Live imaging of excitable axonal microdomains in ankyrin-G-GFP mice.

The axon initial segment (AIS) constitutes not only the site of action potential initiation, but also a hub for activity-dependent modulation of output generation. Recent studies shedding light on AIS function used predominantly post-hoc approaches since no robust murine in vivo live reporters exist. Here, we introduce a reporter line in which the AIS is intrinsically labeled by an ankyrin-G-GFP fusion protein activated by Cre recombinase, tagging the native Ank3 gene. Using confocal, superresolution, and two-photon microscopy as well as whole-cell patch-clamp recordings in vitro, ex vivo, and in vivo, we confirm that the subcellular scaffold of the AIS and electrophysiological parameters of labeled cells remain unchanged. We further uncover rapid AIS remodeling following increased network activity in this model system, as well as highly reproducible in vivo labeling of AIS over weeks. This novel reporter line allows longitudinal studies of AIS modulation and plasticity in vivo in real-time and thus provides a unique approach to study subcellular plasticity in a broad range of applications.

A systematic review of eating disorders and family functioning.

The purpose of the current review was to address four questions: 1) Are there differences in family functioning or family environment among patients with different eating disorder (ED) diagnoses? 2) Are there differences in the perception of family functioning or family environment among different family members? 3) Is family functioning or family environment related to ED symptomatology? 4) Does family functioning or family environment change as a result of ED treatment? and 4a) If so, does this impact ED treatment outcome? Although most studies found no differences among ED diagnostic groups, those that did generally found worse family functioning among those with binge/purge symptoms than among those with the restricting subtype of anorexia nervosa. Differences in perceptions of family functioning among family members were found, with patients generally reporting worse functioning than their parents. Worse family functioning was generally found to be related to worse ED symptoms. The variety of treatment approaches and different assessments of outcome made it somewhat unclear whether family functioning consistently improves with ED treatment. More research is needed on family functioning and EDs, particularly in understudied groups such as males, and those with ED diagnoses other than anorexia nervosa or bulimia nervosa.

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024.

Dietary intake of adults with eating disorders: A systematic review and meta-analysis.

Studies have confirmed the link between altered dietary intake and eating disorders (EDs), although no systematic assessment of this research exists. Rigorous synthesis of dietary intake in anorexia nervosa (AN), bulimia nervosa (BN), binge-eating disorder (BED), and similar EDs is needed to explore similarities and differences. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, we conducted a systematic review and quantitative synthesis of studies of dietary intake. Searches of three electronic databases resulted in thirty-nine included studies. Meta-analyses of subsets of these studies were undertaken to summarise macronutrient intake across AN, BN, and BED. Study quality was assessed using the American Academy of Nutrition and Dietetics Quality Criteria Checklist, with ratings either Positive (k = 27) or Neutral (k = 12). Adults with AN had low energy intake and those with BED reported elevated macronutrient intake. Individuals with BN reported wide variation in energy intake, including some of the highest estimates. Individuals with AN were likely to under-consume key micronutrients, with sodium potentially over-consumed in BN and BED. Vitamin D was under-consumed across all disorders. This meta-analysis highlights important diagnostic differences and synthesises dietary intake in EDs, with particular relevance to risk assessment and treatment.

The incidence of surgical intervention following a suspected scaphoid fracture.

Aims: The underlying natural history of suspected scaphoid fractures (SSFs) is unclear and assumed poor. There is an urgent requirement to develop the literature around SSFs to quantify the actual prevalence of intervention following SSF. Defining the risk of intervention following SSF may influence the need for widespread surveillance and screening of SSF injuries, and could influence medicolegal actions around missed scaphoid fractures. Methods: Data on SSF were retrospectively gathered from virtual fracture clinics (VFCs) across a large Scottish Health Board over a four-year period, from 1 January 2018 to 31 December 2021. The Bluespier Electronic Patient Record System identified any surgical procedure being undertaken in relation to a scaphoid injury over the same time period. Isolating patients who underwent surgical intervention for SSF was performed by cross-referencing the unique patient Community Health Index number for patients who underwent these scaphoid procedures with those seen at VFCs for SSF over this four-year period. Results: In total, 1,739 patients were identified as having had a SSF. Five patients (0.28%) underwent early open reduction and internal fixation (ORIF). One patient (0.06%) developed a nonunion and underwent ORIF with bone grafting. All six patients undergoing surgery were male (p = 0.005). The overall rate of intervention following a SSF was 0.35%. The early intervention rate in those undergoing primary MRI was one (0.36%), compared with three in those without (0.27%) (p > 0.576). Conclusion: Surgical intervention was rare following a SSF and was not required in females. A primary MRI policy did not appear to be associated with any change in primary or secondary intervention. These data are the first and largest in recent literature to quantify the prevalence of surgical intervention following a SSF, and may be used to guide surveillance and screening pathways as well as define medicolegal risk involved in missing a true fracture in SSFs.

Therapeutic alliance in two forms of guided self-help for binge eating.

The role of therapeutic alliance within psychological treatments for eating disorders (EDs), including those delivered remotely, is well established. However, few studies have investigated alliance in guided self-help, a widely recommended first-line treatment for EDs characterised by regular binge eating. Using data from a randomised controlled trial, the current study examined both facilitator and patient assessments of alliance within e-mail-assisted and face-to-face guided self-help and looked at associations between alliance, ED symptoms and ED-related impairment. One hundred thirteen patients and 11 facilitators completed measures of alliance during and following a course of guided self-help. Whilst ratings were reliable across patients and facilitators, alliance scores were higher both in the patient sample and in the face-to-face condition. Ratings of alliance showed no correlations with ED symptoms at post-treatment, and early alliance was not significantly associated with outcome, which could inform how early symptom change is encouraged in guided self-help.

Patient-directed follow-up for the clinical scaphoid fracture.

Aims: Occult (clinical) injuries represent 15% of all scaphoid fractures, posing significant challenges to the clinician. MRI has been suggested as the gold standard for diagnosis, but remains expensive, time-consuming, and is in high demand. Conventional management with immobilization and serial radiography typically results in multiple follow-up attendances to clinic, radiation exposure, and delays return to work. Suboptimal management can result in significant disability and, frequently, litigation. Methods: We present a service evaluation report following the introduction of a quality-improvement themed, streamlined, clinical scaphoid pathway. Patients are offered a removable wrist splint with verbal and written instructions to remove it two weeks following injury, for self-assessment. The persistence of pain is the patient's guide to 'opt-in' and to self-refer for a follow-up appointment with a senior emergency physician. On confirmation of ongoing signs of clinical scaphoid injury, an urgent outpatient 'fast'-wrist protocol MRI scan is ordered, with instructions to maintain wrist immobilization. Patients with positive scan results are referred for specialist orthopaedic assessment via a virtual fracture clinic. Results: From February 2018 to January 2019, there were 442 patients diagnosed as clinical scaphoid fractures. 122 patients (28%) self-referred back to the emergency department at two weeks. Following clinical review, 53 patients were discharged; MRI was booked for 69 patients (16%). Overall, six patients (< 2% of total; 10% of those scanned) had positive scans for a scaphoid fracture. There were no known missed fractures, long-term non-unions or malunions resulting from this pathway. Costs were saved by avoiding face-to-face clinical review and MRI scanning. Conclusion: A patient-focused opt-in approach is safe and effective to managing the suspected occult (clinical) scaphoid fracture.

Physical and functional convergence of the autism risk genes Scn2a and Ank2 in neocortical pyramidal cell dendrites.

Dysfunction in sodium channels and their ankyrin scaffolding partners have both been implicated in neurodevelopmental disorders, including autism spectrum disorder (ASD). In particular, the genes SCN2A, which encodes the sodium channel NaV1.2, and ANK2, which encodes ankyrin-B, have strong ASD association. Recent studies indicate that ASD-associated haploinsufficiency in Scn2a impairs dendritic excitability and synaptic function in neocortical pyramidal cells, but how NaV1.2 is anchored within dendritic regions is unknown. Here, we show that ankyrin-B is essential for scaffolding NaV1.2 to the dendritic membrane of mouse neocortical neurons and that haploinsufficiency of Ank2 phenocopies intrinsic dendritic excitability and synaptic deficits observed in Scn2a+/- conditions. These results establish a direct, convergent link between two major ASD risk genes and reinforce an emerging framework suggesting that neocortical pyramidal cell dendritic dysfunction can contribute to neurodevelopmental disorder pathophysiology.

Clinical Outcomes in Hospitalized Patients with Cancer and New versus Preexistent Atrial Fibrillation.

BACKGROUND: There is limited information on the prognostic impact of new onset versus preexistent atrial fibrillation (AF) in hospitalized patients with cancer. OBJECTIVES: We sought to determine the clinical impact of new onset AF (NOAF) compared with preexistent AF in hospitalized patients with cancer. METHODS: All patients with cancer hospitalized over the course of one year with clinically manifest new or preexistent AF were enrolled in the Memorial Sloan Kettering Cancer Center (MSKCC) AF registry. The relationship of NOAF to the primary composite outcome of all cause death, cardiovascular (CV) rehospitalization or cerebrovascular event (CVE), as well as secondary CV endpoints, were analyzed using proportional hazards regression. Where applicable, the competing risk of death was accounted for using methodology described by Fine and Gray. RESULTS: Among 606 patients included in the analysis, 313 (51.7%) had NOAF and 293 (48.3%) had preexistent AF. Patients with NOAF were younger and had less frequent prior history of CV disease compared with patients with preexistent AF. At follow up, patients with NOAF had a higher adjusted hazard for the primary composite outcome versus patients with prior AF (HR 1.64, 95% CI 1.27, 2.13, p=0.002), as well as the secondary CV composite outcome of clinical AF recurrence, CV death, CV rehospitalization or CVE (HR 2.17, 95% CI 1.57, 2.99, P<0.0001). CONCLUSIONS: In hospitalized patients with cancer and electrocardiographically manifest new versus preexistent AF, NOAF was associated with a higher risk for the primary composite outcome of all-cause death, CV rehospitalization or CVE.

Inhibitory synaptic transmission is impaired in the Kölliker-Fuse of male, but not female, Rett syndrome mice.

Rett syndrome (RTT) is a severe neurodevelopmental disorder that mainly affects females due to silencing mutations in the X-linked MECP2 gene. One of the most troubling symptoms of RTT is breathing irregularity, including apneas, breath-holds, and hyperventilation. Mice with silencing mutations in Mecp2 exhibit breathing abnormalities similar to human patients and serve as useful models for studying mechanisms underlying breathing problems in RTT. Previous work implicated the pontine, respiratory-controlling Kölliker-Fuse (KF) in the breathing problems in RTT. The goal of this study was to test the hypothesis that inhibitory synaptic transmission is deficient in KF neurons from symptomatic male and female RTT mice. We performed whole cell voltage-clamp recordings from KF neurons in acute brain slices to examine spontaneous and electrically evoked inhibitory post-synaptic currents (IPSCs) in RTT mice and age- and sex-matched wild-type mice. The frequency of spontaneous IPSCs was reduced in KF neurons from male RTT mice but surprisingly not in female RTT mice. In addition, electrically evoked IPSCs were less reliable in KF neurons from male, but not female, RTT mice, which was positively correlated with paired-pulse facilitation, indicating decreased probability of release. KF neurons from male RTT mice were also more excitable and exhibited shorter-duration action potentials. Increased excitability of KF neurons from male mice was not explained by changes in axon initial segment length. These findings indicate impaired inhibitory neurotransmission and increased excitability of KF neurons in male but not female RTT mice and suggest that sex-dependent mechanisms contribute to breathing problems in RTT.NEW & NOTEWORTHY Kölliker-Fuse (KF) neurons in acute brain slices from male Rett syndrome (RTT) mice receive reduced inhibitory synaptic inputs compared with wild-type littermates. In female RTT mice, inhibitory transmission was not different in KF neurons compared with controls. The results from this study show that sex-specific alterations in synaptic transmission occur in the KF of RTT mice.

Effects of chronic lithium treatment on neuronal excitability and GABAergic transmission in an Ank3 mutant mouse model.

Bipolar disorder (BD) is a common psychiatric disease that can lead to psychosocial disability, decreased quality of life, and high risk for suicide. Genome-wide association studies have shown that the ANK3 gene is a significant risk factor for BD, but the mechanisms involved in BD pathophysiology are not yet fully understood. Previous work has shown that ankyrin-G, the protein encoded by ANK3, stabilizes inhibitory synapses in vivo through its interaction with the GABAA receptor-associated protein (GABARAP). We generated a mouse model with a missense p.W1989R mutation in Ank3, that abolishes the interaction between ankyrin-G and GABARAP, which leads to reduced inhibitory signaling in the somatosensory cortex and increased pyramidal cell excitability. Humans with the same mutation exhibit BD symptoms, which can be attenuated with lithium therapy. In this study, we describe that chronic treatment of Ank3 p.W1989R mice with lithium normalizes neuronal excitability in cortical pyramidal neurons and increases inhibitory GABAergic postsynaptic currents. The same outcome in inhibitory transmission was observed when mice were treated with the GSK-3ß inhibitor Tideglusib. These results suggest that lithium treatment modulates the excitability of pyramidal neurons in the cerebral cortex by increasing GABAergic neurotransmission, likely via GSK-3 inhibition. In addition to the importance of these findings regarding ANK3 variants as a risk factor for BD development, this study may have significant implications for treating other psychiatric disorders associated with alterations in inhibitory signaling, such as schizophrenia, autism spectrum disorder, and major depressive disorder.

Empirical Investigation of Different Factor Structures for the Eating Disorder Examination-Questionnaire in Adult Women With Anorexia Nervosa.

The Eating Disorder Examination-Questionnaire (EDE-Q) is a widely used self-report measure of eating pathology. Despite widespread use, investigations of its factor structure have proved inconclusive and rarely supported the "original" interpretation. The current study evaluates several proposed factor solutions of the EDE-Q using latent variable analysis in a sample of adult women with anorexia nervosa (AN). A total of 804 patients from a specialist treatment center in the United States participated in the study. Confirmatory factor analysis was conducted on 22 EDE-Q items assessing attitudinal features of eating pathology. Findings suggested that three full-item versions (none of which was the "original" interpretation) fit the data adequately, with a brief, seven-item version showing excellent fit. The study is one of the first to examine this within a sample of women with AN and provides an empirical foundation for how best to use the EDE-Q among clinical and research participants with AN. Findings suggest that the "original" factor structure lacks structural validity in women with AN. Its use should generally be discouraged, and future work on screening and treatment outcomes might consider the EDE-Q7.

Interventional radiology training in the UK: a view from within-a national survey.

OBJECTIVE: Interventional radiology (IR) training in the UK has evolved since recognition as a subspecialty in 2010 and introduction of a new curriculum in 2021. The changing landscape, increasing workload and COVID-19 have affected training. The purpose of this study was to review trainees' perspectives on training and develop strategies to further improve training. METHODS: Online survey approved by the British Society of Interventional Radiology Council distributed to British Society of Interventional Radiology Trainee members between 9 March 22 and 25 March 2022. The survey was open to all UK based ST4-6 IR trainees and fellows. Descriptive and thematic analysis was undertaken. RESULTS: 43 responses were received from 17/19 UK training regions. Females represented 10% (4/41) and 5% (2/43) less than full time (LTFT) trainees. 82% (31/38) felt their curriculum was suitable for their training and 28/38 (74%) were satisfied with IR training. Vascular IR, Interventional Oncology, paediatrics and stroke thrombectomy were identified as areas of training desiring improvement. 45% (18/40) stated exposure to IR led clinics and 17.5% (7/40) to IR led ward rounds. Only 6/38 (15.7%) received structured IR teaching at least once a month. Approximately, a third of respondents (13/38) stated training opportunities were significantly compromised secondary to COVID-19. CONCLUSION: This survey shows overall good satisfaction with IR training. However, improved training opportunities in vascular IR, interventional oncology, paediatric IR and stroke thrombectomy are required. In addition, access to clinics, ward rounds and protected time for research is needed to improve training quality. ADVANCES IN KNOWLEDGE: New national UK IR training survey.

Factors associated with injury among Maine logging workers.

INTRODUCTION: Despite dramatic improvements in safety, logging remains one of the most dangerous industries in the United States. The purpose of this study was to explore longitudinal injury trends among Maine logging workers. METHODS: Loggers participated in seven quarterly surveys, over the course of 18 months. Categorical and free text data related to traumatic and acute injury, musculoskeletal disorders (MSD), and chronic pain were exported from REDCap into SAS 9.4, Excel, and NVivo, for quantitative and qualitative analysis, respectively. Time to injury was modeled using two different approaches: (1) time to the occurrence of first injury modeled by proportional hazard regression and (2) an intensity model for injury frequency. Two research team members also analyzed qualitative data using a content analysis approach. RESULTS: During the study, 204 injuries were reported. Of the 154 participants, 93 (60.4%) reported musculoskeletal pain on at least one survey. The majority of injuries were traumatic, including fractures, sprains, and strains. Lack of health insurance was found to be related to increased risk of first injury [HR = 1.41, 95% CI = 0.97-2.04, p = 0.069]. Variables found to be related to injury intensity at the univariate level were: (1) a lack of health insurance [HR = 1.51, 95% CI = 1.04-2.20, p = 0.030], (2) age [HR for 10-year age increase;= 1.12, 95% CI = 0.99-1.27, p = 0.082], and (3) years employed in logging industry [HR for 10-year increase = 1.12, 95% CI = 0.99-1.26, p = 0.052]. Seeking medical attention for injury was not a priority for this cohort, and narratives revealed a trend for self-assessment. A variety of barriers, including finances, prevented loggers from seeking medical attention. DISCUSSION: We found that loggers still experience serious, and sometimes disabling, injuries associated with their work. It was unsurprising that many injuries were due to slips, trips, and falls, along with contact with logging equipment and trees/logs. The narratives revealed various obstacles preventing loggers from achieving optimal health. Examples included geographic distance from healthcare, lack of time to access care, and entrenched values that prioritized independence and traditional masculinity. Financial considerations were also consistently cited as a primary barrier to adequate care. CONCLUSION: There is a continued need to emphasize occupational health and safety in the logging industry. Implementation of relevant safety programs is key, but it is likely that the benefits of these will not be fully realized until a cultural shift takes place within this industry.

Factor structure and measurement invariance of the Mood and Feelings Questionnaire: a cross-cultural study among Thai and British adolescents.

The Mood and Feelings Questionnaire-child self-report (MFQ-C) is a widely used measure of child and adolescent depression. This study evaluated possible factor solutions and examined the measurement invariance of the MFQ-C as a prerequisite for its use in cross-cultural comparisons between Thai (N = 1272) and British samples (N = 1817) by using multigroup confirmatory factor analysis (MGCFA). The latent means of Thai and British samples were also examined. A five-factor structure of the MFQ-C was confirmed through confirmatory factor analysis. A partial scalar invariant model was supported, and thus latent means were compared, with British adolescents reporting significantly higher mean MFQ-C scores than Thai adolescents on four of the five factors (Vegetative Symptoms, Suicidality, Cognitive Symptoms, Agitated Distress). There was no difference for the Core Symptoms factor. The findings also suggest that the MFQ-C is a valid measure to assess depression in Thai and British adolescents and maybe useful in cross-cultural comparisons of adolescent depression.

SIRVA: Shoulder injury related to vaccine administration.

Shoulder injury related to vaccine administration (SIRVA) is a prolonged episode of shoulder dysfunction that commences within 24 to 48 hours of a vaccination. Symptoms include a combination of shoulder pain, stiffness, and weakness. There has been a recent rapid increase in reported cases of SIRVA within the literature, particularly in adults, and is likely related to the mass vaccination programmes associated with COVID-19 and influenza. The pathophysiology is not certain, but placement of the vaccination in the subdeltoid bursa or other pericapsular tissue has been suggested to result in an inflammatory capsular process. It has been hypothesized that this is associated with a vaccine injection site that is "too high" and predisposes to the development of SIRVA. Nerve conduction studies are routinely normal, but further imaging can reveal deep-deltoid collections, rotator cuff tendinopathy and tears, or subacromial subdeltoid bursitis. However, all of these are common findings within a general asymptomatic population. Medicolegal claims in the UK, based on an incorrect injection site, are unlikely to meet the legal threshold to determine liability.

A Novel Approach to Study Coherent γ-Band Oscillations in Hippocampal Brain Sections.

γ-Band oscillations (GBOs) are generated by fast-spiking interneurons (FSIs) and are critical for cognitive functions. Abnormalities in GBOs are frequently observed in schizophrenia and bipolar disorder and are strongly correlated with cognitive impairment. However, the underlying mechanisms are poorly understood. Studying GBOs in ex vivo preparations is challenging because of high energy demands and the need for continuous oxygen delivery to the tissue. As a result, GBOs are typically studied in brain tissue from very young animals or in experimental setups that maximize oxygen supply but compromise spatial resolution. Thus, there is a limited understanding of how GBOs interact within and between different brain structures and in brain tissue from mature animals. To address these limitations, we have developed a novel approach for studying GBOs in ex vivo hippocampal slices from mature animals, using 60-channel, perforated microelectrode arrays (pMEAs). pMEAs enhance oxygen delivery and increase spatial resolution in electrophysiological recordings, enabling comprehensive analyses of GBO synchronization within discrete brain structures. We found that transecting the Schaffer collaterals, a neural pathway within the hippocampus, impairs GBO coherence between CA1 and CA3 subfields. Furthermore, we validated our approach by studying GBO coherence in an Ank3 mutant mouse model exhibiting inhibitory synaptic dysfunction. We discovered that GBO coherence remains intact in the CA3 subfield of these mutant mice but is impaired within and between the CA1 subfield. Overall, our approach offers significant potential to characterize GBOs in ex vivo brain sections of animal models, enhancing our understanding of network dysfunction in psychiatric disorders.

An estimator for the recombination rate from a continuously observed diffusion of haplotype frequencies.

Recombination is a fundamental evolutionary force, but it is difficult to quantify because the effect of a recombination event on patterns of variation in a sample of genetic data can be hard to discern. Estimators for the recombination rate, which are usually based on the idea of integrating over the unobserved possible evolutionary histories of a sample, can therefore be noisy. Here we consider a related question: how would an estimator behave if the evolutionary history actually was observed? This would offer an upper bound on the performance of estimators used in practice. In this paper we derive an expression for the maximum likelihood estimator for the recombination rate based on a continuously observed, multi-locus, Wright-Fisher diffusion of haplotype frequencies, complementing existing work for an estimator of selection. We show that, contrary to selection, the estimator has unusual properties because the observed information matrix can explode in finite time whereupon the recombination parameter is learned without error. We also show that the recombination estimator is robust to the presence of selection in the sense that incorporating selection into the model leaves the estimator unchanged. We study the properties of the estimator by simulation and show that its distribution can be quite sensitive to the underlying mutation rates.

Extracellular Tau Oligomers Damage the Axon Initial Segment.

BACKGROUND: In Alzheimer's disease (AD) brain, neuronal polarity and synaptic connectivity are compromised. A key structure for regulating polarity and functions of neurons is the axon initial segment (AIS), which segregates somatodendritic from axonal proteins and initiates action potentials. Toxic tau species, including extracellular oligomers (xcTauOs), spread tau pathology from neuron to neuron by a prion-like process, but few other cell biological effects of xcTauOs have been described. OBJECTIVE: Test the hypothesis that AIS structure is sensitive to xcTauOs. METHODS: Cultured wild type (WT) and tau knockout (KO) mouse cortical neurons were exposed to xcTauOs, and quantitative western blotting and immunofluorescence microscopy with anti-TRIM46 monitored effects on the AIS. The same methods were used to compare TRIM46 and two other resident AIS proteins in human hippocampal tissue obtained from AD and age-matched non-AD donors. RESULTS: Without affecting total TRIM46 levels, xcTauOs reduce the concentration of TRIM46 within the AIS and cause AIS shortening in cultured WT, but not TKO neurons. Lentiviral-driven tau expression in tau KO neurons rescues AIS length sensitivity to xcTauOs. In human AD hippocampus, the overall protein levels of multiple resident AIS proteins are unchanged compared to non-AD brain, but TRIM46 concentration within the AIS and AIS length are reduced in neurons containing neurofibrillary tangles. CONCLUSION: xcTauOs cause partial AIS damage in cultured neurons by a mechanism dependent on intracellular tau, thereby raising the possibility that the observed AIS reduction in AD neurons in vivo is caused by xcTauOs working in concert with endogenous neuronal tau.