain Chris J,Menniti Frank S,Vance Katie M,Ogden Kevin K,Hansen Kasper B,Yuan Hongjie,Myers Scott J,Dingledine Ray Pharmacological reviews The mammalian ionotropic glutamate receptor family encodes 18 gene products that coassemble to form ligand-gated ion channels containing an agonist recognition site, a transmembrane ion permeation pathway, and gating elements that couple agonist-induced conformational changes to the opening or closing of the permeation pore. Glutamate receptors mediate fast excitatory synaptic transmission in the central nervous system and are localized on neuronal and non-neuronal cells. These receptors regulate a broad spectrum of processes in the brain, spinal cord, retina, and peripheral nervous system. Glutamate receptors are postulated to play important roles in numerous neurological diseases and have attracted intense scrutiny. The description of glutamate receptor structure, including its transmembrane elements, reveals a complex assembly of multiple semiautonomous extracellular domains linked to a pore-forming element with striking resemblance to an inverted potassium channel. In this review we discuss International Union of Basic and Clinical Pharmacology glutamate receptor nomenclature, structure, assembly, accessory subunits, interacting proteins, gene expression and translation, post-translational modifications, agonist and antagonist pharmacology, allosteric modulation, mechanisms of gating and permeation, roles in normal physiological function, as well as the potential therapeutic use of pharmacological agents acting at glutamate receptors. 10.1124/pr.109.002451
    Selective stabilization and synaptic specificity: a new cell-biological model. Jontes James D,Phillips Greg R Trends in neurosciences How are appropriate connections between neurons sorted from the overwhelming surplus of potential, yet inappropriate, connections? Despite the apparently improbable nature of the process, brains wire themselves with a high degree of reproducibility that has been conserved across evolutionary history. Here, we outline a viable cell-biological model for generating synaptic specificity that features selection of nascent synapses based on adhesion and recognition. This process uses the highly dynamic and stochastic nature of intracellular trafficking to generate reproducible patterns of synaptic connectivity. 10.1016/j.tins.2006.02.002
    Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration. Maness Patricia F,Schachner Melitta Nature neuroscience Recognition molecules of the immunoglobulin superfamily have important roles in neuronal interactions during ontogeny, including migration, survival, axon guidance and synaptic targeting. Their downstream signal transduction events specify whether a cell changes its place of residence or projects axons and dendrites to targets in the brain, allowing the construction of a dynamic neural network. A wealth of recent discoveries shows that cell adhesion molecules interact with attractant and repellent guidance receptors to control growth cone and cell motility in a coordinate fashion. We focus on the best-studied subclasses, the neural cell adhesion molecule NCAM and the L1 family of adhesion molecules, which share important structural and functional features. We have chosen these paradigmatic molecules and their interactions with other recognition molecules as instructive for elucidating the mechanisms by which other recognition molecules may guide cell interactions during development or modify their function as a result of injury, learning and memory. 10.1038/nn1827
    Evolution of synapse complexity and diversity. Emes Richard D,Grant Seth G N Annual review of neuroscience Proteomic studies of the composition of mammalian synapses have revealed a high degree of complexity. The postsynaptic and presynaptic terminals are molecular systems with highly organized protein networks producing emergent physiological and behavioral properties. The major classes of synapse proteins and their respective functions in intercellular communication and adaptive responses evolved in prokaryotes and eukaryotes prior to the origins of neurons in metazoa. In eukaryotes, the organization of individual proteins into multiprotein complexes comprising scaffold proteins, receptors, and signaling enzymes formed the precursor to the core adaptive machinery of the metazoan postsynaptic terminal. Multiplicative increases in the complexity of this protosynapse machinery secondary to genome duplications drove synaptic, neuronal, and behavioral novelty in vertebrates. Natural selection has constrained diversification in mammalian postsynaptic mechanisms and the repertoire of adaptive and innate behaviors. The evolution and organization of synapse proteomes underlie the origins and complexity of nervous systems and behavior. 10.1146/annurev-neuro-062111-150433
    Deep molecular diversity of mammalian synapses: why it matters and how to measure it. O'Rourke Nancy A,Weiler Nicholas C,Micheva Kristina D,Smith Stephen J Nature reviews. Neuroscience Pioneering studies in the middle of the twentieth century revealed substantial diversity among mammalian chemical synapses and led to a widely accepted classification of synapse type on the basis of neurotransmitter molecule identity. Subsequently, powerful new physiological, genetic and structural methods have enabled the discovery of much deeper functional and molecular diversity within each traditional neurotransmitter type. Today, this deep diversity continues to pose both daunting challenges and exciting new opportunities for neuroscience. Our growing understanding of deep synapse diversity may transform how we think about and study neural circuit development, structure and function. 10.1038/nrn3170