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A better understanding of the mechanisms underlying the action of antidepressants is urgently needed. Moda-Sava et al. explored a possible mode of action for the drug ketamine, which has recently been shown to help patients recover from depression (see the Perspective by Beyeler). Ketamine rescued behavior in mice that was associated with depression-like phenotypes by selectively reversing stress-induced spine loss and restoring coordinated multicellular ensemble activity in prefrontal microcircuits. The initial induction of ketamine's antidepressant effect on mouse behavior occurred independently of effects on spine formation. Instead, synaptogenesis in the prefrontal region played a critical role in nourishing these effects over time. Interventions aimed at enhancing the survival of restored synapses may thus be useful for sustaining the behavioral effects of fast-acting antidepressants. Science , this issue p. eaat8078 ; see also p. 129 Spine formation in the prefrontal cortex is central to the long-term antidepressant effects of ketamine. The neurobiological mechanisms underlying the induction and remission of depressive episodes over time are not well understood. Through repeated longitudinal imaging of medial prefrontal microcircuits in the living brain, we found that prefrontal spinogenesis plays a critical role in sustaining specific antidepressant behavioral effects and maintaining long-term behavioral remission. Depression-related behavior was associated with targeted, branch-specific elimination of postsynaptic dendritic spines on prefrontal projection neurons. Antidepressant-dose ketamine reversed these effects by selectively rescuing eliminated spines and restoring coordinated activity in multicellular ensembles that predict motivated escape behavior. Prefrontal spinogenesis was required for the long-term maintenance of antidepressant effects on motivated escape behavior but not for their initial induction.

Multicellular organisms have co-evolved with complex consortia of viruses, bacteria, fungi and parasites, collectively referred to as the microbiota 1 . In mammals, changes in the composition of the microbiota can influence many physiologic processes (including development, metabolism and immune cell function) and are associated with susceptibility to multiple diseases 2 . Alterations in the microbiota can also modulate host behaviours—such as social activity, stress, and anxiety-related responses—that are linked to diverse neuropsychiatric disorders 3 . However, the mechanisms by which the microbiota influence neuronal activity and host behaviour remain poorly defined. Here we show that manipulation of the microbiota in antibiotic-treated or germ-free adult mice results in significant deficits in fear extinction learning. Single-nucleus RNA sequencing of the medial prefrontal cortex of the brain revealed significant alterations in gene expression in excitatory neurons, glia and other cell types. Transcranial two-photon imaging showed that deficits in extinction learning after manipulation of the microbiota in adult mice were associated with defective learning-related remodelling of postsynaptic dendritic spines and reduced activity in cue-encoding neurons in the medial prefrontal cortex. In addition, selective re-establishment of the microbiota revealed a limited neonatal developmental window in which microbiota-derived signals can restore normal extinction learning in adulthood. Finally, unbiased metabolomic analysis identified four metabolites that were significantly downregulated in germ-free mice and have been reported to be related to neuropsychiatric disorders in humans and mouse models, suggesting that microbiota-derived compounds may directly affect brain function and behaviour. Together, these data indicate that fear extinction learning requires microbiota-derived signals both during early postnatal neurodevelopment and in adult mice, with implications for our understanding of how diet, infection, and lifestyle influence brain health and subsequent susceptibility to neuropsychiatric disorders. A diverse intestinal microbiota is required for mice to undergo extinction-related neuronal plasticity and normal fear extinction learning.

A subanesthetic dose of ketamine causes acute psychotomimetic symptoms and sustained antidepressant effects. In prefrontal cortex, the prevailing disinhibition hypothesis posits that N-methyl-d-aspartate receptor (NMDAR) antagonists such as ketamine act preferentially on GABAergic neurons. However, cortical interneurons are heterogeneous. In particular, somatostatin-expressing (SST) interneurons selectively inhibit dendrites and regulate synaptic inputs, yet their response to systemic NMDAR antagonism is unknown. Here, we report that ketamine acutely suppresses the activity of SST interneurons in the medial prefrontal cortex of the awake mouse. The deficient dendritic inhibition leads to greater synaptically evoked calcium transients in the apical dendritic spines of pyramidal neurons. By manipulating NMDAR signaling via GluN2B knockdown, we show that ketamine’s actions on the dendritic inhibitory mechanism has ramifications for frontal cortex-dependent behaviors and cortico-cortical connectivity. Collectively, these results demonstrate dendritic disinhibition and elevated calcium levels in dendritic spines as important local-circuit alterations driven by the administration of subanesthetic ketamine. The authors show that a subanesthetic dose of ketamine markedly elevate calcium signals in apical dendritic spines in the mouse prefrontal cortex. This effect is driven by a local-circuit mechanism that involves the suppression of somatostatin interneurons leading to dendritic disinhibition.

Cortical pathology contributes to chronic cognitive impairment of patients suffering from the neuroinflammatory disease multiple sclerosis (MS). How such gray matter inflammation affects neuronal structure and function is not well understood. In the present study, we use functional and structural in vivo imaging in a mouse model of cortical MS to demonstrate that bouts of cortical inflammation disrupt cortical circuit activity coincident with a widespread, but transient, loss of dendritic spines. Spines destined for removal show local calcium accumulations and are subsequently removed by invading macrophages or activated microglia. Targeting phagocyte activation with a new antagonist of the colony-stimulating factor 1 receptor prevents cortical synapse loss. Overall, our study identifies synapse loss as a key pathological feature of inflammatory gray matter lesions that is amenable to immunomodulatory therapy. Synapse loss is prominent in the cortex in multiple sclerosis (MS). In a cortical MS model, Jafari et al. show that phagocytes remove synapses by engulfment, which is triggered by local calcium accumulations and prevented by blocking colony-stimulating factor 1 signaling.

Numerous brain diseases are associated with abnormalities in morphology and density of dendritic spines, small membranous protrusions whose structural geometry correlates with the strength of synaptic connections. Thus, the quantitative analysis of dendritic spines remodeling in microscopic images is one of the key elements towards understanding mechanisms of structural neuronal plasticity and bases of brain pathology. In the following article, we review experimental approaches designed to assess quantitative features of dendritic spines under physiological stimuli and in pathological conditions. We compare various methodological pipelines of biological models, sample preparation, data analysis, image acquisition, sample size, and statistical analysis. The methodology and results of relevant experiments are systematically summarized in a tabular form. In particular, we focus on quantitative data regarding the number of animals, cells, dendritic spines, types of studied parameters, size of observed changes, and their statistical significance.

During cortical synaptic development, thalamic axons must establish synaptic connections despite the presence of the more abundant intracortical projections. How thalamocortical synapses are formed and maintained in this competitive environment is unknown. Here, we show that astrocyte-secreted protein hevin is required for normal thalamocortical synaptic connectivity in the mouse cortex. Absence of hevin results in a profound, long-lasting reduction in thalamocortical synapses accompanied by a transient increase in intracortical excitatory connections. Three-dimensional reconstructions of cortical neurons from serial section electron microscopy (ssEM) revealed that, during early postnatal development, dendritic spines often receive multiple excitatory inputs. Immuno-EM and confocal analyses revealed that majority of the spines with multiple excitatory contacts (SMECs) receive simultaneous thalamic and cortical inputs. Proportion of SMECs diminishes as the brain develops, but SMECs remain abundant in Hevin-null mice. These findings reveal that, through secretion of hevin, astrocytes control an important developmental synaptic refinement process at dendritic spines. The central nervous system—which is made up of the brain and spinal cord—processes information from all over the body. The information travels through cells called neurons, which connect to each other at junctions called synapses. A single neuron can receive information from many different places because it is covered with protrusions known as dendritic spines that enable it to form synapses with a variety of other neurons. In recent years, it has become apparent that brain cells other than neurons can influence synapse formation. The most abundant cells in the central nervous system are star-shaped cells known as astrocytes, which secrete molecules that control the timing and extent of synapse formation. Many previous studies on synapses have used a type of neuron found in the eye—called retinal ganglion cells—because these cells can be purified and grown in the laboratory in the absence of astrocytes. Under these conditions, they form very few synapses. However, in the presence of astrocytes the retinal ganglion cells form many more synapses, which is thought to be due to a protein called hevin and several other proteins that are secreted by the astrocytes. Risher et al. studied a region of the brain called the cerebral cortex in mice that were missing hevin. In the cortex of normal mice, the neurons generally form synapses with other neurons within the cortex, or with neurons from other parts of the brain that send long-distance projections into the cortex. The experiments revealed that fewer of these long-distance synapses formed in the cortex of the mice missing hevin compared to normal mice. When hevin was injected directly into the brains of the mice, more long-distance synapses were formed. Using a technique called three-dimensional electron microscopy, Risher et al. examined the structure of the synapses. In mice missing hevin, the synapses were much smaller and the dendritic spines were thin and long, indicating that they were not fully grown. The images also show that in normal mice, the dendritic spines often have multiple synapses when the animal is young, but many are lost as the brain matures so that only a single synapse remains in each dendritic spine. However, multiple synapses persist in the dendritic spines of mice lacking hevin, which could lead to competition between short and long distance synapses and may contribute to neurological diseases. These results indicate that astrocytes are crucial for controlling the formation of synapses in dendritic spines. In humans, defects in hevin have been implicated in autism, schizophrenia and other neurological conditions. Future studies will seek to determine the precise role of astrocytes in these conditions, which may help us to develop new therapies.

Autism spectrum disorders (ASDs) are neurodevelopmental disorders caused by various genetic and environmental factors that result in synaptic abnormalities. ASD development is suggested to involve microglia, which have a role in synaptic refinement during development. Autophagy and related pathways are also suggested to be involved in ASDs. However, the precise roles of microglial autophagy in synapses and ASDs are unknown. Here, we show that microglial autophagy is involved in synaptic refinement and neurobehavior regulation. We found that deletion of atg7, which is vital for autophagy, from myeloid cell-specific lysozyme M-Cre mice resulted in social behavioral defects and repetitive behaviors, characteristic features of ASDs. These mice also had increases in dendritic spines and synaptic markers and altered connectivity between brain regions, indicating defects in synaptic refinement. Synaptosome degradation was impaired in atg7-deficient microglia and immature dendritic filopodia were increased in neurons co-cultured with atg7-deficient microglia. To our knowledge, our results are the first to show the role of microglial autophagy in the regulation of the synapse and neurobehaviors. We anticipate our results to be a starting point for more comprehensive studies of microglial autophagy in ASDs and the development of putative therapeutics.

Modeling studies suggest that clustered structural plasticity of dendritic spines is an efficient mechanism of information storage in cortical circuits. However, why new clustered spines occur in specific locations and how their formation relates to learning and memory (L&M) remain unclear. Using in vivo two-photon microscopy, we track spine dynamics in retrosplenial cortex before, during, and after two forms of episodic-like learning and find that spine turnover before learning predicts future L&M performance, as well as the localization and rates of spine clustering. Consistent with the idea that these measures are causally related, a genetic manipulation that enhances spine turnover also enhances both L&M and spine clustering. Biophysically inspired modeling suggests turnover increases clustering, network sparsity, and memory capacity. These results support a hotspot model where spine turnover is the driver for localization of clustered spine formation, which serves to modulate network function, thus influencing storage capacity and L&M. Structural remodeling of dendritic spines is thought to be a mechanism of memory storage. Here, the authors look at how spine turnover and clustering predict future learning and memory performance, and see that a genetically modified mouse with enhanced spine turnover has enhanced learning.

Live fluorescent imaging of murine hippocampal slices shows that NMDAR-dependent glutamate signalling leads to postsynaptic BDNF release, with associated signalling of its receptor, TrkB, on the same dendritic spine, suggesting autocrine BDNF signalling. Mechanisms of neuronal plasticity Secreted messenger molecules such as brain-derived neurotrophic factor (BDNF) are known to participate in various forms of neuronal plasticity, such as long-term synaptic potentiation (LTP) and associated changes in dendritic spine morphology, but the exact sites of BDNF release and action remain poorly defined. Two papers from Ryohei Yasuda's lab, published in this issue of Nature , tackle this question. Stephen Harward et al . use live fluorescent imaging of murine hippocampal slices to show that NMDAR-dependent glutamate signalling leads to postsynaptic BDNF release, with associated signalling of its receptor, TrkB, on the same dendritic spine, suggesting autocrine BDNF signalling. In the second study Nathan Hedrick et al . find that the three small GTPases Rac1, RhoA and Cdc42 are differentially involved in structural long-term potentiation of rodent dendritic spines, simultaneously ensuring signal specificity while also priming the system for plasticity. Taken together these results suggest molecular mechanisms for both signal specificity at single spines and synaptic cross-talk, a unique biochemical computation involved in neuronal plasticity and learning. Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for many forms of neuronal plasticity 1 , 2 , 3 , 4 , 5 , 6 , including structural long-term potentiation (sLTP) 7 , 8 , which is a correlate of an animal’s learning 7 , 9 , 10 , 11 , 12 . However, it is unknown whether BDNF release and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescence resonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imaging microscopy 13 , 14 , 15 , 16 , we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to sLTP induction 9 , 14 , 15 , 16 , we find fast (onset < 1 min) and sustained (>20 min) activation of TrkB in the stimulated spine that depends on NMDAR ( N -methyl- d -aspartate receptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused to superecliptic pHluorin 17 , 18 , 19 . We demonstrate that this postsynaptic BDNF–TrkB signalling pathway is necessary for both structural and functional LTP 20 . Together, these findings reveal a spine-autonomous, autocrine signalling mechanism involving NMDAR–CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity.

Erythropoietin (EPO), named after its role in hematopoiesis, is also expressed in mammalian brain. In clinical settings, recombinant EPO treatment has revealed a remarkable improvement of cognition, but underlying mechanisms have remained obscure. Here, we show with a novel line of reporter mice that cognitive challenge induces local/endogenous hypoxia in hippocampal pyramidal neurons, hence enhancing expression of EPO and EPO receptor (EPOR). High-dose EPO administration, amplifying auto/paracrine EPO/EPOR signaling, prompts the emergence of new CA1 neurons and enhanced dendritic spine densities. Single-cell sequencing reveals rapid increase in newly differentiating neurons. Importantly, improved performance on complex running wheels after EPO is imitated by exposure to mild exogenous/inspiratory hypoxia. All these effects depend on neuronal expression of the Epor gene. This suggests a model of neuroplasticity in form of a fundamental regulatory circle, in which neuronal networks—challenged by cognitive tasks—drift into transient hypoxia, thereby triggering neuronal EPO/EPOR expression. EPO treatment improves cognition, but underlying mechanisms were unknown. Here the authors describe a regulatory loop in which brain networks challenged by cognitive tasks drift into functional hypoxia that drives—via neuronal EPO synthesis—neurodifferentiation and dendritic spine formation.