A guiding map for inflammation.

Biologists, physicians and immunologists have contributed to the understanding of the cellular participants and biological pathways involved in inflammation. Here, we provide a general guide to the cellular and humoral contributors to inflammation as well as to the pathways that characterize inflammation in specific organs and tissues.

Loss of all three APP family members during development impairs synaptic function and plasticity, disrupts learning, and causes an autism-like phenotype.

The key role of APP for Alzheimer pathogenesis is well established. However, perinatal lethality of germline knockout mice lacking the entire APP family has so far precluded the analysis of its physiological functions for the developing and adult brain. Here, we generated conditional APP/APLP1/APLP2 triple KO (cTKO) mice lacking the APP family in excitatory forebrain neurons from embryonic day 11.5 onwards. NexCre cTKO mice showed altered brain morphology with agenesis of the corpus callosum and disrupted hippocampal lamination. Further, NexCre cTKOs revealed reduced basal synaptic transmission and drastically reduced long-term potentiation that was associated with reduced dendritic length and reduced spine density of pyramidal cells. With regard to behavior, lack of the APP family leads not only to severe impairments in a panel of tests for learning and memory, but also to an autism-like phenotype including repetitive rearing and climbing, impaired social communication, and deficits in social interaction. Together, our study identifies essential functions of the APP family during development, for normal hippocampal function and circuits important for learning and social behavior.

APPsα rescues impaired Ca2+ homeostasis in APP- and APLP2-deficient hippocampal neurons.

Alterations in Ca2+ homeostasis have been reported in several in vitro and in vivo studies using mice expressing the Alzheimer's disease-associated transgenes, presenilin and the amyloid precursor protein (APP). While intense research focused on amyloid-ß-mediated functions on neuronal Ca2+ handling, the physiological role of APP and its close homolog APLP2 is still not fully clarified. We now elucidate a mechanism to show how APP and its homolog APLP2 control neuronal Ca2+ handling and identify especially the ectodomain APPsα as an essential regulator of Ca2+ homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca2+ handling, the refill of the endoplasmic reticulum Ca2+ stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca2+ channel-associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsα, but not acute application of the recombinant protein, restored physiological Ca2+ homeostasis and synaptic plasticity in APP/APLP2 cDKO cultures. Overall, our analysis reveals an essential role of the APP family and especially of the ectodomain APPsα in Ca2+ homeostasis, thereby highlighting its therapeutic potential.

APPsα Rescues Tau-Induced Synaptic Pathology.

Alzheimer's disease (AD) is histopathologically characterized by Aß plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Aß is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aß-dependent impairments. Here, we examined the potential of APPsα to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsα to hippocampal slices, indicating a homeostatic function of APPsα on a rapid time scale. Further, AAV-mediated in vivo expression of APPsα restored normal spine density of CA1 neurons even at stages of advanced Tau pathology not only in P301S mice, but also in independent THY-Tau22 mice. Strikingly, when searching for the mechanism underlying aberrantly increased LTP in P301S mice, we identified an early and progressive loss of major GABAergic interneuron subtypes in the hippocampus of P301S mice, which may lead to reduced GABAergic inhibition of principal cells. Interneuron loss was paralleled by deficits in nest building, an innate behavior highly sensitive to hippocampal impairments. Together, our findings indicate that APPsα has therapeutic potential for Tau-mediated synaptic dysfunction and suggest that loss of interneurons leads to disturbed neuronal circuits that compromise synaptic plasticity as well as behavior.SIGNIFICANCE STATEMENT Our findings indicate, for the first time, that APPsα has the potential to rescue Tau-induced spine loss and abnormal synaptic plasticity. Thus, APPsα might have therapeutic potential not only because of its synaptotrophic functions, but also its homeostatic capacity for neuronal network activity. Hence, APPsα is one of the few molecules which has proven therapeutic effects in mice, both for Aß- and Tau-dependent synaptic impairments and might therefore have therapeutic potential for patients suffering from AD or primary tauopathies. Furthermore, we found in P301S mice a pronounced reduction of inhibitory interneurons as the earliest pathologic event preceding the accumulation of hyperphosphorylated Tau species. This loss of interneurons most likely disturbs neuronal circuits that are important for synaptic plasticity and behavior.

Cellular and System Biology of Memory: Timing, Molecules, and Beyond.

The storage of information in the mammalian nervous systems is dependent on a delicate balance between change and stability of neuronal networks. The induction and maintenance of processes that lead to changes in synaptic strength to a multistep process which can lead to long-lasting changes, which starts and ends with a highly choreographed and perfectly timed dance of molecules in different cell types of the central nervous system. This is accompanied by synchronization of specific networks, resulting in the generation of characteristic "macroscopic" rhythmic electrical fields, whose characteristic frequencies correspond to certain activity and information-processing states of the brain. Molecular events and macroscopic fields influence each other reciprocally. We review here cellular processes of synaptic plasticity, particularly functional and structural changes, and focus on timing events that are important for the initial memory acquisition, as well as mechanisms of short- and long-term memory storage. Then, we cover the importance of epigenetic events on the long-time range. Furthermore, we consider how brain rhythms at the network level participate in processes of information storage and by what means they participating in it. Finally, we examine memory consolidation at the system level during processes of sleep.

Prolonged and specific spatial training during adolescence reverses adult hippocampal network impairments in a mouse model of fragile X syndrome.

The fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism. A hallmark of FXS in patients and the FXS mouse model (Fmr1 KO) is an overabundance of immature appearing dendritic spines in the cortex and hippocampus which is associated with behavioral deficits. Spine analysis in the different hippocampal subregions and at different developmental stages revealed that in adult mice, hippocampal spine pathology occurs specifically in the CA3 subregion, which plays a pivotal role in pattern completion processes important for efficient memory recall from parts of the initial memory stimulus. In line with this synaptic defect we document an impairment in memory recall during partially cued reference memory test in the Morris water maze task. This is accompanied by impaired recruitment of engram cells as well as impaired spine structural plasticity in the CA3 region. In order to promote hippocampal network development adolescent mice were either raised in an enriched environment or subjected to specific hippocampus-dependent spatial training. Intriguingly, only specific spatial training alleviated the cognitive symptoms and the spine phenotype shown in adult Fmr1 KO mice suggesting that specific stimulation of hippocampal networks during development might be used in the future as a therapeutic strategy.

How viral infections cause neuronal dysfunction: a focus on the role of microglia and astrocytes.

In recent decades, a number of infectious viruses have emerged from wildlife or reemerged that pose a serious threat to global health and economies worldwide. Although many of these viruses have a specific target tissue, neurotropic viruses have evolved mechanisms to exploit weaknesses in immune defenses that eventually allow them to reach and infect cells of the central nervous system (CNS). Once in the CNS, these viruses can cause severe neuronal damage, sometimes with long-lasting, life-threatening consequences. Remarkably, the ability to enter the CNS and cause neuronal infection does not appear to determine whether a viral strain causes neurological complications. The cellular mechanisms underlying the neurological consequences of viral infection are not fully understood, but they involve neuroimmune interactions that have so far focused mainly on microglia. As the major immune cells in the brain, reactive microglia play a central role in neuroinflammation by responding directly or indirectly to viruses. Chronic reactivity of microglia leads to functions that are distinct from their beneficial roles under physiological conditions and may result in neuronal damage that contributes to the pathogenesis of various neurological diseases. However, there is increasing evidence that reactive astrocytes also play an important role in the response to viruses. In this review article, we summarize the recent contributions of microglia and astrocytes to the neurological impairments caused by viral infections. By expanding knowledge in this area, therapeutic approaches targeting immunological pathways may reduce the incidence of neurological and neurodegenerative disorders and increase the therapeutic window for neural protection.

The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer's disease.

Numerous studies demonstrate that neuroinflammation is a key player in the progression of Alzheimer's disease (AD). Interleukin (IL)-1ß is a main inducer of inflammation and therefore a prime target for therapeutic options. The inactive IL-1ß precursor requires processing by the the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome into a mature and active form. Studies have shown that IL-1ß is up-regulated in brains of patients with AD, and that genetic inactivation of the NLRP3 inflammasome improves behavioral tests and synaptic plasticity phenotypes in a murine model of the disease. In the present study, we analyzed the effect of pharmacological inhibition of the NLRP3 inflammasome using dapansutrile (OLT1177), an oral NLRP3-specific inhibitor that is safe in humans. Six-month-old WT and APP/PS1 mice were fed with standard mouse chow or OLT1177-enriched chow for 3 mo. The Morris water maze test revealed an impaired learning and memory ability of 9-mo-old APP/PS1 mice (P = 0.001), which was completely rescued by OLT1177 fed to mice (P = 0.008 to untreated APP/PS1). Furthermore, our findings revealed that 3 mo of OLT1177 diet can rescue synaptic plasticity in this mouse model of AD (P = 0.007 to untreated APP/PS1). In addition, microglia were less activated (P = 0.07) and the number of plaques was reduced in the cortex (P = 0.03) following NLRP3 inhibition with OLT1177 administration. We also observed an OLT1177 dose-dependent normalization of plasma metabolic markers of AD to those of WT mice. This study suggests the therapeutic potential of treating neuroinflammation with an oral inhibitor of the NLRP3 inflammasome.

Distinct in vivo roles of secreted APP ectodomain variants APPsα and APPsß in regulation of spine density, synaptic plasticity, and cognition.

Increasing evidence suggests that synaptic functions of the amyloid precursor protein (APP), which is key to Alzheimer pathogenesis, may be carried out by its secreted ectodomain (APPs). The specific roles of APPsα and APPsß fragments, generated by non-amyloidogenic or amyloidogenic APP processing, respectively, remain however unclear. Here, we expressed APPsα or APPsß in the adult brain of conditional double knockout mice (cDKO) lacking APP and the related APLP2. APPsα efficiently rescued deficits in spine density, synaptic plasticity (LTP and PPF), and spatial reference memory of cDKO mice. In contrast, APPsß failed to show any detectable effects on synaptic plasticity and spine density. The C-terminal 16 amino acids of APPsα (lacking in APPsß) proved sufficient to facilitate LTP in a mechanism that depends on functional nicotinic α7-nAChRs. Further, APPsα showed high-affinity, allosteric potentiation of heterologously expressed α7-nAChRs in oocytes. Collectively, we identified α7-nAChRs as a crucial physiological receptor specific for APPsα and show distinct in vivo roles for APPsα versus APPsß. This implies that reduced levels of APPsα that might occur during Alzheimer pathogenesis cannot be compensated by APPsß.

Not just amyloid: physiological functions of the amyloid precursor protein family.

Amyloid precursor protein (APP) gives rise to the amyloid-ß peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.

Neuroligin-1 mediates presynaptic maturation through brain-derived neurotrophic factor signaling.

BACKGROUND: Maturation is a process that allows synapses to acquire full functionality, optimizing their activity to diverse neural circuits, and defects in synaptic maturation may contribute to neurodevelopmental disorders. Neuroligin-1 (NL1) is a postsynaptic cell adhesion molecule essential for synapse maturation, a role typically attributed to binding to pre-synaptic ligands, the neurexins. However, the pathways underlying the action of NL1 in synaptic maturation are incompletely understood, and some of its previously observed effects seem reminiscent of those described for the neurotrophin brain-derived neurotrophic factor (BDNF). Here, we show that maturational increases in active zone stability and synaptic vesicle recycling rely on the joint action of NL1 and brain-derived neurotrophic factor (BDNF). RESULTS: Applying BDNF to hippocampal neurons in primary cultures or organotypical slice cultures mimicked the effects of overexpressing NL1 on both structural and functional maturation. Overexpressing a NL1 mutant deficient in neurexin binding still induced presynaptic maturation. Like NL1, BDNF increased synaptic vesicle recycling and the augmentation of transmitter release by phorbol esters, both hallmarks of presynaptic maturation. Mimicking the effects of NL1, BDNF also increased the half-life of the active zone marker bassoon at synapses, reflecting increased active zone stability. Overexpressing NL1 increased the expression and synaptic accumulation of BDNF. Inhibiting BDNF signaling pharmacologically or genetically prevented the effects of NL1 on presynaptic maturation. Applying BDNF to NL1-knockout mouse cultures rescued defective presynaptic maturation, indicating that BDNF acts downstream of NL1 and can restore presynaptic maturation at late stages of network development. CONCLUSIONS: Our data introduce BDNF as a novel and essential component in a transsynaptic pathway linking NL1-mediated cell adhesion, neurotrophin action, and presynaptic maturation. Our findings connect synaptic cell adhesion and neurotrophin signaling and may provide a therapeutic approach to neurodevelopmental disorders by targeting synapse maturation.

Enduring Changes in Neuronal Function upon Systemic Inflammation Are NLRP3 Inflammasome Dependent.

Neuroinflammation can be caused by various insults to the brain and represents an important pathologic hallmark of neurodegenerative diseases including Alzheimer's disease (AD). Infection-triggered acute systemic inflammation is able to induce neuroinflammation and may negatively affect neuronal morphology, synaptic plasticity, and cognitive function. In contrast to acute effects, persisting consequences for the brain on systemic immune stimulation remain largely unexplored. Here, we report an age-dependent vulnerability of wild-type (WT) mice of either sex toward a systemic immune stimulation by Salmonella typhimurium lipopolysaccharide (LPS). Decreased neuronal complexity three months after peripheral immune stimulation is accompanied by impairment in long-term potentiation (LTP) and spatial learning. Aged APP/PS1 mice reveal an increased sensitivity also to LPS of Escherichia coli, which had no effect in WT mice. We further report that these effects are mediated by NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation, since the genetic ablation and pharmacological inhibition using the NLRP3 inhibitor MCC950 rescue the morphological and electrophysiological phenotype.SIGNIFICANCE STATEMENT Acute peripheral immune stimulation has been shown to have both positive and negative effects on Aß deposition. Improvements or worsening may be possible in acute inflammation. However, there is still no evidence of effects longer than a month after stimulation. The data are pointing to an important role of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome for mediating the long-term consequences of systemic immune stimulation, which in addition turns out to be age dependent.

Lack of APP and APLP2 in GABAergic Forebrain Neurons Impairs Synaptic Plasticity and Cognition.

Amyloid-ß precursor protein (APP) is central to the pathogenesis of Alzheimer's disease, yet its physiological functions remain incompletely understood. Previous studies had indicated important synaptic functions of APP and the closely related homologue APLP2 in excitatory forebrain neurons for spine density, synaptic plasticity, and behavior. Here, we show that APP is also widely expressed in several interneuron subtypes, both in hippocampus and cortex. To address the functional role of APP in inhibitory neurons, we generated mice with a conditional APP/APLP2 double knockout (cDKO) in GABAergic forebrain neurons using DlxCre mice. These DlxCre cDKO mice exhibit cognitive deficits in hippocampus-dependent spatial learning and memory tasks, as well as impairments in species-typic nesting and burrowing behaviors. Deficits at the behavioral level were associated with altered neuronal morphology and synaptic plasticity Long-Term Potentiation (LTP). Impaired basal synaptic transmission at the Schafer collateral/CA1 pathway, which was associated with altered compound excitatory/inhibitory synaptic currents and reduced action potential firing of CA1 pyramidal cells, points to a disrupted excitation/inhibition balance in DlxCre cDKOs. Together, these impairments may lead to hippocampal dysfunction. Collectively, our data reveal a crucial role of APP family proteins in inhibitory interneurons to maintain functional network activity.

Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System.

Purkinje cells (PCs) are primarily affected in neurodegenerative spinocerebellar ataxias (SCAs). For generating animal models for SCAs, genetic regulatory elements specifically targeting PCs are required, thereby linking pathological molecular effects with impaired function and organismic behavior. Because cerebellar anatomy and function are evolutionary conserved, zebrafish represent an excellent model to study SCAs in vivo We have isolated a 258 bp cross-species PC-specific enhancer element that can be used in a bidirectional manner for bioimaging of transgene-expressing PCs in zebrafish (both sexes) with variable copy numbers for tuning expression strength. Emerging ectopic expression at high copy numbers can be further eliminated by repurposing microRNA-mediated posttranslational mRNA regulation.Subsequently, we generated a transgenic SCA type 13 (SCA13) model, using a zebrafish-variant mimicking a human pathological SCA13R420H mutation, resulting in cell-autonomous progressive PC degeneration linked to cerebellum-driven eye-movement deficits as observed in SCA patients. This underscores that investigating PC-specific cerebellar neuropathologies in zebrafish allows for interconnecting bioimaging of disease mechanisms with behavioral analysis suitable for therapeutic compound testing.SIGNIFICANCE STATEMENT SCA13 patients carrying a KCNC3R420H allele have been shown to display mid-onset progressive cerebellar atrophy, but genetic modeling of SCA13 by expressing this pathogenic mutant in different animal models has not resulted in neuronal degeneration so far; likely because the transgene was expressed in heterologous cell types. We developed a genetic system for tunable PC-specific coexpression of several transgenes to manipulate and simultaneously monitor cerebellar PCs. We modeled a SCA13 zebrafish accessible for bioimaging to investigate disease progression, revealing robust PC degeneration, resulting in impaired eye movement. Our transgenic zebrafish mimicking both neuropathological and behavioral changes manifested in SCA-affected patients will be suitable for investigating causes of cerebellar diseases in vivo from the molecular to the behavioral level.

BDNF signaling during the lifetime of dendritic spines.

Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

FMRP Modulates Activity-Dependent Spine Plasticity by Binding Cofilin1 mRNA and Regulating Localization and Local Translation.

Multiple variants of intellectual disability, e.g., the Fragile X Syndrome are associated with alterations in dendritic spine morphology, thereby pointing to dysregulated actin dynamics during development and processes of synaptic plasticity. Surprisingly, although the necessity of spine actin remodeling was demonstrated repeatedly, the importance and precise role of actin regulators is often undervalued. Here, we provide evidence that structural and functional plasticity are severely impaired after NMDAR-dependent LTP in the hippocampus of Fmr1 KO mice. We can link these defects to an aberrant activity-dependent regulation of Cofilin 1 (cof1) as activity-dependent modulations of local cof1 mRNA availability, local cof1 translation as well as total cof1 expression are impaired in the absence of FMRP. Finally, we can rescue activity-dependent structural plasticity in KO neurons by mimicking the regulation of cof1 observed in WT cells, thereby illustrating the potential of actin modulators to provide novel treatment strategies for the Fragile X Syndrome.

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer's disease.

Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyR-mediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.

Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner.

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

Long-Term Neuroinflammation Induced by Influenza A Virus Infection and the Impact on Hippocampal Neuron Morphology and Function.

Acute influenza infection has been reported to be associated with neurological symptoms. However, the long-term consequences of an infection with neurotropic and non-neurotropic influenza A virus (IAV) variants for the CNS remain elusive. We can show that spine loss in the hippocampus after infection with neurotropic H7N7 (rSC35M) and non-neurotropic H3N2 (maHK68) in female C57BL/6 mice persists well beyond the acute phase of the disease. Although spine number was significantly reduced at 30 d postinfection (dpi) with H7N7 or H3N2, full recovery could only be observed much later at 120 dpi. Infection with H1N1 virus, which was shown previously to affect spine number and hippocampus-dependent learning acutely, had no significant long-term effects. Spine loss was associated with an increase in the number of activated microglia, reduced long-term potentiation in the hippocampus, and impairment in spatial memory formation, indicating that IAV-associated inflammation induced functional and structural alterations in hippocampal networks. Transcriptome analyses revealed regulation of many inflammatory and neuron- and glia-specific genes in H3N2- and H7N7-infected mice at day 18 and in H7N7-infected mice at day 30 pi that related to the structural and functional alterations. Our data provide evidence that neuroinflammation induced by neurotropic H7N7 and infection of the lung with a non-neurotropic H3N2 IAV result in long-term impairments in the CNS. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.SIGNIFICANCE STATEMENT In the acute phase of influenza infection, neuroinflammation can lead to alterations in hippocampal neuronal morphology and cognitive deficits. The results of this study now also provide evidence that neuroinflammation induced by influenza A virus (IAV) infection can induce longer-lasting, virus-specific alterations in neuronal connectivity that are still detectable 1 month after infection and are associated with impairments in spatial memory formation. IAV infection in humans may therefore not only lead to short-term responses in infected organs, but may also trigger neuroinflammation and associated chronic alterations in the CNS.