Mouse Central Nervous System Research Articles

Microglia form satellites with different neuronal subtypes in the adult murine central nervous system.

Microglia are the innate immune cells of the central nervous system (CNS). In the adult uncompromised CNS, they have a highly ramified morphology and continuously extend and retract their processes. A subpopulation of microglial cells forms close soma-to-soma contacts with neurons and have been termed satellite microglia, yet the role of such interaction is largely unknown. Here, we analyzed the distribution of satellite microglia in different areas of the CNS of adult male mice applying transgenic- and immunolabeling of neuronal subtypes and microglia followed by three-dimensional imaging analysis. We quantified satellite microglia associated with GABAergic and glutamatergic neurons in the somatosensory cortex, striatum, and thalamus; with dopaminergic and serotonergic neurons in the basal forebrain and raphe nucleus, respectively; and with cerebellar Purkinje cell neurons. Satellite microglia in the retina were assessed qualitatively. Microglia form satellites with all neuronal subtypes studied, whereas a preference for a specific neuron subtype was not found. The occurrence and frequency of satellite microglia is determined by the histo-architectural organization of the brain area and the densities of neuronal somata therein.

SARS-CoV-2 Infects Primary Neurons from Human ACE2 Expressing Mice and Upregulates Genes Involved in the Inflammatory and Necroptotic Pathways.

Transgenic mice expressing human angiotensin-converting enzyme 2 under the cytokeratin 18 promoter (K18-hACE2) have been extensively used to investigate the pathogenesis and tissue tropism of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Neuroinvasion and the replication of SARS-CoV-2 within the central nervous system (CNS) of K18-hACE2 mice is associated with increased mortality; although, the mechanisms by which this occurs remain unclear. In this study, we generated primary neuronal cultures from K18-hACE2 mice to investigate the effects of a SARS-CoV-2 infection. We also evaluated the immunological response to SARS-CoV-2 infection in the CNS of K18-hACE2 mice and mouse neuronal cultures. Our data show that neuronal cultures obtained from K18-hACE2 mice are permissive to SARS-CoV-2 infection and support productive virus replication. Furthermore, SARS-CoV-2 infection upregulated the expression of genes involved in innate immunity and inflammation, including IFN-α, ISG-15, CXCL10, CCL2, IL-6 and TNF-α, in the neurons and mouse brains. In addition, we found that SARS-CoV-2 infection of neurons and mouse brains activates the ZBP1/pMLKL-regulated necroptosis pathway. Together, our data provide insights into the neuropathogenesis of SARS-CoV-2 infection in K18-hACE2 mice.

Variational autoencoding of gene landscapes during mouse CNS development uncovers layered roles of Polycomb Repressor Complex 2.

A prominent aspect of most, if not all, central nervous systems (CNSs) is that anterior regions (brain) are larger than posterior ones (spinal cord). Studies in Drosophila and mouse have revealed that Polycomb Repressor Complex 2 (PRC2), a protein complex responsible for applying key repressive histone modifications, acts by several mechanisms to promote anterior CNS expansion. However, it is unclear what the full spectrum of PRC2 action is during embryonic CNS development and how PRC2 intersects with the epigenetic landscape. We removed PRC2 function from the developing mouse CNS, by mutating the key gene Eed, and generated spatio-temporal transcriptomic data. To decode the role of PRC2, we developed a method that incorporates standard statistical analyses with probabilistic deep learning to integrate the transcriptomic response to PRC2 inactivation with epigenetic data. This multi-variate analysis corroborates the central involvement of PRC2 in anterior CNS expansion, and also identifies several unanticipated cohorts of genes, such as proliferation and immune response genes. Furthermore, the analysis reveals specific profiles of regulation via PRC2 upon these gene cohorts. These findings uncover a differential logic for the role of PRC2 upon functionally distinct gene cohorts that drive CNS anterior expansion. To support the analysis of emerging multi-modal datasets, we provide a novel bioinformatics package that integrates transcriptomic and epigenetic datasets to identify regulatory underpinnings of heterogeneous biological processes.

Evidence of Microglial Immune Response Following Coronavirus PHEV Infection of CNS

Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurotropic coronavirus that invades the host central nervous system (CNS) and causes neurological dysfunction. Microglia are key immune cells in the CNS, however, whether and how they response to PHEV infection remains unclear. Herein, microglial activation and proliferation were detected in the CNS of PHEV-infected mice, as along with the proinflammatory response. Moreover, the production of proinflammatory cytokines induced by moderately activated microglia limited viral replication in the early stage of infection. Microglial depletion assays showed that during late infection, excess activation of microglia aggravated neurological symptoms, BBB destruction, and peripheral monocyte/macrophage infiltration into the CNS. Using an in vitro brain slice model, PHEV was identified to specifically and moderately induce microglial activation in the absence of peripheral immune cells infiltration. Consistently, macrophage clearance from circulating blood indicated that peripheral monocytes/macrophages crossing the BBB of mice were responsible for excess activation of microglia and CNS damage in late PHEV infection. Overall, our findings provide evidence supporting a dual role for microglia in the host CNS in response to coronavirus PHEV invasion.

Effects of different doses of dezocine on central nervous system in mice

Dezocine is an opioid receptor agonist – antagonist gaining popularity in clinical practice. It is both μ-receptor agonist and antagonist activities. This study was designed to investigate the effects of dezocine on the CNS oxidative and inflammation in mice. Eight-week old female BALB/c mice were obtained from Shanghai General Hospital of Nanjing Medical University animal center. All animal procedures were approved by the Animal Care and Use Committee of Nanjing Medical University. We found that increasing dose of dezocine induced oxidative stress and inflammation in multiple brain regions, including the prefrontal cortex, cerebellum, temporal cortex, and striatum. Elevated expression levels of anti- oxidants (NRF2, SOD-1 and HO-1), KEAP-1, GSH and MDA were found in the prefrontal cortex and striatum. Elevated HO-1 and NRF2 levels were detected in the cerebellum and temporal cortex in the 3.0 mg/kg dezocine treated group. The SOD-1, HO-1, KEAP-1, NRF2, GSH and MDA levels were similar among groups in the olfactory bulb. The prefrontal cortex and striatum showed the most elevated oxidative stress (NRF2, SOD-1, and HO-1) marker levels. The number of PV-positive interneurons was decreased in the 1.5 mg/kg dezocine treated group, while the number of PNNs steadily increased over 3.0 mg/kg dezocine treated.

Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system.

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity. Starting with transcriptomic analyses, we find that age- and tau-induced transposable element activation occurs in the mouse brain. Among transposable elements that are activated at the RNA level in the context of brain aging and tauopathy, we find that the endogenous retrovirus (ERV) class of retrotransposons is particularly enriched. We show that protein encoded by Intracisternal A-particle, a highly active mouse ERV, is elevated in brains of tau transgenic mice. Using two complementary approaches, we find that brains of tau transgenic mice contain increased DNA copy number of transposable elements, raising the possibility that these elements actively retrotranspose in the context of tauopathy. Taken together, our study lays the groundwork for future mechanistic studies focused on transposable element regulation in the aging mouse brain and in mouse models of tauopathy and provides support for ongoing therapeutic efforts targeting transposable element activation in patients with Alzheimer's disease.

Effect Of Gut Microbiome On Immune Regulation Of Central Nervous System (CNS) In EAE Mouse Model

The gut microbiome plays a crucial role regulating immune responses in the central nervous system (CNS). This study investigates the effect of the gut microbiome on immune regulation in a mouse model of experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. Using high-throughput sequencing techniques, we analyzed the composition of the gut microbiome in EAE mice and its impact on immune responses in the CNS. Our results demonstrate that alterations in the gut microbiome composition are associated with changes in the immune regulation of the CNS in EAE mice. These findings highlight the importance of the gut-brain axis in regulating immune responses in neuroinflammatory diseases.

CHL1-Deficient and Wild-Type Male Mice do Not Differ in Locomotor Recovery from Spinal Cord Injury.

CHL1 is a close homolog of L1, a cell adhesion molecule that plays major roles in neural and tumor cell functions. We had found that young adult female mice deficient in CHL1 recovered better than their wild-type female littermates after thoracic Spinal Cord Injury (SCI). This observation was surprising, because CHL1 increases neurite outgrowth in vitro. Injury of adult mouse central and peripheral nervous systems upregulate CHL1 expression in neurons and astrocytes, consistent with CHL1's pro-active, homophilic interaction between CHL1 surface molecules in wild-type mice. After SCI, CHL1 expression was observed to increase in the glial scar, areas of axonal regrowth and remodeling of neural circuits. These observations were made only in females, and we therefore sought to analyze SCI in CHL1-deficient male mice. We now show that CHL1-deficient males did not recover better or worse than their male wild-type littermates. Primary and secondary lesion volumes were similar in the two genotypes, as seen in female mice which were studied in parallel with male mice. Assessment of peripheral leukocytes showed a significant increase in numbers of blood neutrophils at 24 h after SCI in males, but not in females. Lymphocyte numbers in mutant males increased slightly, but numbers of lymphocytes or monocytes did not differ significantly between males or females. These results indicate that CHL1-deficient males and females differ in the number of neutrophils but not lymphocytes or monocytes, suggesting that the difference between males and females is unlikely due to differences in leukocytes.

Covering the Role of PGC-1α in the Nervous System.

The peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a well-known transcriptional coactivator involved in mitochondrial biogenesis. PGC-1α is implicated in the pathophysiology of many neurodegenerative disorders; therefore, a deep understanding of its functioning in the nervous system may lead to the development of new therapeutic strategies. The central nervous system (CNS)-specific isoforms of PGC-1α have been recently identified, and many functions of PGC-1α are assigned to the particular cell types of the central nervous system. In the mice CNS, deficiency of PGC-1α disturbed viability and functioning of interneurons and dopaminergic neurons, followed by alterations in inhibitory signaling and behavioral dysfunction. Furthermore, in the ALS rodent model, PGC-1α protects upper motoneurons from neurodegeneration. PGC-1α is engaged in the generation of neuromuscular junctions by lower motoneurons, protection of photoreceptors, and reduction in oxidative stress in sensory neurons. Furthermore, in the glial cells, PGC-1α is essential for the maturation and proliferation of astrocytes, myelination by oligodendrocytes, and mitophagy and autophagy of microglia. PGC-1α is also necessary for synaptogenesis in the developing brain and the generation and maintenance of synapses in postnatal life. This review provides an outlook of recent studies on the role of PGC-1α in various cells in the central nervous system.

Efficacy of Boron Neutron Capture Therapy in Primary Central Nervous System Lymphoma: In Vitro and In Vivo Evaluation.

Background: Boron neutron capture therapy (BNCT) is a nuclear reaction-based tumor cell-selective particle irradiation method. High-dose methotrexate and whole-brain radiation therapy (WBRT) are the recommended treatments for primary central nervous system lymphoma (PCNSL). This tumor responds well to initial treatment but relapses even after successful treatment, and the prognosis is poor as there is no safe and effective treatment for relapse. In this study, we aimed to conduct basic research to explore the possibility of using BNCT as a treatment for PCNSL. Methods: The boron concentration in human lymphoma cells was measured. Subsequently, neutron irradiation experiments on lymphoma cells were conducted. A mouse central nervous system (CNS) lymphoma model was created to evaluate the biodistribution of boron after the administration of borono-phenylalanine as a capture agent. In the neutron irradiation study of a mouse PCNSL model, the therapeutic effect of BNCT on PCNSL was evaluated in terms of survival. Results: The boron uptake capability of human lymphoma cells was sufficiently high both in vitro and in vivo. In the neutron irradiation study, the BNCT group showed a higher cell killing effect and prolonged survival compared with the control group. Conclusions: A new therapeutic approach for PCNSL is urgently required, and BNCT may be a promising treatment for PCNSL. The results of this study, including those of neutron irradiation, suggest success in the conduct of future clinical trials to explore the possibility of BNCT as a new treatment option for PCNSL.

Topoisomerase IIIβ Deficiency Induces Neuro-Behavioral Changes and Brain Connectivity Alterations in Mice.

Topoisomerase IIIβ (Top3β), the only dual-activity topoisomerase in mammals that can change topology of both DNA and RNA, is known to be associated with neurodevelopment and mental dysfunction in humans. However, there is no report showing clear associations of Top3β with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3β on neuro-behavior using newly generated Top3β deficient (Top3β−/−) mice. We found that Top3β−/− mice showed decreased anxiety and depression-like behaviors. The lack of Top3β was also associated with changes in circadian rhythm. In addition, a clear expression of Top3β was demonstrated in the central nervous system of mice. Positron emission tomography/computed tomography (PET/CT) analysis revealed significantly altered connectivity between many brain regions in Top3β−/− mice, including the connectivity between the olfactory bulb and the cerebellum, the connectivity between the amygdala and the olfactory bulb, and the connectivity between the globus pallidus and the optic nerve. These connectivity alterations in brain regions are known to be linked to neurodevelopmental as well as psychiatric and behavioral disorders in humans. Therefore, we conclude that Top3β is essential for normal brain function and behavior in mice and that Top3β could be an interesting target to study neuropsychiatric disorders in humans.

A restored humoral environment ameliorates acute brain injury after Angiostrongylus cantonensis infection

Circulating factors in the circulatory system support important functions of living tissues and the body. Parabiosis is a condition in which two living animals are connected using surgical methods and share a single circulatory system. Angiostrongylus cantonensis is the major cause of infectious eosinophilic meningitis, which causes severe damage to the central nervous system (CNS) and immune system. However, the mechanism of immunopathology remains largely unknown. We hypothesize that a restored humoral environment can help relieve damage to the CNS and immune system. In the present study, we found that administration of normal serum significantly reduced mortality, alleviated thymic atrophy and reduced inflammation in the brains of mice infected with A. cantonensis. We further generated parabiotic pairs between two healthy mice, one of which was then orally infected with A. cantonensis. The results showed that compared with singleton mice, mice connected with a healthy parabiotic partner were protected against CNS and immune system damage, as revealed by significantly reduced inflammation in the brain, alleviated thymic atrophy, and decreased expression of proinflammatory cytokines. These findings revealed that a healthy systemic environment can relieve damage to the CNS and immune system in infected mice, suggesting novel therapeutic approaches for diseases involving severe brain and immune system damage.

NFIL3 deficiency alleviates EAE through regulating different immune cell subsets

IntroductionThe transcription factor NFIL3 exerts comprehensive effects on the immune system. Previous studies revealed that NFIL3 is related to the function and development of different immune cell subsets. Experimental autoimmune encephalomyelitis (EAE) is mediated by immune cells which results in inflammatory demyelination in the central nervous system (CNS). However, how NFIL3 affects EAE has not been thoroughly studied. ObjectivesThe current study aimed to investigate how NFIL3 affects EAE, especially the changes of T cells and dendritic cells as well as the crosstalk between them. MethodsWe used NFIL3-/- mice and C57BL/6J mice (wildtype) to establish MOG35-55-induced EAE. The clinical scores were recorded daily. The immune cells within and outside the CNS of EAE mice were analyzed by flow cytometry. Histology was used to evaluated the neuroinflammation and demyelination in the CNS. Besides, CD11c+ dendritic cells (DCs) were cocultured with T cells and the interplay was measured. ResultsAt the peak of EAE, Th17 cells decreased within the CNS accompanying with lower clinical scores and milder neuroinflammation and demyelination in NFIL3 knockout EAE mice. Outside the CNS, PD-1 and ICOS on CD4+T cells increased, whereas Th2, Th9, CD8+CD103+T cells and GM-CSF+CD4+T cells decreased. Besides, the pro-inflammatory capacity of NFIL3-/- CD11c+ dendritic cells was impaired while the anti-inflammatory capacity was promoted. ConclusionsThis study suggests that NFIL3 deficiency could alleviate MOG35-55-induced EAE through regulating different immune cell subsets, which is not only related with adaptive immunity and innate immunity, but also related with the cross-talk between them, especially CD4+ T cells and CD11c+ dendritic cells.

Chronic lithium administration in a mouse model for Krabbe disease.

Krabbe disease (KD; or globoid cell leukodystrophy) is an autosomal recessive lysosomal storage disorder caused by deficiency of the galactosylceramidase (GALC) enzyme. No cure is currently available for KD. Clinical applied treatments are supportive only. Recently, we demonstrated that two differently acting autophagy inducers (lithium and rapamycin) can improve some KD hallmarks in‐vitro, laying the foundation for their in‐vivo pre‐clinical testing. Here, we test lithium carbonate in‐vivo, in the spontaneous mouse model for KD, the Twitcher (TWI) mouse. The drug is administered ad libitum via drinking water (600 mg/L) starting from post natal day 20. We longitudinally monitor the mouse motor performance through the grip strength, the hanging wire and the rotarod tests, and a set of biochemical parameters related to the KD pathogenesis [i.e., GALC enzymatic activity, psychosine (PSY) accumulation and astrogliosis]. Additionally, we investigate the expression of some crucial markers related to the two pathways that could be altered by lithium: the autophagy and the β‐catenin‐dependent pathways. Results demonstrate that lithium has not a significant rescue effect on the TWI phenotype, although it can slightly and transiently improves muscle strength. We also show that lithium, with this administration protocol, is unable to stimulate autophagy in the TWI mice central nervous system, whereas results suggest that it can restore the β‐catenin activation status in the TWI sciatic nerve. Overall, these data provide intriguing inputs for further evaluations of lithium treatment in TWI mice.

DSS-induced inflammation in the colon drives a proinflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod

BackgroundInflammatory bowel disease (IBD) is established to drive pathological sequelae in organ systems outside the intestine, including the central nervous system (CNS). Many patients exhibit cognitive deficits, particularly during disease flare. The connection between colonic inflammation and neuroinflammation remains unclear and characterization of the neuroinflammatory phenotype in the brain during colitis is ill-defined.MethodsTransgenic mice expressing a bioluminescent reporter of active caspase-1 were treated with 2% dextran sodium sulfate (DSS) for 7 days to induce acute colitis, and colonic, systemic and neuroinflammation were assessed. In some experiments, mice were prophylactically treated with paquinimod (ABR-215757) to inhibit S100A9 inflammatory signaling. As a positive control for peripheral-induced neuroinflammation, mice were injected with lipopolysaccharide (LPS). Colonic, systemic and brain inflammatory cytokines and chemokines were measured by cytokine bead array (CBA) and Proteome profiler mouse cytokine array. Bioluminescence was quantified in the brain and caspase activation was confirmed by immunoblot. Immune cell infiltration into the CNS was measured by flow cytometry, while light sheet microscopy was used to monitor changes in resident microglia localization in intact brains during DSS or LPS-induced neuroinflammation. RNA sequencing was performed to identify transcriptomic changes occurring in the CNS of DSS-treated mice. Expression of inflammatory biomarkers were quantified in the brain and serum by qRT-PCR, ELISA and WB.ResultsDSS-treated mice exhibited clinical hallmarks of colitis, including weight loss, colonic shortening and inflammation in the colon. We also detected a significant increase in inflammatory cytokines in the serum and brain, as well as caspase and microglia activation in the brain of mice with ongoing colitis. RNA sequencing of brains isolated from DSS-treated mice revealed differential expression of genes involved in the regulation of inflammatory responses. This inflammatory phenotype was similar to the signature detected in LPS-treated mice, albeit less robust and transient, as inflammatory gene expression returned to baseline following cessation of DSS. Pharmacological inhibition of S100A9, one of the transcripts identified by RNA sequencing, attenuated colitis severity and systemic and neuroinflammation.ConclusionsOur findings suggest that local inflammation in the colon drives systemic inflammation and neuroinflammation, and this can be ameliorated by inhibition of the S100 alarmin, S100A9.

Influenza infection perturbs oligodendrocyte homeostasis in the adult mouse central nervous system

Influenza infection perturbs oligodendrocyte homeostasis in the adult mouse central nervous system

Upper respiratory infection alters lipid biochemistry in myelin and adult mouse central nervous system

Upper respiratory infection alters lipid biochemistry in myelin and adult mouse central nervous system

CD8+ T cells specific for cryptic apoptosis-associated epitopes exacerbate experimental autoimmune encephalomyelitis

The autoimmune immunopathology occurring in multiple sclerosis (MS) is sustained by myelin-specific and -nonspecific CD8+ T cells. We have previously shown that, in MS, activated T cells undergoing apoptosis induce a CD8+ T cell response directed against antigens that are unveiled during the apoptotic process, namely caspase-cleaved structural proteins such as non-muscle myosin and vimentin. Here, we have explored in vivo the development and the function of the immune responses to cryptic apoptosis-associated epitopes (AEs) in a well-established mouse model of MS, experimental autoimmune encephalomyelitis (EAE), through a combination of immunization approaches, multiparametric flow cytometry, and functional assays. First, we confirmed that this model recapitulated the main findings observed in MS patients, namely that apoptotic T cells and effector/memory AE-specific CD8+ T cells accumulate in the central nervous system of mice with EAE, positively correlating with disease severity. Interestingly, we found that AE-specific CD8+ T cells were present also in the lymphoid organs of unprimed mice, proliferated under peptide stimulation in vitro, but failed to respond to peptide immunization in vivo, suggesting a physiological control of this response. However, when mice were immunized with AEs along with EAE induction, AE-specific CD8+ T cells with an effector/memory phenotype accumulated in the central nervous system, and the disease severity was exacerbated. In conclusion, we demonstrate that AE-specific autoimmunity may contribute to immunopathology in neuroinflammation.

The role of T-cells in neurobehavioural development: Insights from the immunodeficient nude mice

Mice homozygous for the nude mutation (Foxn1nu) are hairless and exhibit congenital dysgenesis of the thymic epithelium, resulting in a primary immunodeficiency of mature T-cells, and have been used for decades in research with tumour grafts. Early studies have already demonstrated social behaviour impairments and central nervous system (CNS) alterations in these animals, but did not address the complex interplay between CNS, immune system and behavioural alterations. Here we investigate the impact of T-cell immunodeficiency on behaviours relevant to the study of neurodevelopmental and neuropsychiatric disorders. Moreover, we aimed to characterise in a multidisciplinary manner the alterations related to those findings, through evaluation of the excitatory/inhibitory synaptic proteins, cytokines expression and biological spectrum signature of different biomolecules in nude mice CNS. We demonstrate that BALB/c nude mice display sociability impairments, a complex pattern of repetitive behaviours and higher sensitivity to thermal nociception. These animals also have a reduced IFN-γ gene expression in the prefrontal cortex and an absence of T-cells in meningeal tissue, both known modulators of social behaviour. Furthermore, excitatory synaptic protein PSD-95 immunoreactivity was also reduced in the prefrontal cortex, suggesting an intricate involvement of social behaviour related mechanisms. Lastly, employing biospectroscopy analysis, we have demonstrated that BALB/c nude mice have a different CNS spectrochemical signature compared to their heterozygous littermates. Altogether, our results show a comprehensive behavioural analysis of BALB/c nude mice and potential neuroimmunological influences involved with the observed alterations.

Synaptic Vesicle Glycoprotein 2A Is Affected in the Central Nervous System of Mice with Huntington Disease and in the Brain of a Human with Huntington Disease Postmortem.

Synaptic dysfunction is a primary mechanism underlying Huntington disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of 11C-UCB-J small-animal PET imaging in the central nervous system of mice with HD. Methods: Dynamic 11C-UCB-J small-animal PET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 mo) in the heterozygous knock-in Q175DN mouse model of HD and wild-type littermates (16-18 mice per genotype and time point). Cerebral 11C-UCB-J analyses were performed to assess genotypic differences during presymptomatic (3 mo) and symptomatic (7-16 mo) disease stages. 11C-UCB-J binding in the spinal cord was quantified at 16 mo. 3H-UCB-J autoradiography and SV2A immunofluorescence were performed postmortem in mouse and human brain tissues. Results:11C-UCB-J binding was lower in symptomatic heterozygous mice than in wild-type littermates in parallel with disease progression (7 and 10 mo: P < 0.01; 16 mo: P < 0.0001). Specific 11C-UCB-J binding was detectable in the spinal cord, with symptomatic heterozygous mice displaying a significant reduction (P < 0.0001). 3H-UCB-J autoradiography and SV2A immunofluorescence corroborated the invivo measurements demonstrating lower SV2A in heterozygous mice (P < 0.05). Finally, preliminary analysis of SV2A in the human brain postmortem suggested lower SV2A in HD gene carriers than in controls without dementia. Conclusion:11C-UCB-J PET detected SV2A deficits during symptomatic disease in heterozygous mice in both the brain and the spinal cord and therefore may be suitable as a novel marker of synaptic integrity widely distributed in the central nervous system. On clinical application, 11C-UCB-J PET imaging may have promise for SV2A measurement in patients with HD during disease progression and after disease-modifying therapeutic strategies.