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Objective: To conduct a pilot study to evaluate and compare the 24-hour habitual intraocular pressure (IOP) and ocular perfusion pressure (OPP) fluctuation in glaucoma patients treated with medical therapy, selective laser trabeculoplasty (SLT) or trabeculectomy., Design: Pilot study., Participants: Criteria for inclusion were patients aged 18 years or older with well-controlled IOP with either maximum tolerated medical therapy, previous SLT, or previous trabeculectomy., Methods: Recruited patients were admitted to the sleep lab for 24-hour serial habitual IOP and blood pressure measurements. IOP and OPP fluctuation among the 3 treatment groups were compared., Results: Thirty three (33) eyes from 33 patients were recruited in this study, including 11 patients in the medical therapy group, 11 patients in the SLT group, and 11 patients in the trabeculectomy group. The medical therapy group was found to have significantly higher 24-hour IOP fluctuation (8.3 ± 1.6 mmHg) than the SLT (3.5 ± 1.9 mmHg) and trabeculectomy (4.3 ± 1.3 mmHg) groups (P < 0.001). Mean 24-hour OPP fluctuation was also significantly higher in the medical therapy group (18.5 ± 4.0 mmHg) than the SLT (11.9 ± 7.3 mmHg) and trabeculectomy (14.1 ± 3.9 mmHg) groups (P < 0.05). No difference in IOP or OPP fluctuation was found between SLT and trabeculectomy groups (P > 0.05)., Conclusions: Both SLT and trabeculectomy may be more effective in reducing 24-hour IOP and OPP fluctuation than medical therapy alone. IOP and OPP fluctuation was comparable between SLT and trabeculectomy cohorts. Future studies are warranted to investigate this further., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To describe the 3-year outcomes of patients who underwent ab interno trabeculectomy revision with a translimbal sclerostomy spatula augmented with 5-flourouracil., Design: Retrospective cohort study., Participants: In this single-centre study, inclusion criteria included patients who were 18 years of age or older with advanced glaucoma who had undergone ab interno trabeculectomy revision with 5-flourouracil due to subconjunctival fibrosis and above-target intraocular pressure (IOP). Patients were required to have a minimum follow-up of 3 years., Methods: The primary outcome measure was IOP. Secondary outcome measures included number of topical IOP-lowering medications, best-corrected distance visual acuity, visual field mean deviation, and postoperative complications., Results: Forty-one eyes of 41 patients met the criteria for inclusion. Survival analysis demonstrated success defined by criterion A (IOP <15 mm Hg and >20% reduction) in 44% of eyes without medication (complete success) and 71% of eyes with or without medication (qualified success) at 3-year follow-up. Complete and qualified successes defined by criterion B (IOP <12 mm Hg and >20% reduction) were achieved by 31% and 44% of eyes, respectively. Early complications included transient hypotony in 26 eyes (63%) and transient hyphema in 3 eyes (7.3%). No persistent complications were reported within the 3-year study period., Conclusion: Ab interno trabeculectomy revision can be an effective technique for achieving a low target IOP in patients with advanced glaucoma in up to 3-year follow-up., (Copyright © 2023 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Background: Attention deficit hyperactivity disorder (ADHD) therapies including atomoxetine, methylphenidate, and amphetamines are some of the most prescribed medications in North America. Due to their sympathomimetic action, these drugs are contraindicated in patients with a history of angle closure glaucoma (ACG). This study aims to determine the risk of ACG and open angle glaucoma (OAG) among users of these treatments., Methods: This is a retrospective cohort study with a case control analysis using the PharMetrics Plus Database (IQVIA, USA). We created a cohort of new users of atomoxetine, methylphenidate, and amphetamines and they were followed to the first diagnosis of (1) ACG or OAG; or (2) end of follow up. For each case, four age-matched controls were selected. A conditional logistic regression model was used to adjust for confounders and to calculate adjusted incidence-rate-ratios (aIRRs)., Results: A total of 240,257 new users of the ADHD medications were identified. The mean age was 45.0 ± 19.4 years and 55% of the cohort was female. Regular users of atomoxetine and amphetamines had a higher aIRR for developing ACG compared with non-users (aIRR = 2.55 95% CI [1.20-5.43] and 2.27 95% CI [1.42-3.63], respectively); while users of methylphenidate had a higher aIRR for developing OAG (aIRR = 1.23 95% CI [1.05-1.59])., Conclusions: Use of amphetamines and atomoxetine had a higher risk for ACG, while use of methylphenidate was associated with a higher risk for OAG. Given the prevalence of ADHD medication use (medically and recreationally), our current data on their associated risk of glaucoma have profound public health implications., (© 2024. The Author(s), under exclusive licence to The Royal College of Ophthalmologists.)

Objective: To describe the outcomes of patients who underwent a single ab interno trabeculectomy revision augmented with 5-fluorouracil., Design: Retrospective cohort study., Participants: All patients who had undergone ab interno trabeculectomy revision at a single tertiary care centre during the 5-year study period. All patients had advanced glaucomatous optic neuropathy, and all treated ages and glaucoma subtypes were included., Methods: Outcome measures included surgical success, number of topical intraocular pressure (IOP)-lowering drops, best-corrected visual acuity, visual field mean deviation, and postoperative complications. Success at 12 months was defined using 2 criteria: criterion A (IOP <15 mm Hg and >20% reduction) and criterion B (IOP <12 mm Hg and >20% reduction). Each success criterion was subdivided into patients who achieved success without topical IOP-lowering drops (complete success) or with topical therapy (qualified success)., Results: This study included 46 eyes of 46 patients. Of these, 34 patients were followed for 12 months or more to assess surgical success. Success defined by criterion A was achieved by 68% of these 34 patients (53% complete, 15% qualified). Success defined by criterion B was achieved by 47% of these patients (38% complete, 9% qualified). Early hypotony was noted in 68% of eyes but was not associated with negative visual acuity or visual field outcomes., Conclusions: An IOP of <12 mm Hg and a >20% IOP reduction were achieved by 47% of patients overall (with or without topical therapy) at 12 months of follow-up. Transient early postoperative hypotony should be expected following ab interno revision trabeculectomy., (Copyright © 2022 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors report no conflicts of interest.

Purpose: To describe a unique case of unilateral open angle glaucoma secondary to heterotopic bone formation in the anterior chamber angle., Observations: A 57 year-old male with an unremarkable history presented with right eye pain. Anterior segment examination demonstrated a solid, white deposit overlying the trabecular meshwork and peripheral iris associated with an intraocular pressure of 44 mmHg. The left eye examination was unremarkable. Biopsy of the material surprisingly showed heterotopic bone. Removal of the material and medical treatment were unable to adequately control the intraocular pressure and a trabeculectomy was successfully performed., Conclusions and Importance: This case demonstrates a unique cause of secondary open angle glaucoma: heterotopic bone formation in the anterior chamber angle., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2023 Published by Elsevier Inc.)

Purpose: To report on a case of angle-closure glaucoma secondary to iridocorneal endothelial (ICE) syndrome effectively managed with the PreserFlo Microshunt., Observations: We report successful implantation of a PreserFlo Microshunt in a 57-year-old patient with secondary angle-closure glaucoma in the context of ICE syndrome. Following failure of medical therapy to adequately control intraocular pressure (IOP), the patient was consented for surgical intervention and underwent combined cataract surgery and PreserFlo Microshunt implantation. IOP at the last post-operative follow-up (5 months) was 12 mmHg with the patient on brinzolamide/timolol maleate (Azarga®). We report no complications in the post-operative period., Conclusions and Importance: The PreserFlo Microshunt may be a promising option for patients with ICE syndrome who fail medical therapy. Implantation of this device was well tolerated in the presented case., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Purpose: Post-acute non-arteritic ischemic optic neuropathy (NAION) and glaucomatous optic neuropathy (GON) can be difficult to differentiate clinically. Our objective was to identify optical coherence tomography (OCT) parameters to help differentiate these optic neuropathies., Methods: We compared 12 eyes of 8 patients with NAION and 12 eyes of 12 patients with GON, matched for age and visual field mean deviation (MD). All patients underwent clinical assessment, automated perimetry (Humphrey Field Analyzer II; Carl Zeiss Meditec, Dublin, CA, USA), and OCT imaging (Spectralis OCT2; Heidelberg Engineering, Heidelberg, Germany) of the optic nerve head and macula. We derived the neuroretinal minimum rim width (MRW), peripapillary retinal nerve fibre layer (RNFL) thickness, central anterior lamina cribrosa depth, and macular retinal thickness., Results: MRW was markedly thicker, both globally and in all sectors, in the NAION group compared to the GON group. There was no significant group difference in RFNL thickness, globally or in any sector, with the exception of the temporal sector that was thinner in the NAION group. The group difference in MRW increased with increasing visual field loss. Other differences observed included lamina cribrosa depth significantly greater in the GON group and significantly thinner central macular retinal layers in the NAION group. The ganglion cell layer was not significantly different between the groups., Conclusions: The neuroretinal rim is altered in a dissimilar manner in NAION and GON and MRW is a clinically useful index for differentiating these two neuropathies. The fact that the difference in MRW between the two groups increased with disease severity suggests distinct remodelling patterns in response to differing insults with NAION and GON., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Eadie et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Alzheimer's disease (AD) is the most prevalent form of dementia, accounting for 60-70% of all dementias. AD is often under-diagnosed and recognized only at a later, more advanced stage, and this delay in diagnosis has been suggested as a contributing factor in the numerous unsuccessful AD treatment trials. Although there is no known cure for AD, early diagnosis is important for disease management and care. A hallmark of AD is the deposition of amyloid-β (Aβ)-containing senile neuritic plaques and neurofibrillary tangles composed of hyperphosporylated tau in the brain. However, current in vivo methods to quantify Aβ in the brain are invasive, requiring radioactive tracers and positron emission tomography. Toward development of alternative methods to assess AD progression, we focus on the retinal manifestation of AD pathology. The retina is an extension of the central nervous system uniquely accessible to light-based, non-invasive ophthalmic imaging. However, earlier studies in human retina indicate that the literature is divided on the presence of Aβ in the AD retina. To help resolve this disparity, this study assessed retinal tissues from neuropathologically confirmed AD cases to determine the regional distribution of Aβ in retinal wholemounts and to inform on future retinal image studies targeting Aβ. Concurrent post-mortem brain tissues were also collected. Neuropathological cortical assessments including neuritic plaque (NP) scores and cerebral amyloid angiopathy (CAA) were correlated with retinal Aβ using immunohistochemistry, confocal microscopy, and quantitative image analysis. Aβ load was compared between AD and control (non-AD) eyes. Our results indicate that levels of intracellular and extracellular Aβ retinal deposits were significantly higher in AD than controls. Mid-peripheral Aβ levels were greater than central retina in both AD and control eyes. In AD retina, higher intracellular Aβ was associated with lower NP score, while higher extracellular Aβ was associated with higher CAA score. Our data support the feasibility of using the retinal tissue to assess ocular Aβ as a surrogate measure of Aβ in the brain of individuals with AD. Specifically, mid-peripheral retina possesses more Aβ deposition than central retina, and thus may be the optimal location for future in vivo ocular imaging., (Copyright © 2020 Lee, Jiang, McIlmoyle, To, Xu, Hirsch-Reinshagen, Mackenzie, Hsiung, Eadie, Sarunic, Beg, Cui and Matsubara.)

Purpose: Delayed hypotony can be a vision threatening complication following aqueous shunt surgery in patients with glaucoma. Multiple medical and surgical management strategies have been utilized, but results have been inconsistent. The present case series describes management of delayed hypotony associated with the Baerveldt glaucoma implant (BGI) by surgically introducing 4-0 polypropylene suture into the tube lumen., Observations: The cases of four patients who presented with hypotony following BGI surgery were reviewed. Following BGI tube lumen occlusion with suture, sustained intraocular pressure increase (mean 7.25 mmHg, range 4-14) was noted in all patients and visual acuity improved in three cases., Conclusions and Importance: This is the first report of ab interno suture occlusion of the BGI for management of post-operative hypotony. Further studies are required to determine the utility of this procedure, but our results suggest that in select patients, ab interno suture occlusion be advantageous in managing delayed hypotony refractive to medical therapy., Competing Interests: The following authors have no financial disclosures: AP, AM, MC, RG, BE., (© 2020 The Authors.)

Importance: Intravitreous injections of anti-vascular endothelial growth factor (VEGF) agents are associated with a sustained increase in intraocular pressure. This sustained elevated intraocular pressure could lead to higher rates of glaucoma surgery to lower this pressure., Objective: To determine the risk of glaucoma surgery following repeated intravitreous bevacizumab injections., Design, Setting, Participants: This nested, case-control study acquired and analyzed data from large, population-based, linked health databases supported by the British Columbia Ministry of Health in Canada. Study participants included all patients with ophthalmic issues in British Columbia, such as those of the Provincial Retinal Diseases Treatment Program, who had received intravitreous bevacizumab injections for exudative age-related macular degeneration between January 1, 2009, and December 31, 2013. Cases were identified using glaucoma surgical codes for trabeculectomy, complicated trabeculectomy, glaucoma drainage device, and cycloablative procedure. For each case, 10 controls were identified and matched for age, preexisting glaucoma, calendar time, and follow-up time. The number of intravitreous bevacizumab injections received per year-3 or fewer, 4 to 6, or 7 or more-was determined for both cases and controls. Data analysis was performed from February 23, 2016, to November 14, 2016., Main Outcomes and Measures: Risk of glaucoma surgery compared with the number of intravitreous bevacizumab injections per year in cases and controls. Rate ratios were adjusted for covariates (diabetes mellitus, myocardial infarction, stroke, and verteporfin use)., Results: Seventy-four cases of glaucoma surgery and 740 controls were identified, with a mean (SD) age of 81.3 (8.4) years for cases and 81.4 (7.9) for controls. The case group had more males than the control group (38 [51.4%] vs 272 [36.8%]). The adjusted rate ratio of glaucoma surgery among those who received 7 or more injections per year was 2.48 (95% CI, 1.25-4.93). There was a 10.3% higher number of 7 or more injections among cases compared with controls. The adjusted rate ratio for those who received 4 to 6 injections per year compared with those who received 3 or fewer was 1.65% (95% CI, 0.84-3.23)., Conclusions and Relevance: Findings from this large, pharmacoepidemiologic study suggest that 7 or more intravitreous injections of bevacizumab annually is associated with a higher risk of glaucoma surgery and that 4 to 6 injections per year show a nonstatistically significant rate ratio in the same direction.

Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits. We, and others, have recently reported that there is significant impairment in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal dentate gyrus (DG) of male Fmr1 knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmr1 gene (Fmr1 +/- ) would exhibit similar impairments in DG-dependent spatial memory processing and NMDAR hypofunction. We found that Female Fmr1 +/- mice did not show impaired metabotropic glutamate receptor (mGluR)-LTD in the CA1 region, and could perform well on a temporal ordering task that is thought to involve this brain region. In contrast, female Fmr1 +/- mice showed impairments in a pattern separation task thought to involve the DG, and also displayed a significant impairment in both NMDAR-dependent LTD and LTP in this region. The LTP impairment could be rescued by administering the NMDAR co-agonist, glycine. Our data suggests that NMDAR hypofunction in the DG may partly contribute to learning and memory impairment in female Fmr1 +/- mice. Targeting NMDAR-dependent mechanisms may offer hope as a new therapeutic approach for treating female FXS patients with learning and memory impairments., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The different secondary subunits of the N-methyl-d-aspartate (NMDA) receptor each convey unique biophysical properties to the receptor complex, and may be key in determining the functional role played by NMDA receptors. In the hippocampus, the GluN2A and GluN2B subunits are particularly abundant; however, their exact roles in synaptic plasticity and behavior remain controversial. Here, we show that mice carrying a deletion for the GluN2A subunit (GluN2A(-/-)) demonstrate a severely compromised NMDA to AMPA receptor current ratio in granule cells from the dentate gyrus (DG), while granule cell morphology is unaltered. This deficit is accompanied by significant impairments in both LTP and LTD in the DG, whereas only minor impairments are observed in the CA1. In accordance with these hippocampal region-specific deficits, GluN2A(-/-) mice show impaired performance on the DG-associated task of spatial pattern separation. In contrast, GluN2A(-/-) mice show no deficit in temporal pattern separation, a process associated with CA1 functioning. Thus, our results establish the GluN2A subunit as a significant contributor to both bidirectional synaptic plasticity and spatial pattern separation in the DG., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and results from a loss of Fragile X mental retardation protein (FMRP). FMRP is important for mRNA shuttling and translational control and binds to proteins important for synaptic plasticity. Like many developmental disorders, FXS is associated with alterations in synaptic plasticity that may impair learning and memory processes in the brain. However, it remains unclear whether FMRP plays a ubiquitous role in synaptic plasticity in all brain regions. We report that a loss of FMRP leads to impairments in N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic plasticity in the dentate gyrus (DG), but not in the cornu ammonis area 1 (CA1) subregion of the hippocampus of adult mice. DG-specific deficits are accompanied by a significant reduction in NMDAR GluN1, GluN2A, and GluN2B subunit levels and reduced serine 831 GluA1 phosphorylation specifically in this region. Importantly, we demonstrate that treatment with NMDAR co-agonists (glycine or D-serine) independently rescue impairments in NMDAR-dependent synaptic plasticity in the DG of the Fragile X mental retardation 1 (Fmr1) knockout mouse. These findings implicate the NMDAR in the pathophysiology of FXS and suggest that indirect agonists of the NMDAR may be a successful therapeutic intervention in FXS., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The medial perforant path (MPP) and lateral perforant path (LPP) inputs to the hippocampal dentate gyrus form two distinct laminar inputs onto the middle and distal aspects of granule cell dendrites. Previous evidence indicated that paired stimuli reliably produced paired-pulse depression (PPD) in the MPP and paired-pulse facilitation (PPF) in the LPP. Despite this, several years of practical experience in our laboratory questioned the utility of using paired-pulse administration to reliably differentiate the MPP and LPP in vitro. Using visualized field and whole-cell recordings in male Sprague-Dawley rats, we demonstrate that both pathways show net PPF of the excitatory postsynaptic potential (fEPSP) at 50-ms interpulse intervals. LPP afferents did reliably exhibit greater PPF than MPP afferents. Thus, the LPP reliably exhibits a greater paired-pulse ratio than the MPP. The magnitude of the paired-pulse ratio was reduced in both afferents by raising calcium levels or lowering the temperature of the recording chamber. PPD of MPP-evoked fEPSPs was only reliably detected at moderate to high stimulus intensities when population spike activity was evident. PPD was more evident in whole cell voltage clamp recordings but nonetheless was not completely diagnostic as PPD was occasionally observed with LPP stimulation as well. We found the MPP and LPP could be reliably identified using conventional microscopy with hippocampal slices, and that they could be distinguished through the analysis of evoked waveform kinetics. This work refines our knowledge of electrophysiological differences between MPP and LPP projections and will help to facilitate the selective activation of these pathways., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Objective: To report the findings of a knowledge survey of nurse and physician immunization providers., Design: Cross-sectional postal survey assessing demographic characteristics and vaccine knowledge., Setting: British Columbia (BC)., Participants: Nurse and physician immunization providers in BC., Main Outcome Measures: Knowledge of vaccine-preventable diseases, vaccines in general, and vaccine administration and handling practices., Results: Survey responses were received from 256 nurses and 292 physicians (response rates of 48.6% and 18.3%, respectively). Most nurses (98.4%) reported receiving immunization training outside of the academic setting compared with 55.6% of physicians. Overall, nurse immunizers scored significantly higher than physician immunizers on all 3 domains of immunization knowledge (83.7% vs 72.8%, respectively; P < .001). Physicians scored highest on the vaccine-preventable disease domain and least well on the general vaccine domain. Nurses with more experience as health care providers scored higher. Physicians scored higher if they were female, served patient populations predominantly younger than 5 years, or received immunization training outside of academic settings., Conclusion: In BC, nurse immunizers appear to have higher overall immunization knowledge than physicians and are more likely to receive immunization training when in practice. Physician immunizers might benefit most from further training on vaccines and vaccine administration and handling.

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in humans. This X-linked disorder is caused by the transcriptional repression of a single gene, Fmr1. The loss of Fmr1 transcription prevents the production of Fragile X mental retardation protein (FMRP) which in turn disrupts the expression of a variety of key synaptic proteins that appear to be important for intellectual ability. A clear link between synaptic dysfunction and behavioral impairment has been elusive, despite the fact that several animal models of FXS have been generated. Here we report that Fmr1 knockout mice exhibit impaired bidirectional synaptic plasticity in the dentate gyrus (DG) of the hippocampus. These deficits are associated with a novel decrease in functional NMDARs (N-methyl-D-aspartate receptors). In addition, mice lacking the Fmr1 gene show impaired performance in a context discrimination task that normally requires functional NMDARs in the DG. These data indicate that Fmr1 deletion results in significant NMDAR-dependent electrophysiological and behavioral impairments specific to the DG., (Copyright © 2010 Wiley Periodicals, Inc.)

Trans-synaptic cell-adhesion molecules have been implicated in regulating CNS synaptogenesis. Among these, the Neuroligin (NL) family (NLs 1-4) of postsynaptic adhesion proteins has been shown to promote the development and specification of excitatory versus inhibitory synapses. NLs form a heterophilic complex with the presynaptic transmembrane protein Neurexin (NRX). A differential association of NLs with postsynaptic scaffolding proteins and NRX isoforms has been suggested to regulate the ratio of excitatory to inhibitory synapses (E/I ratio). Using transgenic mice, we have tested this hypothesis by overexpressing NL1 in vivo to determine whether the relative levels of these cell adhesion molecules may influence synapse maturation, long-term potentiation (LTP), and/or learning. We found that NL1-overexpressing mice show significant deficits in memory acquisition, but not in memory retrieval. Golgi and electron microscopy analysis revealed changes in synapse morphology indicative of increased maturation of excitatory synapses. In parallel, electrophysiological examination indicated a shift in the synaptic activity toward increased excitation as well as impairment in LTP induction. Our results demonstrate that altered balance in the expression of molecules necessary for synapse specification and development (such as NL1) can lead to defects in memory formation and synaptic plasticity and outline the importance of rigidly controlled synaptic maturation processes.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by the selective loss of the expression of the Fmr1 gene. Key symptoms in FXS include intellectual impairment and abnormal anxiety-related behaviors. Fmr1 knockout (KO) mice exhibited reduced anxiety on two behavioral tests as well as a blunted corticosterone response to acute stress. Spatial learning and memory was not impaired when tested with both the classic Morris water and Plus-shaped mazes. Adult hippocampal neurogenesis has been associated with spatial learning and memory and emotions such as anxiety and depression. The process of neurogenesis appears abnormal in young adult Fmr1 KO mice, with significantly fewer bromodeoxyuridine-positive cells surviving for at least 4 weeks in the ventral subregion of the dentate gyrus (DG), a hippocampal subregion more closely associated with emotion than the dorsal DG. Within this smaller pool of surviving cells, we observed a concomitant increase in the proportion of surviving cells that acquire a neuronal phenotype. We did not observe a clear difference in cell proliferation using both endogenous and exogenous markers. This work indicates that loss of Fmr1 expression can alter anxiety-related behaviors in mice as well as produce region-specific alterations in hippocampal adult neurogenesis.

Background: Cognitive deficits are a hallmark feature of both Down Syndrome (DS) and Alzheimer's Disease (AD). Extra copies of the genes on chromosome 21 may also play an important role in the accelerated onset of AD in DS individuals. Growing evidence suggests an important function for cholesterol in the pathogenesis of AD, particularly in APP metabolism and production of A beta peptides. The ATP-Binding Cassette-G1 (ABCG1) transporter is located on chromosome 21, and participates in the maintenance of tissue cholesterol homeostasis., Results: To assess the role of ABCG1 in DS-related cognition, we evaluated the cognitive performance of mice selectively over-expressing the ABCG1 gene from its endogenous regulatory signals. Both wild-type and ABCG1 transgenic mice performed equivalently on several behavioral tests, including measures of anxiety, as well as on reference and working memory tasks. No deficits in hippocampal CA1 synaptic plasticity as determined with electrophysiological studies were apparent in mice over-expressing ABCG1., Conclusion: These findings indicate that although ABCG1 may play a role in maintaining cellular or tissue cholesterol homeostasis, it is unlikely that excess ABCG1 expression contributes to the cognitive deficits in DS individuals.

Exercise that engages the cardiovascular system has a myriad of effects on the body; however, we usually do not give much consideration to the benefits it may have for our minds. An increasing body of evidence suggests that exercise can have some remarkable effects on the brain. In this article, we will introduce how exercise can impact the capacity for neurons in the brain to communicate with one another. To properly convey this information, we will first briefly introduce the field of synaptic plasticity and then examine how the introduction of exercise to the experimental setting can actually alter the basic properties of synaptic plasticity in the brain. Next, we will examine some of the candidate physiological processes that might underlay these alterations. Finally, we will close by noting that, taken together, this data points toward our brains being dynamic systems that are in a continual state of flux and that physical exercise may help us to maximize the performance of both our body and our minds.

The spontaneous or targeted deletion of the nuclear receptor transcription factor Nr2e1 produces a mouse that shows hypoplasia of the hippocampal formation and reduced neurogenesis in adult mice. In these studies we show that hippocampal synaptic transmission appears normal in the dentate gyrus and cornu ammonis 1 subfields of adult mice that lack Nr2e1 (Nr2e1-/-), and that fEPSP shape, paired-pulse responses, and short-term plasticity are not substantially altered in either subfield. In contrast, the expression of long-term potentiation is selectively impaired in the dentate gyrus, and not in the cornu ammonis 1 subfield. Golgi analysis revealed that there was a significant reduction in both dendritic branching and dendritic length that was specific to dentate gyrus granule cells in the Nr2e1-/- mice. These results indicate that Nr2e1 deletion can significantly alter both synaptic plasticity and dendritic structure in the dentate gyrus.

Environmental enrichment (EE) and voluntary exercise (VEx) have consistently been shown to increase adult hippocampal neurogenesis and improve spatial learning ability. Although it appears that these two manipulations are equivalent in this regard, evidence exists that EE and VEx affect different phases of the neurogenic process in distinct ways. We review the data suggesting that EE increases the likelihood of survival of new cells, whereas VEx increases the level of proliferation of progenitor cells. We then outline the factors that may mediate these relationships. Finally, we provide a model showing that VEx leads to the convergence of key somatic and cerebral factors in the dentate gyrus (DG) to induce cell proliferation. Although insufficient evidence exists to provide a similar model for EE, we suggest that EE-induced cell survival in the DG involves cortical restructuring as a means of promoting survival. We conclude that EE and VEx lead to an increase in overall hippocampal neurogenesis via dissociable pathways, and should therefore, be considered distinct interventions with regard to hippocampal plasticity and associated behaviors., ((c) 2006 Wiley-Liss, Inc.)

Voluntary exercise produces a dramatic increase in the number of bromodeoxyuridine (BrdU)-positive cells in the adult dentate gyrus (DG); however, it has never been determined whether this increase reflects neurogenic activity or some exercise-induced change in the metabolic processing of systemically injected BrdU. In these experiments, we show that 1) 200 mg/kg is a saturating dose for single injections of BrdU in both control and voluntary exercise animals; 2) there is significantly more cell labeling in animals that exercise when saturating doses of BrdU are employed; 3) high doses of BrdU do not affect the number, appearance, or distribution of labeled cells; 4) voluntary exercise leads to similar increases in the number of cells expressing Ki67, an intrinsic marker of cellular proliferation; 5) both dendritic length and complexity are significantly increased in the DG of animals that exercise; and 6) spine density is significantly greater on dendrites in the DG following voluntary exercise. This study demonstrates that exercise up-regulates neurogenic activity in the DG of adult rats, independently of any putative changes in altered BrdU metabolism, and that it also substantially alters the morphology of dentate granule cell dendrites. The dramatic changes in the cytoarchitecture of the DG induced by voluntary exercise might underlie the enhancement of hippocampal long-term potentiation and hippocampal-dependent memory that our group has previously described. These results suggest that exercise may be an effective component of therapeutic regimes aimed at improving the functioning of individuals with neuropathologies that involve the degradation of cells in the hippocampus., ((c) 2005 Wiley-Liss, Inc.)

DNA methylation-mediated epigenetic regulation plays critical roles in regulating mammalian gene expression, but its role in normal brain function is not clear. Methyl-CpG binding protein 1 (MBD1), a member of the methylated DNA-binding protein family, has been shown to bind methylated gene promoters and facilitate transcriptional repression in vitro. Here we report the generation and analysis of MBD1-/- mice. MBD1-/- mice had no detectable developmental defects and appeared healthy throughout life. However, we found that MBD1-/- neural stem cells exhibited reduced neuronal differentiation and increased genomic instability. Furthermore, adult MBD1-/- mice had decreased neurogenesis, impaired spatial learning, and a significant reduction in long-term potentiation in the dentate gyrus of the hippocampus. Our findings indicate that DNA methylation is important in maintaining cellular genomic stability and is crucial for normal neural stem cell and brain functions.