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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.

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.

Experiments in transgenic mouse models of early Alzheimer’s disease show that the amnesia seen at this stage of the disease is probably caused by a problem with memory retrieval from the hippocampus rather than an encoding defect. Rescue of forgotten memories The hippocampus plays a crucial role in the encoding, consolidation, and retrieval of episodic memories, which are the first to go missing in the early stages of Alzheimer's disease. This study shows in transgenic mouse models of early Alzheimer's disease that the amnesia is due to a defect in memory retrieval rather than in encoding. Importantly, the 'forgotten' memories can be rescued by direct activation of hippocampal dentate gyrus engram cells, and the amnesia correlates with a progressive reduction of dentate gyrus engram cell spine density. The authors suggest that selective rescue of dentate gyrus engram cells and their spine density may lead to new therapeutic strategies to recoup lost memories in early Alzheimer's disease. Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions 1 . Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role 2 . However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent 3 , 4 , 5 , which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

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.

The complement component 4 ( C4 ) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4 , human C4A and/or C4B . Human C4A bound synapses more efficiently than C4B. C4A (but not C4B ) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia. Overexpression of complement C4A is associated with schizophrenia risk. Using a novel mouse model, Yilmaz et al. find that increased expression of C4A leads to abnormal synaptic pruning and behavior, suggesting its importance as a therapeutic target.

Long-term treatments to ameliorate peripheral neuropathic pain that includes mechanical allodynia are limited. While glial activation and altered nociceptive transmission within the spinal cord are associated with the pathogenesis of mechanical allodynia, changes in cortical circuits also accompany peripheral nerve injury and may represent additional therapeutic targets. Dendritic spine plasticity in the S1 cortex appears within days following nerve injury; however, the underlying cellular mechanisms of this plasticity and whether it has a causal relationship to allodynia remain unsolved. Furthermore, it is not known whether glial activation occurs within the S1 cortex following injury or whether it contributes to this S1 synaptic plasticity. Using in vivo 2-photon imaging with genetic and pharmacological manipulations of murine models, we have shown that sciatic nerve ligation induces a re-emergence of immature metabotropic glutamate receptor 5 (mGluR5) signaling in S1 astroglia, which elicits spontaneous somatic Ca2+ transients, synaptogenic thrombospondin 1 (TSP-1) release, and synapse formation. This S1 astrocyte reactivation was evident only during the first week after injury and correlated with the temporal changes in S1 extracellular glutamate levels and dendritic spine turnover. Blocking the astrocytic mGluR5-signaling pathway suppressed mechanical allodynia, while activating this pathway in the absence of any peripheral injury induced long-lasting (>1 month) allodynia. We conclude that reawakened astrocytes are a key trigger for S1 circuit rewiring and that this contributes to neuropathic mechanical allodynia.

Synaptic failure is an immediate cause of cognitive decline and memory dysfunction in Alzheimer’s disease. Dendritic spines are specialized structures on neuronal processes, on which excitatory synaptic contacts take place and the loss of dendritic spines directly correlates with the loss of synaptic function. Dendritic spines are readily accessible for both in vitro and in vivo experiments and have, therefore, been studied in great detail in Alzheimer’s disease mouse models. To date, a large number of different mechanisms have been proposed to cause dendritic spine dysfunction and loss in Alzheimer’s disease. For instance, amyloid beta fibrils, diffusible oligomers or the intracellular accumulation of amyloid beta have been found to alter the function and structure of dendritic spines by distinct mechanisms. Furthermore, tau hyperphosphorylation and microglia activation, which are thought to be consequences of amyloidosis in Alzheimer’s disease, may also contribute to spine loss. Lastly, genetic and therapeutic interventions employed to model the disease and elucidate its pathogenetic mechanisms in experimental animals may cause alterations of dendritic spines on their own. However, to date none of these mechanisms have been translated into successful therapeutic approaches for the human disease. Here, we critically review the most intensely studied mechanisms of spine loss in Alzheimer’s disease as well as the possible pitfalls inherent in the animal models of such a complex neurodegenerative disorder.

Age-dependent dendritic spine loss is a hypothesized mechanism by which increased chronological age lowers the threshold for developing cognitive decline after ADRD pathologies accumulate. Therefore, slowing spine loss during normal aging may be a strategy to enhance resilience to cognitive decline induced by the accumulation of ADRD pathologies. In a recent human postmortem study of precuneus tissue, we identified repurposed drugs that are predicted to reverse the proteome signature of age-dependent spine loss, thus slowing spine loss and enhancing resilience to cognitive decline. NIA has promulgated HET3 mice as a preferred model for preclinical evaluation of anti-aging therapies. We therefore sought to evaluate the face validity of the HET3 mouse as a model of age-dependent spine loss and its associated proteome alterations and cognitive deficits. Male HET3 mice 6 and 21 months of age (n = 6 per age group) were sacrificed and perfused with normal saline, after which left cerebral cortices and right hemibrains were harvested for proteomics and immunohistochemistry/confocal microscopy, respectively. Dendritic spine densities at 12-15 randomly selected sites per mouse in retrosplenial cortex (RSC) were quantified with immunohistochemistry/confocal microscopy by colocalization of antibody-mediated detection of spinophillin and filamentous actin by phalloidin. Left cerebral cortex gray matter was homogenized in Syn-Per reagent and protein abundances quantified by liquid chromatography/mass spectrometry. Male HET3 mice between 6 and 21 months of age exhibit reduction in spine density in RSC of large effect size (Cohen's d=0.893), nearly reaching significance in this small sample (one-sided t-test p = 0.076) (Figure 1). The magnitude of spine density reduction (7.8%) was similar to that which we previously observed between the youngest (20-30 years of age) and oldest (>70 years of age) subjects in our study of human postmortem precuneus (8.5%). The proteome signature of aging in HET3 mice and age-dependent cognitive deficits detected in a separate sample cohort will be presented. The HET3 mouse may be a viable model for studies designed to test candidate interventions for their abilities to slow age-dependent spine loss and protect against cognitive decline. Additional studies with larger sample sizes of both sexes designed to replicate age-dependent spine loss in HET3 are warranted.

Brain tissue as a material presents unique properties with a multitude of cell types and densities, varying degrees of axonal fiber diameters and blood vessels. These neural components are contained within a very viscous environment that upon impact, can result in a variety of tensile, compressive and rotational forces. The depths of the sulcus appear to be particularly vulnerable to biomechanical forces following an impact. The movement and subsequent forces loaded on to the brain have been shown to produce a variety of biomechanical responses that impair neurophysiological functioning at the cellular level. We recently reported a decrease in microtubule associated protein 2 (MAP2) within the depths of the porcine sulcus in an ex vivo model, along with elevated tensile strain in this region within 1 hour after impact. In the current work, using the same impact model, we explored whether changes in spine morphology and density occurred within the same timeframe following impact. The Golgi-Cox method was used to visualize dendritic spine morphology. Cortical pyramidal neurons within the depths and the arms of the sulcus were reconstructed. One hour after impact, there was a change in the distribution of spine type resulting in an increased proportion of mushroom-type spines compared to nonimpacted tissue. The increased proportion of mushroom-type spines was proportional to tensile strain measurements in the apical dendrites. These results demonstrate the sensitivity of dendritic spine morphology to tensile strain within the porcine cortex and suggest a state of hyperexcitability during the hyperacute phase following an impact.