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Objectives: Cerebral small vessel disease is a group of pathologies in which alterations of the brain's blood vessels contribute to stroke and neurocognitive changes. Recently, a neurotoxic waste clearance system composed of perivascular spaces abutting the brain's blood vessels, termed the glymphatic system, has been identified as a key player in brain homeostasis. Given that small vessel disease and the glymphatic system share anatomical structures, this review aims to reexamine small vessel disease in the context of the glymphatic system and highlight novel aspects of small vessel disease physiology., Materials and Methods: This review was conducted with an emphasis on studies that examined aspects of small vessel disease and on works characterizing the glymphatic system. We searched PubMed for relevant articles using the following keywords: glymphatics, cerebral small vessel disease, arterial pulsatility, hypertension, blood-brain barrier, endothelial dysfunction, stroke, diabetes., Results: Cerebral small vessel disease and glymphatic dysfunction are anatomically connected and significant risk factors are shared between the two. These include hypertension, type 2 diabetes, advanced age, poor sleep, obesity, and neuroinflammation. There is clear evidence that CSVD hinders the effective functioning of glymphatic system., Conclusion: These shared risk factors, as well as the model of cerebral amyloid angiopathy pathogenesis, hint at the possibility that glymphatic dysfunction could independently contribute to the pathogenesis of cerebral small vessel disease. However, the current evidence supports a model of cascading dysfunction, wherein concurrent small vessel and glymphatic injury hinder glymphatic-mediated recovery and promote the progression of subclinical to clinical disease., Competing Interests: Declaration of competing interest James R. Brorson is supported by National Institutes of Health grants R01AG06263 (Aggarwal) and R61NS135583 (Brorson), and has provided medical-legal consultation and consultation to the National Peer Review Corporation., (Copyright © 2024. Published by Elsevier Inc.)

Background: The transradial approach (TRA) for neurointerventional procedures is increasingly being used given its technical feasibility and safety. However, catheter trackability and device deliverability are reported barriers to TRA adoption., Methods: This is the first report describing the technical feasibility and performance of using the Zoom RDL Radial Access System (Imperative Care, Inc., Campbell, CA) in 29 patients who underwent neurointerventional procedures from October 2022 to January 2023 in a single-center institution., Results: Mean age of the study population was 61.9±17.2 years, 79.3% were male (23/29), and 62.1% were black (18/29). The most common procedures were stroke thrombectomy (31.0%, 9/29) and aneurysm embolization (27.6%, 8/29). All the stroke thrombectomy procedures were successfully performed; first-pass effect rate (mTICI≥2 c in one pass) was achieved in 66.7% (6/9) of cases. We used TRA in 86.2% of cases (25/29), including distal radial/snuffbox access in 31.0% (9/29) of cases. The radial diameter was >2 mm for all cases. An intermediate/aspiration catheter was used in 89.7% (26/29) of cases. Access success was achieved in 89.7% of cases (26/29); two cases required conversion from TRA to transfemoral approach (6.9%) and one case required conversion to a different guide catheter (3.4%). There were no access site complications or other Zoom RDL-related complications. One intracerebral hemorrhage, and one procedure-related thrombus were observed., Conclusions: The use of Zoom RDL Radial Access System is technically feasible and effective for complex neurointerventional procedures with low complication rates., Competing Interests: Competing interests: TK – Brainomix: Consultant, Cerenovus: Consultant, Imperative Care: Consultant, Medtronic Inc.: Consultant, Microvention: Consultant, Stryker Neurovascular: Consultant. The remaining authors declared no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: To this date, whether to administer intravenous thrombolysis (IVT) prior to endovascular thrombectomy (EVT) for stroke patients still stirs some debate. We aimed to systematically update the evidence from randomized trials comparing EVT alone vs EVT with bridging IVT., Methods: We searched MEDLINE, EMBASE, and the Cochrane Library to identify randomized controlled trials (RCTs) comparing EVT with or without IVT in patients presenting with stroke secondary to a large vessel occlusion. We conducted meta-analyses using random-effects models to compare functional independence, mortality, and symptomatic intracranial hemorrhage (sICH), between EVT and EVT with IVT. We assessed risk of bias using the Cochrane risk-of-bias tool and certainty of evidence for each outcome using the GRADE approach., Results: Of 11,111 citations, we included 6 studies with a total of 2336 participants. We found low-certainty evidence of possibly a small decrease in the proportion of patients with functional independence (risk difference [RD] -2.0%, 95% CI -5.9% to 2.0%), low-certainty evidence that there is possibly a small increase in mortality (RD 1.0%, 95% CI -2.2% to 4.7%), and moderate-certainty evidence that there is probably a decrease in sICH (RD -1.0%, 95% CI -1.6% to .7%) for patients with EVT alone compared to EVT plus IVT, respectively., Conclusion: Low-certainty evidence shows that there is possibly a small decrease in functional independence, low-certainty evidence shows that there is possibly a small increase in mortality, and moderate-certainty evidence that there is probably a decrease in sICH for patients with EVT alone compared to EVT plus IVT., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Background: The optimal antiplatelet therapy regimen for certain neuroendovascular procedures remains unclear. This study investigates the safety and feasibility of intravenous dose-adjusted cangrelor in patients undergoing acute neuroendovascular interventions., Methods: We conducted a retrospective chart review of all consecutive patients on intravenous cangrelor for neuroendovascular procedures between September 1, 2020, and March 13, 2022. We also conducted an updated systematic review and meta-analysis using PubMed, Scopus, Web of Science, Embase and the Cochrane Library up to February 22, 2023., Results: In our cohort, a total of 76 patients were included [mean age (years): 57.2 ± 18.2, males: 39 (51.3), Black: 49 (64.5)]. Cangrelor was most used for embolization and intracranial stent placement ( n  = 24, 32%). Approximately 44% of our patients had a favorable outcome with a modified Rankin Scale (mRS) score of 0 to 2 at 90 days ( n  = 25/57); within 1 year, 8% of patients had recurrent or new strokes ( n  = 5/59), 6% had symptomatic intracranial hemorrhage [sICH] (4/64), 3% had major extracranial bleeding events (2/64), and 3% had a gastrointestinal bleed (2/64). In our meta-analysis, 11 studies with 298 patients were included. The pooled proportion of sICH and intraprocedural thromboembolic complication events were 0.07 [95% CI 0.04 to 1.13] and 0.08 [95% CI 0.05 to 0.15], respectively., Conclusion: Our study found that intravenous cangrelor appears to be safe and effective in neuroendovascular procedures, with low rates of bleeding and ischemic events. However, further research is needed to compare different dosing and titration protocols of cangrelor and other intravenous agents., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Desai, Al-Salihi, Morsi, Vayani, Kothari, Thind, Carrión-Penagos, Baskaran, Tarabichi, Bonderski, Siegler, Hahn, Coleman, Brorson, Mendelson, Mansour, Dabus, Hurley, Prabhakaran, Linfante and Kass-Hout.)

Background and Objectives: Trials of acute secondary prevention after minor stroke or transient ischemic attack (TIA), such as SOCRATES, POINT, and THALES, demonstrate a high initial rate of recurrence after ischemic events that drop quickly to a lower rate, suggesting a transient vulnerable clinical state, which may call for different treatments than the subsequent stabilized state. A kinetic model incorporating vulnerable and stabilized states provides estimates of the distinct kinetic rates reflecting the temporal features of underlying stroke mechanisms. We aimed to compare these kinetic rates between treatments and across trials, asking whether these features point to common pathophysiologic processes underlying stroke recurrence, and inform the targeting and timing of enhanced antiplatelet therapy in recurrent stroke prevention., Methods: Kaplan-Meier recurrence-free survival curves in the SOCRATES, POINT, and THALES trials were estimated for each treatment group and fitted by nonlinear regression to the 2-state kinetic model, producing estimates of kinetic parameters, with standard errors estimated using the nonparametric bootstrap with repetitive resampling., Results: For each trial, the 2-state kinetic model fit the survival curves better than did the null (single-state) kinetic model or the Weibull model ( p < 0.05). Recurrence rates in the vulnerable state ( k 1 ) were 100-fold higher than in the stabilized state ( k 2 ). Transition rates from the vulnerable to stabilized state ( k 0 ) were still more rapid. Kinetic parameters were consistent across the trials, without significant differences between the trials. Enhanced antiplatelet regimens produced significant reductions in k 1 (aspirin alone: 0.030 ± 0.004 d -1 ; active treatment: 0.016 ± 0.003 d -1 ; p < 0.01) but did not affect k 0 or k 2 , suggesting that active treatment only affected risk in the vulnerable state. Modeling based on these kinetic parameters suggests that most of the benefit of active treatment occurred within 3 days., Discussion: Across multiple trials of acute secondary prevention after minor stroke or TIA, recurrence of stroke is well-described by a 2-state kinetic model postulating vulnerable and stabilized states, with similar kinetic parameters across trials. Enhanced antiplatelet regimens only affected the recurrence rates in the vulnerable state, over a brief period. This analysis suggests that 2 distinct states follow acute cerebral ischemic events, subject to differential impact of immediate or delayed therapies., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Thrombectomy for basilar artery occlusion (BAO) has proven efficacy in patients with moderate-to-severe deficits, but has unclear benefits for those with mild symptoms., Methods: Using an observational cohort design, the US National Inpatient Sample (2018-2020) was queried for adult patients with basilar artery occlusion and National Institutes of Health Stroke Scale (NIHSS) <10 for patients treated with thrombectomy versus medical management. The primary outcome of routine discharge (to home or self-care) was evaluated using multivariable logistic regression and propensity score matching, adjusted for baseline characteristics, stroke severity, and treatment with thrombolysis., Results: Of 17 019 with basilar artery occlusion, 5795 patients met the criteria for inclusion criteria for our study, and 880 (15.4%) were treated with endovascular thrombectomy. In the propensity score-matched cohort, 880 patients were treated with medical management and endovascular thrombectomy, respectively. In multivariable regression, endovascular thrombectomy was associated with both an increased odds of routine discharge (odds ratio, 1.95 [95% CI, 1.31-2.90]; P =0.001) and a decreased length of hospital stay (B, -0.74 [95% CI, -1.36 to -0.11]; P =0.02) compared with medical management. In the propensity score matched cohort, endovascular thrombectomy remained associated with greater odds of routine discharge (2.01 [95% CI, 1.21-3.34]; P =0.007) but no difference in length of hospital stay (B, -0.22 [95% CI, -0.90 to 0.46]; P =0.53)., Conclusions: Routine discharge was more common in this representative US cohort of patients with basilar artery occlusion and National Institutes of Health Stroke Scale <10 who underwent thrombectomy compared to conventional medical management. These findings suggest thrombectomy may be associated with better functional outcomes despite lower National Institutes of Health Stroke Scale and should be validated in a clinical trial setting., Competing Interests: Disclosures Dr Nguyen reports research support from SVIN and Medtronic; advisory board with Idorsia. S. Yaghi reports research support from Medtronic. Dr Prabhakaran reports research support from National Institute of Neurological Disorders and Stroke, Agency for Healthcare Research and Quality; royalties from UpToDate; consultant fees from Wolters Kluwer Health Inc. The other authors report no conflicts.

Introduction: Current published guidelines and meta-analyses comparing endovascular thrombectomy (EVT) alone versus EVT with bridging intravenous thrombolysis (IVT) suggest that EVT alone is non-inferior to EVT with bridging thrombolysis in achieving favourable functional outcome. Because of this controversy, we aimed to systematically update the evidence and meta-analyse data from randomised trials comparing EVT alone versus EVT with bridging thrombolysis, and performed an economic evaluation comparing both strategies., Methods and Analysis: We will conduct a systematic review of randomised controlled trials comparing EVT with or without bridging thrombolysis in patients presenting with large vessel occlusions. We will identify eligible studies by systematically searching the following databases from inception without any language restrictions: MEDLINE (through Ovid), Embase and the Cochrane Library. The following criteria will be used to assess eligibility for inclusion: (1) adult patients ≥18 years old; (2) randomised patients to EVT alone or to EVT with IVT; and (3) measured outcomes, including functional outcomes, at least 90 days after randomisation. Pairs of reviewers will independently screen the identified articles, extract information and assess the risk of bias of eligible studies. We will use the Cochrane Risk-of-Bias tool to evaluate risk of bias. We will also use the Grading of Recommendations, Assessment, Development and Evaluation approach to assess the certainty in evidence for each outcome. We will then perform an economic evaluation based on the extracted data., Ethics and Dissemination: This systematic review will not require a research ethics approval because no confidential patient data will be used. We will disseminate our findings by publishing the results in a peer-reviewed journal and via presentation at conferences., Prospero Registration Number: CRD42022315608., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Recent trials of acute secondary prevention in patients with minor ischemic stroke or transient ischemic attack (TIA) have demonstrated high rates of early recurrence within days of the initial event. Identifying clinical features associated with early recurrence may guide focused management., Methods: Using logistic regression applied to the data of the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, we evaluated what baseline clinical factors predict outcome events occurring within 7 days of randomization., Results: In the POINT trial, 181 subjects (3.7%) had early recurrence, defined as primary outcome events within 7 days of trial entry, whereas only 100 outcome events occurred over the remainder of the 90 day trial. Protective effects of dual antiplatelet therapy with clopidogrel plus aspirin were seen only as a reduction in these early recurrences, without any impact on later events. In univariate analysis, systolic blood pressure, diastolic blood pressure, serum glucose, initial carotid imaging results, study cohort (minor stroke or TIA), and treatment assignment were significantly associated with early recurrence. Multivariate logistic regression analysis identified a number of factors with significant independent associations with early recurrence, including carotid stenosis or occlusion (Odds Ratio [OR] 2.77; 95% confidence interval [CI] 1.78-4.31), cohort (minor stroke versus TIA) (OR 1.86; 95% CI 1.33-2.58), race (OR 1.57; 95% CI 1.10-2.25), baseline statin use (OR 0.68; 95% CI 0.49-0.95), systolic blood pressure (OR 1.10; 95% CI 1.03-1.18), serum glucose (OR 1.03; 95% CI 1.01-1.05), and age (OR 1.02; 95% CI 1.00-1.03). Receiver Operator Characteristic (ROC) analysis showed a 70% accuracy of the resulting logistic model in predicting early recurrence., Conclusions: Early recurrence is high, and is concentrated in the first 7 days, in patients with minor stroke or TIA. A number of baseline clinical factors, including carotid disease, presentation with minor stroke rather than TIA, race, absence of statin usage, systolic blood pressure, and serum glucose, are independently associated with early event recurrence in the POINT trial population., (© 2022. The Author(s).)

Recent studies of interventions initiated acutely following onset of minor ischemic stroke or transient ischemic attack (TIA) have disclosed early stroke recurrence rates that are substantially higher than long-term recurrence rates and that can be reduced by acute antiplatelet treatment interventions. These observations, bolstered by analysis based on kinetic modeling of the time course of recurrence following initial events, suggest that acute stroke patients experience an underlying vulnerable state that quickly transitions to a more stable state. Some evidence also supports the benefits of early treatment with direct-acting oral anticoagulants in cardioembolic stroke and of continuation or early initiation of statin therapy in atherosclerotic stroke. Treatment of ischemic stroke should address the transient vulnerable state that follows the initial event, employing measures aiming to avert early recurrence of thromboembolism and to promote stabilization of vulnerable arterial plaque. These measures constitute acute secondary prevention following ischemic stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bulwa, Mendelson and Brorson.)

Background and Purpose: Following an acute ischemic stroke or transient ischemic attack, 2 rates of stroke recurrence are suggested by data from trials of acute secondary prevention treatments: a transient rapid rate followed by a persisting slower rate of stroke., Methods: A kinetic model was constructed based on underlying vulnerable and stabilized states of patients following acute ischemic events related by fixed transition rates. Its predictions were fitted by nonlinear regression to the observed timing of outcome events in patients in the POINT trial (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke)., Results: The modeled survivor function produced a close fit to the observed data. The model's predicted kinetic rates suggest that, among subjects in the control group, the event rate was 100-fold higher in the vulnerable state than in the stabilized state. Active treatment halved this rapid rate and had little effect on event rates in the stabilized state. If at least one-tenth of the study population began in the vulnerable state, the rate of transition from the vulnerable to the stabilized state was still faster, with a half-life of only 1 to 2 days., Conclusions: Examination of kinetics of stroke occurrence, and of the rates associated with modeled state transitions, may provide insights into the underlying pathophysiological events that are targets for acute secondary prevention of stroke.

Technologies for repairing cardiac structures or sustaining cardiac function with implantable devices have helped patients with an ever-expanding array of cardiac conditions. Patients are surviving and thriving with cardiac conditions that would formerly have been disabling or fatal. With the implantation of devices in the heart, however, comes the inevitable risk of neurological complications. This chapter focuses on devices implanted in the chambers or valves of the heart itself, including prosthetic heart valves, closure devices for patent foramen ovale, atrial appendage occluder devices, short-term implantable circulatory assist devices, and long-term ventricular assist devices, but excluding coronary artery stents or extracardiac devices. Further, it considers the procedural and postprocedural risks of the devices, leaving the discussion of clinical effectiveness of the devices to other chapters of this book., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Aim: Ipsilateral nonstenotic carotid disease is increasingly recognized as an etiology of ischemic stroke, however tailored treatment strategies are lacking. We aimed to examine clinical characteristics and treatment effects in patients with minor ischemic stroke associated with ipsilateral nonstenotic carotid disease in the Platelet Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial., Methods: We performed an exploratory analysis of the interaction of the treatment effects of aspirin plus clopidogrel versus aspirin monotherapy, stratified by presence of ipsilateral nonstenotic carotid disease in patients with minor ischemic stroke in the POINT trial., Results: For this exploratory analysis, 167 patients presenting with ischemic stroke and ipsilateral nonstenotic carotid disease, defined as 1%-49% carotid stenosis ipsilateral to the corresponding territory of ischemic stroke, and 833 patients no carotid disease were included. Compared to patients with no carotid disease, patients with ipsilateral nonstenotic carotid disease were older (68.5 ± 11.3 years versus 61.3 ± 12.8 years; P < 0.001), and had a higher prevalence of hypertension (76.6% versus 59.2%, P < 0.001), ischemic heart disease (13.8% versus 5.4%, P < 0.001), and tobacco use (past: 34.1% versus 25.2%, P = 0.005; present: 27.5% versus 22.8%, P = 0.005). 5.4% of patients with ipsilateral nonstenotic carotid disease had recurrent ischemic stroke within 14 days. Patients receiving dual antiplatelet therapy had a numerical reduction in recurrent ischemic stroke compared to patients receiving aspirin monotherapy, however the exploratory analysis was underpowered to detect a statistically significant difference in treatment effect (HR 0.50, 95% CI 0.18-1.40, P = 0.19)., Conclusion: Patients with minor ischemic stroke and ipsilateral nonstenotic carotid disease had a high risk of early stroke recurrence in the POINT trial. Dual antiplatelet therapy provided a non-statistically significant reduction in recurrent ischemic stroke with no difference in safety outcomes compared to aspirin monotherapy. Further study is needed to determine if early and short duration dual antiplatelet therapy is beneficial for all patients with ipsilateral nonstenotic carotid disease., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020. Published by Elsevier Inc.)

Background and Aim: Patients with in-hospital acute ischemic stroke (AIS) have, in general, worse outcomes compared to those presenting from the community, partly attributed to the numerous contraindications to intravenous thrombolysis. We aimed to identify and analyze a group of patients with in-hospital AIS who remain suitable candidates for acute endovascular therapies., Methods: A retrospective 6-year data analysis was conducted in patients evaluated through the in-hospital stroke alert protocol in a single tertiary care university hospital to identify those with in-hospital AIS due to acute intracranial large vessel occlusion (ILVO). Feasibility and safety of mechanical thrombectomy for in-hospital AIS was assessed in a case-control study comparing inpatients to those presenting from the community., Results: From 1460 in-hospital stroke alert activations, 11% had a final diagnosis of AIS (n = 167). One hundred and two patients with in-hospital AIS had emergent intracranial vessel imaging and were included in our cohort. Acute ILVO was identified in 27 patients within this cohort. Patients were younger in the ILVO group and had more severe neurologic deficit on presentation. Compared to a matched (1:2) control group of patients presenting from the community, inpatients who underwent mechanical thrombectomy achieved equivalent technical success, safety, and clinical outcomes., Conclusions: The incidence of acute ILVO in patients with in-hospital AIS who underwent emergent vessel imaging is similar to the reported incidence of ILVO in patients presenting with community-onset AIS. Among patients with in-hospital AIS secondary to ILVO, mechanical thrombectomy is a feasible and safe therapy associated with favorable outcomes., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: We aimed to evaluate the yield of extensive etiologic workup in lacunar stroke patients., Background: As lacunar strokes are infrequently caused by thromboembolism, the clinical relevance of extensive workup for thromboembolic sources is questioned., Methods: Among consecutive stroke admissions to a single center over 3 years, the 100 cases initially classified as lacunar stroke and a sample of 100 cases classified as non-lacunar ischemic strokes were studied. Review of brain imaging resulted in reclassification of 24 cases, and exclusion of 3 cases, producing a final cohort of 86 confirmed lacunar strokes and 111 confirmed non-lacunar strokes. In each of these cases, results of echocardiographic and vascular imaging studies were evaluated., Results: Echocardiography was performed in 93% of both the lacunar stroke cases and non-lacunar stroke cases. High-risk cardiac embolic sources were found less often in lacunar than in non-lacunar stroke cases (19% versus 34%). Findings potentially requiring anticoagulant therapy were found exclusively in the non-lacunar stroke patients. Vascular imaging studies (computed tomography angiography or magnetic resonance angiography) were also performed in similar proportions of lacunar and non-lacunar stroke cases (85% versus 84%). Cerebrovascular occlusions or high-grade stenoses were frequent (62%) in non-lacunar stroke patients but less frequent (25%) in lacunar stroke patients. In the non-lacunar stroke patients, identified vascular lesions were very frequently in a vessel anatomically related to the infarction, but in lacunar stroke patients, this occurred in only 6 cases., Conclusions: Echocardiography and vascular imaging studies rarely disclose findings of etiologic relevance, or of likelihood to change management, in patients with lacunar strokes., (Copyright © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Much of the care provided by practicing neurologists takes place in outpatient clinics. However, neurology trainees often have limited exposure to this setting. Adequate incorporation of outpatient care in neurology training is vital; however it is often hampered by numerous challenges. We detail a number of these challenges and suggest potential means for improvement., (Copyright © 2016 Elsevier B.V. All rights reserved.)

This study examined how volume in certain patient case types and breadth across patient case types in the outpatient clinic setting are related to Neurology Clerkship student performance. Case logs from the outpatient clinic experience of 486 students from The University of Chicago Pritzker School of Medicine, USA, participating in the 4week Neurology Clerkship from July 2008 to June 2013 were reviewed. A total of 12,381 patient encounters were logged and then classified into 13 diagnostic categories. How volume of cases within categories and the breadth of cases across categories relate to the National Board of Medical Examiners Clinical Subject Examination for Neurology and a Neurology Clerkship Objective Structured Clinical Examination was analyzed. Volume of cases was significantly correlated with the National Board of Medical Examiners Clinical Subject Examination for Neurology (r=.290, p<.001), the Objective Structured Clinical Examination physical examination (r=.236, p=.011), and the Objective Structured Clinical Examination patient note (r=.238, p=.010). Breadth of cases was significantly correlated with the National Board of Medical Examiners Clinical Subject Examination for Neurology (r=.231, p=.017), however was not significantly correlated with any component of the Objective Structured Clinical Examination. Volume of cases correlated with higher performance on measures of specialty knowledge and clinical skill. Fewer relationships emerged correlating breadth of cases and performance on the same measures. This study provides guidance to educators who must decide how much emphasis to place on volume versus breadth of cases in outpatient clinic learning experiences., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objectives: This study examines factors affecting reliability, or consistency of assessment scores, from an objective structured clinical examination (OSCE) in neurology through generalizability theory (G theory)., Methods: Data include assessments from a multistation OSCE taken by 194 medical students at the completion of a neurology clerkship. Facets evaluated in this study include cases, domains, and items. Domains refer to areas of skill (or constructs) that the OSCE measures. G theory is used to estimate variance components associated with each facet, derive reliability, and project the number of cases required to obtain a reliable (consistent, precise) score., Results: Reliability using G theory is moderate (Φ coefficient = 0.61, G coefficient = 0.64). Performance is similar across cases but differs by the particular domain, such that the majority of variance is attributed to the domain. Projections in reliability estimates reveal that students need to participate in 3 OSCE cases in order to increase reliability beyond the 0.70 threshold., Conclusions: This novel use of G theory in evaluating an OSCE in neurology provides meaningful measurement characteristics of the assessment. Differing from prior work in other medical specialties, the cases students were randomly assigned did not influence their OSCE score; rather, scores varied in expected fashion by domain assessed., (© 2015 American Academy of Neurology.)

Objective: Due to the burden of neurologic disease, there is high demand for neurologists, child neurologists, and neurosurgeons. Only 2.6% of graduating medical students matched in neuromedicine residencies in 2014. This number will not likely meet the needs of the population or the projected shortfall. To compensate for this, the medical education system has an obligation to ensure competence in neuromedicine for all trainees and mentorship for students pursuing training in the field. We aim to evaluate the state of the neurology clerkship in US medical schools and how this impacts graduates entering the field., Methods: Publicly available curricula of 158 US medical schools were reviewed. Presence of a required neurology clerkship, its duration, and the year offered were tabulated, as were the availability of child neurology and neurosurgery electives and affiliated neuromedicine residencies. The total graduating students from each medical school matching into neuromedicine residencies for 2011-2014 were recorded. Repeated-measure analysis of variance was used to assess the relationship of these variables to number of students matching into the collective neuromedicine., Results: All but 4 schools (97%) published clerkship information. Neurology was a required clerkship at 56% of reporting institutions. Residency match data were not published from 53 schools (35%) and these were excluded from the analysis. In the remaining schools, all variables showed a relationship to students matching in neuromedicine residencies., Conclusions: The presence of a required neurology clerkship and opportunities for students to explore neuromedicine during medical school correlates with students matching into neuromedicine residencies., (© 2015 American Academy of Neurology.)

Background: Neurophobia is a well-described phenomenon among medical students in many countries. Little is reported concerning the perceptions of neurosciences among medical students in China., Methods: We surveyed senior medical students in Wuhan, China, on their perceptions of neuroscience., Results: Students' self-assessments of knowledge in various specialties ranked neurology low, but not the lowest. Students' confidence in diagnosing neurological patients and managing neurological patients demonstrated significant correlation. A positive correlation was noted between confidence in these clinical parameters and the likelihood of specializing in neurology. Students reported bedside teaching and small group sessions as having the greatest value in learning neurology., Conclusions: The low, but not the lowest ranking of self-perceived knowledge in neurology by medical students in Wuhan, China, differs from findings reported in other countries. In this exploratory study the investigators hypothesize that the well-described phenomenon of neurophobia may exhibit a less pronounced influence in Wuhan, China., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In neurology education there is evidence that trainees may have greater ability in general localization and diagnosis than they do in treatment decisions, particularly with considering longer term care and supportive care. We hypothesized that medical students completing a neurology clerkship would exhibit greater skill at considering the acute diagnostic and therapeutic management than at considering supportive management measures. Data from 720 standardized patient encounters by 360 medical students completing a neurology clerkship being evaluated via an objective structured clinical examination were analyzed for skill in three components of clinical decision making: diagnostic evaluation, therapeutic intervention, and supportive intervention. Scores for all standardized patient encounters over the 2008-2012 interval revealed a significantly higher percentage of correct responses in both the diagnostic (mean [M]=62.6%, standard deviation [SD]=20.3%) and therapeutic (M=63.0%, SD=28.8%) categories in comparison to the supportive (M=31.8%, SD=45.2%) category. However, only scores in therapeutic and supportive treatment plans were found to be significant predictors of the USA National Board of Medical Examiners (NBME) clinical neurology subject examination scores; on average, a percent increase in therapeutic and support scores led to 5 and 2 point increases in NBME scores, respectively. We demonstrate empirical evidence of deficits in a specific component of clinical reasoning in medical students at the completion of a neurology clerkship., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

A 16-year-old African-American male with no past medical history presented with gait instability and somnolence. He had intermittent neurological complaints during the prior 4 months, including dizziness, left arm paresthesias, decreased hearing, and inability to control his hands. After an initial diagnosis of vertigo, his symptoms progressed, leading to reevaluation and a second emergency department head computed tomography (CT) scan, which revealed a large area of hypodensity in the cerebellum. Repeat head CT on arrival to the intensive care unit showed a large, left cerebellar hemispheric stroke. This case study discusses the findings of the patient's cerebral angiogram, the diagnosis of fibromuscular dysplasia, and the aggressive treatment that likely prevented further devastating strokes in the brainstem, thalamus, and occipital lobe. This case serves as a reminder that strokes are not just an adult disease and that classic presentations can occur even in unconventional patients., (Copyright 2014, SLACK Incorporated.)

Objective: Using outpatient neurology clinic case logs completed by medical students on neurology clerkships, we examined the impact of outpatient clinical encounter volume per student on outcomes of knowledge assessed by the National Board of Medical Examiners (NBME) Clinical Neurology Subject Examination and clinical skills assessed by the Objective Structured Clinical Examination (OSCE)., Methods: Data from 394 medical students from July 2008 to June 2012, representing 9,791 patient encounters, were analyzed retrospectively. Pearson correlations were calculated examining the relationship between numbers of cases logged per student and performance on the NBME examination. Similarly, correlations between cases logged and performance on the OSCE, as well as on components of the OSCE (history, physical examination, clinical formulation), were evaluated., Results: There was a correlation between the total number of cases logged per student and NBME examination scores (r = 0.142; p = 0.005) and OSCE scores (r = 0.136; p = 0.007). Total number of cases correlated with the clinical formulation component of the OSCE (r = 0.172; p = 0.001) but not the performance on history or physical examination components., Conclusion: The volume of cases logged by individual students in the outpatient clinic correlates with performance on measures of knowledge and clinical skill. In measurement of clinical skill, seeing a greater volume of patients in the outpatient clinic is related to improved clinical formulation on the OSCE. These findings may affect methods employed in assessment of medical students, residents, and fellows.

Parkinson's disease (PD) has multiple proposed etiologies with implication of abnormalities in cellular homeostasis ranging from proteostasis to mitochondrial dynamics to energy metabolism. PINK1 mutations are associated with familial PD and here we discover a novel PINK1 mechanism in cellular stress response. Using hypoxia as a physiological trigger of oxidative stress and disruption in energy metabolism, we demonstrate that PINK1(-/-) mouse cells exhibited significantly reduced induction of HIF-1α protein, HIF-1α transcriptional activity, and hypoxia-responsive gene upregulation. Loss of PINK1 impairs both hypoxia-induced 4E-BP1 dephosphorylation and increase in the ratio of internal ribosomal entry site (IRES)-dependent to cap-dependent translation. These data suggest that PINK1 mediates adaptive responses by activating IRES-dependent translation, and the impairments in translation and the HIF-1α pathway may contribute to PINK1-associated PD pathogenesis that manifests under cellular stress.

The cellular distribution of TAR DNA binding protein (TDP-43) is disrupted in several neurodegenerative disorders, including frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U subtype) and amyotrophic lateral sclerosis (ALS). In these conditions, TDP-43 is found in neuronal cytoplasmic inclusions, with loss of the normal nuclear expression. The mechanisms leading to TDP-43 redistribution and its role in disease pathophysiology remain unknown. We describe an in vitro neural tissue model that reproduces TDP-43 relocalization and inclusion formation. Two week-old coronal organotypic mouse brain slice cultures were treated with tunicamycin for 7 days. In cortical regions of treated slice cultures, cytoplasmic inclusions of TDP-43 immunoreactivity were observed, with loss of nuclear TDP-43 immunoreactivity. These inclusions were found in both astrocytes and neurons, and were of both skein-like and round morphologies. In contrast, TDP-43 cytoplasmic inclusions were not found in slices treated with staurosporine to induce apoptosis, or with trans-4-carboxy-l-proline (PDC) to induce chronic glutamate excitotoxicity. Furthermore, TDP-43 cytoplasmic inclusions did not co-localize with cleaved caspase-3, suggesting that TDP-43 mislocalization does not generally accompany caspase activation or apoptosis. The induction of TDP-43 cytoplasmic translocation in cerebrocortical slice cultures by tunicamycin provides a platform for further mechanistic investigations of pathological processing of TDP-43., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objectives: Acute liver failure (ALF) produces cerebral dysfunction and edema, mediated in part by elevated ammonia concentrations, often leading to coma and death. The pathophysiology of cerebral edema in ALF is incompletely understood. In vitro models of the cerebral effects of ALF have predominately consisted of dissociated astrocyte cultures or acute brain slices. We describe a stable long-term culture model incorporating both neural and glial elements in a three-dimensional tissue structure offering significant advantages to the study of astrocytic-neuronal interactions in the pathophysiology of cerebral edema and dysfunction in ALF., Methods: We utilized chronic organotypic slice cultures from mouse forebrain, applying ammonium acetate in iso-osmolar fashion for 72 hours. Imaging of slice thickness to assess for tissue swelling was accomplished in living slices with optical coherence tomography, and confocal microscopy of fluorescence immunochemical and histochemical staining served to assess astrocyte and neuronal numbers, morphology, and volume in the fixed brain slices., Results: Ammonia exposure at 1-10 mM produced swelling of immunochemically identified astrocytes, and at 10 mM resulted in macroscopic tissue swelling, with slice thickness increasing by about 30%. Astrocytes were unchanged in number. In contrast, 10 mM ammonia treatment severely disrupted neuronal morphology and reduced neuronal survival at 72 hours by one-half., Discussion: Elevated ammonia produces astrocytic swelling, tissue swelling, and neuronal toxicity in cerebral tissues. Ammonia-treated organotypic brain slice cultures provide an In vitro model of cerebral effects of conditions relevant to ALF, applicable to pathophysiological investigations.

Continuous exposure of cultured cortical neurons to moderate hypoxia (1% O(2)) elevates cellular accumulation of hypoxia-inducible factor-1α (HIF-1α) and improves basal survival of cultured cortical neurons. We examined the effects of adaptation to moderate hypoxia on the vulnerability of cultured neurons to the acute injury of simulated ischemia-reperfusion. Cortical neurons cultured continuously in 1% O(2) were markedly protected against simulated ischemia-reperfusion, with protection persisting through 72h after ischemia. Neurons from 1% O(2) conditions were also highly resistant to glutamate-induced NMDA receptor-dependent excitotoxic injury, despite expression of NMDA receptors at levels not significantly changed from controls. Inhibition of prolyl hydroxylase, mimicking cellular signaling effects of hypoxia including HIF-1α stabilization, also protected neurons against simulated ischemia-reperfusion injury. Nevertheless, genetic deletion of HIF-1α expression did not diminish the protection of neurons adapted to 1% O(2) from excitotoxicity or ischemia-reperfusion injury, nor did it prevent the protective effect of prolyl hydroxylase inhibition. We conclude that chronic exposure to moderate hypoxia, through HIF-1α-independent mechanisms, produces strong protective effects against excitotoxic and ischemia-reperfusion related injury., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Septic encephalopathy is a frequent complication of the sepsis syndrome, with no therapies available that can prevent the associated neurological dysfunction in humans. It is caused by a number of processes and networks going awry, the exact cellular and molecular mechanisms of which remain an enigma. Several mediators of inflammation have been assigned a key role in sepsis, including cytokines, chemokines and complement cascade. With the observations that brain dysfunction in a sepsis setting can be alleviated by regulation of the cytokines and complement proteins in various species of animals, optimism is building for a possible therapy of sepsis-damaged brain. This article reviewed the advances in the understanding of the underlying mechanisms causing pathology in SE, with an emphasis on the inflammatory and excitatory mediators such as the cytokines, complement proteins and neurotransmitters, investigating their potential as possible therapeutic targets., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

To investigate the role of C5a generated on complement activation in brain, the lupus model, MRL/lpr mice were treated with C5a receptor(R) antagonist (ant). Neutrophil infiltration, ICAM, TNF-alpha and iNOS mRNA expression, neuronal apoptosis and the expression of p-JNK, pSTAT1 and p-Erk were reduced and p-Akt increased on C5aR inhibition in MRL/lpr brains. MRL/lpr serum caused increased apoptosis in neurons showing that lupus had a direct effect on these cells. C5aRant pretreatment prevented the lupus serum induced loss of neuronal cells. Our findings demonstrate for the first time that C5a/C5aR signaling plays an important role in the pathogenesis of CNS lupus., (Copyright 2010. Published by Elsevier B.V.)

It is believed that gene/environment interaction (GEI) plays a pivotal role in the development of motor skills, which are acquired via practicing or motor training. However, the underlying molecular/neuronal mechanisms are still unclear. Here, we reported that the expression of NR2B, a subunit of NMDA receptors, in cerebellar granule cells specifically enhanced the effect of voluntary motor training on motor learning in the mouse. Moreover, this effect was characterized as motor learning-specific and developmental stage-dependent, because neither emotional/spatial memory was affected nor was the enhanced motor learning observed when the motor training was conducted starting at the age of 3 months old in these transgenic mice. These results indicate that changes in the expression of gene(s) that are involved in regulating synaptic plasticity in cerebellar granule cells may constitute a molecular basis for the cerebellum to be involved in the GEI by facilitating motor skill learning.

Observations in real time can provide insights into the timing of injury and the mechanisms of damage in neural ischemia-reperfusion. Continuous digital imaging of morphology and cell viability was applied in a novel model of simulated ischemia-reperfusion in cultured cortical neurons, consisting of exposure to severe hypoxia combined with glucose deprivation, mild acidosis, hypercapnia, and elevated potassium, followed by return of oxygenated, glucose-containing physiological saline. Substantial acute injury resulted following 1 h of simulated ischemia, with 36+/-8% neurons dying within 2 h of reperfusion. Inclusion of moderate glutamate elevation (30 microM) in the simulation of ischemia increased the acute neuronal death to 51+/-6% at 2 h of reperfusion. While some swelling and neuritic breakdown occurred during ischemia, particularly with inclusion of glutamate, neuronal death, as marked by loss of somatic membrane integrity, was entirely restricted to the reperfusion phase. Morphological and cytoskeletal changes suggested a predominance of necrotic death in the acute phase of reperfusion, with more complete delayed death accompanied by some apoptotic features occurring over subsequent days. Prolonged simulated ischemia, without reperfusion, did not induce significant acute neuronal death even when extended to 3 h. We conclude that while morphological changes suggesting initiation of neuronal injury appear during severe simulated ischemia, the irreversible injury signaled by membrane breakdown is accelerated by the events of reperfusion itself.

In addition to the loss of spinal motor neurons, amyotrophic lateral sclerosis (ALS) is also associated with degeneration of corticospinal layer V pyramidal neurons and decreased glutamate transport in the cortex. We characterized the glutamate receptors on corticospinal neurons in acutely isolated rat motor cortex slices and found that the synaptic inputs to the corticospinal layer V neurons had a lesser proportional contribution from NMDA receptors relative to AMPA receptors than did layer II/III pyramidal neurons. The synaptic I(AMPA) was also more inwardly rectified, indicating a greater Ca(2+)-permeable component, in layer V. In a cortical organotypic slice culture model, blockade of glutamate transporters elevated glutamate in the media and led to pyramidal neuron loss in both layers. The loss of layer V pyramidal neurons was attenuated by antagonists of AMPA/kainate or Ca(2+)-permeable AMPA receptors, suggesting their therapeutic potential in the protection of the motor cortex in ALS.

Physiological oxygen (O2) tensions in brain tissues vary widely, from approximately 5 to 40 Torr (1-6%), encompassing levels of moderate hypoxia that have often been considered neurotoxic in vitro. The effects of such hypoxia were examined in embryonic murine cortical neurons cultured continuously from plating in an atmosphere of 1% O2. Remarkably, cortical neurons thrived in 1% O2, with survival at 7-14 days significantly greater than that of neurons cultured in ambient conditions (20% O2). Immunostaining for microtubule-associated protein-2 (MAP-2) and NeuN confirmed the neuronal identity of surviving cells, and demonstrated robust development of dendritic structures and MAP-2 expression in hypoxia. Survival of neurons in 20% O2 could be promoted by transfer of medium conditioned by neurons in 1% O2, or by pharmacological induction of hypoxia-inducible factor-1alpha (HIF-1alpha), suggesting a possible role for secreted factors under transcriptional regulation by HIF-1 in the trophic effects of hypoxia. Vascular endothelial growth factor (VEGF), a factor regulated by HIF-1, was strongly stimulated in neurons cultured in 1% O2. Treatment of neurons with exogenous VEGF partially improved survival in 20% O2, and inhibitors of VEGF action reduced survival of neurons in 1% O2. These data point to the dynamic role played by hypoxia, associated with HIF-1 up-regulation, in promoting survival of cortical neurons, in part through stimulation of VEGF expression and release.

For pathophysiological studies, it is advantageous to label specific neuronal populations in living animals. This study aimed to establish a method for stable and long-lasting fluorescent labeling of corticospinal neurons in the living animal. The two fluorescent dyes Fluoro-Red and Fluoro-Green were injected in the cervical spinal cord of anesthetized newborn rats. After a recovery period, treated rats were returned to the mother. After 24 h and 14 days, fixed brain sections revealed wide-spread fluorescence in elongated or pyramidal-shaped cell profiles in a discrete internal cortical layer, consistent with layer V pyramidal cells. Labeled neurons displayed spontaneous synaptic activity using the slice patch clamp method. These results suggest that these dyes are effective tools for pathophysiological and slice patch clamp studies focused on specific neuron groups.

Initial models of AMPA receptor assembly postulated the unrestricted stochastic association of individual subunits. The low Ca(2+) permeability and nonrectified current-voltage relationship of most native AMPA receptors were ascribed to dominant effects of the glutamate receptor 2 (GluR2) subunit. A recent model, however, proposes instead the preferred assembly of GluR1 and GluR2 subunits into tetrameric complexes as pairs of identical heteromeric dimers. To compare unrestricted versus selective models of GluR1 and GluR2 assembly, these subunits, in both flip and flop isoforms, were expressed in varying ratios in human embryonic kidney 293 cells. Coexpression of pairs of wild-type subunits produced expression of a predominance of heteromeric over homomeric receptors. Only a single functional type of heteromeric receptor was observed, indicating a pattern of apparent dominance not only of GluR2 for ion selectivity, but also of the flip isoform for receptor desensitization. Expression of wild-type GluR1 flip, however, with a mutant form of the same subunit carrying an arginine residue at the glutamine/arginine site (GluR1(R) flip) demonstrated a lack of dominance of GluR1(R) in determination of ion selectivity, whereas expression of GluR1(R) flip with GluR1 flop reproduced the pattern of apparent complete dominance. Together, the data support the selective expression of heteromeric receptors and are compatible with an equilibrium model of assembly of tetramers as pairs of identical heteromeric dimers. Expression of co-assemblies of the flip and flop isoforms, like that of the GluR1 and GluR2 subunits, is strongly favored over that of homomeric assemblies.

Activation of Ca(2+)-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been linked to potent effects on survival and dendritic outgrowth of spinal motoneurons. Ca(2+) permeability of AMPA receptors is controlled by the GluR2 subunit. Whole-cell electrophysiological studies have suggested that GluR2-containing and GluR2-lacking AMPA receptors may coexist in individual motoneurons. However, there has not been a direct demonstration of heterogeneity in AMPA receptor subunit composition in single motoneurons, nor of distinct subcellular distributions of GluR2-containing and GluR2-lacking receptors. In the present study, we have used confocal microscopy, immunocytochemistry and Ca(2+) imaging to characterize the subcellular localization of AMPA receptors in cultured rat spinal motoneurons. Immunoreactivity for GluR2 and GluR4 was concentrated in clusters, the vast majority of which were found in dendrites at synapses. Double-labelling for GluR2 and GluR4 revealed variability in relative expression of GluR2 and GluR4 between clusters within individual motoneurons; most AMPA receptor clusters were immunoreactive for both GluR2 and GluR4, but a significant minority of clusters were immunoreactive for GluR2 only or for GluR4 only. The majority of GluR2-immunonegative AMPA receptor clusters was present in dendrites, but the relative proportion of GluR2-immunonegative and GluR2-immunopositive clusters was similar in dendrites and soma. Imaging of [Ca(2+)](i) rises triggered by AMPA receptor activation confirmed Ca(2+) influx in motoneuron dendrites. These findings strongly support a model in which GluR2-containing and GluR2-lacking AMPA receptors coexist in motoneurons, clustered at synapses, and mixed in a relative proportion that varies considerably between cell membrane microdomains.

Spinal motoneurons are more susceptible to AMPA receptor-mediated injury than are other spinal neurons, a property that has been implicated in their selective degeneration in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether this difference in vulnerability between motoneurons and other spinal neurons can be attributed to a difference in AMPA receptor desensitization and/or to a difference in density of functional AMPA receptors. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. Single-cell RT-PCR quantification of the relative abundance of the flip and flop isoforms of the AMPA receptor subunits, which are known to affect receptor desensitization, did not reveal any difference between the two cell populations. Examination of AMPA receptor desensitization by patch-clamp electrophysiological measurements on nucleated and outside-out patches and in the whole-cell mode also yielded similar results for the two cell groups. However, AMPA receptor current density was two- to threefold higher in motoneurons than in dorsal horn neurons, suggesting a higher density of functional AMPA receptors in motoneuron membranes. Pharmacological reduction of AMPA receptor current density in motoneurons to the level found in dorsal horn neurons eliminated selective motoneuron vulnerability to AMPA receptor activation. These results suggest that the greater AMPA receptor current density of spinal motoneurons may be sufficient to account for their selective vulnerability to AMPA receptor agonists in vitro.

The Hypoxia-Inducible Factor-1 (HIF-1) activates the transcription of many genes required for cellular and organismal responses to oxygen deprivation. The HIF-1 complex is composed of the ubiquitously expressed basic helix-loop-helix/PAS (bHLH/PAS) proteins HIF-1alpha and Arylhydrocarbon Receptor Nuclear Translocator (ARNT). ARNT2 is a conserved ARNT homolog that is highly expressed in neurons, suggesting that ARNT2/HIF-1alpha heterodimers mediate transcriptional responses to oxygen deprivation in the nervous system. We show here that ARNT2 forms functional HIF complexes in vivo, and that ARNT2 restores hypoxia-induced gene expression to ARNT-deficient ES cells and hepatocytes. Formation of neural ARNT2/HIF-1alpha complexes in Arnt(-/-) ES cell-derived teratocarcinomas may explain why these tumors express VEGF, vascularize and grow efficiently, in contrast to ARNT-deficient hepatomas. Interestingly, all neural cell types studied accumulate both ARNT- and ARNT2-containing HIF complexes. We conclude that ARNT2 forms functional HIF complexes in neurons and plays an integral role in hypoxic responses in the CNS., (Copyright 2000 Academic Press.)

AMPA receptor-mediated excitotoxicity is proposed to play a major pathogenic role in the selective motoneuron death of amyotrophic lateral sclerosis. Motoneurons have been shown in various models to be more susceptible to AMPA receptor-mediated injury than other spinal neurons. It has been hypothesized that this selective vulnerability of motoneurons is caused by the expression of highly Ca(2+)-permeable AMPA receptors and a complete or relative lack of the AMPA receptor subunit Glu receptor 2 (GluR2). The aim of this study was to quantify the relative Ca(2+) permeability of AMPA receptors and the fractional expression of GluR2 in motoneurons by combining whole-cell patch-clamp electrophysiology and single-cell RT-PCR and to compare these properties with those of dorsal horn neurons. Spinal motoneurons and dorsal horn neurons were isolated from embryonic rats and cultured on spinal astrocytes. As in previous studies, motoneurons were significantly more vulnerable to AMPA and kainate than dorsal horn neurons. However, all motoneurons expressed GluR2 mRNA ( approximately 40% of total AMPA receptor subunit mRNA), and their AMPA receptors had intermediate whole-cell relative Ca(2+) permeability (P(Ca(2+))/P(Cs(+)) approximately 0. 4). AMPA receptor P(Ca(2+))/P(Cs(+)) and the relative abundance of GluR2 varied more widely in dorsal horn neurons than in motoneurons, but the mean values did not differ significantly between the two cell populations. GluR2 was virtually completely edited at the Q/R site both in motoneurons and dorsal horn neurons. These results indicate that the selective vulnerability of motoneurons to AMPA receptor agonists is not determined solely by whole-cell relative Ca(2+) permeability of AMPA receptors.

AMPA receptors in cultured cerebellar neurons were characterized by whole-cell electrophysiological studies and single cell PCR-based quantitation of subunit mRNA expression. Purkinje neurons consistently expressed high levels of Glu receptor 2 (GluR2) mRNA and AMPA receptors with low but nonzero Ca(2+) permeability. Other cerebellar neurons expressed AMPA receptors with a wide range of Ca(2+) permeability and of fractional GluR2. These properties correlated on a cell-by-cell basis. Their relationship was well fit by a model that assumed stochastic assembly of subunits and GluR2 dominance in controlling divalent cation permeation, suggesting that AMPA receptor properties in individual neurons may be determined primarily by relative levels of subunit transcription. A fraction of receptors, lacking GluR2, can contribute a highly Ca(2+)-permeable component to AMPA receptor responses, even in cells expressing GluR2.