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Early-life seizures (ELSs) can cause permanent cognitive deficits and network hyperexcitability, but it is unclear whether ELSs induce persistent changes in specific neuronal populations and whether these changes can be targeted to mitigate network dysfunction. We used the targeted recombination of activated populations (TRAP) approach to genetically label neurons activated by kainate-induced ELSs in immature mice. The ELS-TRAPed neurons were mainly found in hippocampal CA1, remained uniquely susceptible to reactivation by later-life seizures, and displayed sustained enhancement in [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated (AMPAR-mediated) excitatory synaptic transmission and inward rectification. ELS-TRAPed neurons, but not non-TRAPed surrounding neurons, exhibited enduring decreases in Gria2 mRNA, responsible for encoding the GluA2 subunit of the AMPARs. This was paralleled by decreased synaptic GluA2 protein expression and heightened phosphorylated GluA2 at Ser880 in dendrites, indicative of GluA2 internalization. Consistent with increased GluA2-lacking AMPARs, ELS-TRAPed neurons showed premature silent synapse depletion, impaired long-term potentiation, and impaired long-term depression. In vivo postseizure treatment with IEM-1460, an inhibitor of GluA2-lacking AMPARs, markedly mitigated ELS-induced changes in TRAPed neurons. These findings show that enduring modifications of AMPARs occur in a subpopulation of ELS- activated neurons, contributing to synaptic dysplasticity and network hyperexcitability, but are reversible with early IEM- 1460 intervention., Introduction Both clinical and experimental evidence suggest that seizures in early life can be associated with long-lasting cognitive and behavioral deficits (1-6), yet the mechanisms of these long-term changes remain [...]

Children at increased genetic risk for type 1 diabetes (T1D) after environmental exposures may develop pancreatic islet autoantibodies (IA) at a very young age. Metabolic profile changes over time may imply responses to exposures and signal development of the first IA. Our present research in The Environmental Determinants of Diabetes in the Young (TEDDY) study aimed to identify metabolome-wide signals preceding the first IA against GAD (GADA-first) or against insulin (IAA-first). We profiled metabolomes by mass spectrometry from children's plasma at 3-month intervals after birth until appearance of the first IA. A trajectory analysis discovered each first IA preceded by reduced amino acid proline and branched-chain amino acids (BCAAs), respectively. With independent time point analysis following birth, we discovered dehydroascorbic acid (DHAA) contributing to the risk of each first IA, and γ-aminobutyric acid (GABAs) associated with the first autoantibody against insulin (IAA-first). Methionine and alanine, compounds produced in BCAA metabolism and fatty acids, also preceded IA at different time points. Unsaturated triglycerides and phosphatidylethanolamines decreased in abundance before appearance of either autoantibody. Our findings suggest that IAA-first and GADA-first are heralded by different patterns of DHAA, GABA, multiple amino acids, and fatty acids, which may be important to primary prevention of T1D.

The article focuses on a study on the impact of emergency department(ED)-based physical therapy (PT) (ED-PT) on PT access in both ED and outpatient settings. Topics discussed include the methods used in the study, the rates of outpatient PT referral and success outpatient PT participation, and conclusion of the study.

Early-life seizures (ELSs) can cause permanent cognitive deficits and network hyperexcitability, but it is unclear whether ELSs induce persistent changes in specific neuronal populations and whether these changes can be targeted to mitigate network dysfunction. We used the targeted recombination of activated populations (TRAP) approach to genetically label neurons activated by kainate-induced ELSs in immature mice. The ELS-TRAPed neurons were mainly found in hippocampal CA1, remained uniquely susceptible to reactivation by later-life seizures, and displayed sustained enhancement in á-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor--mediated (AMPAR-mediated) excitatory synaptic transmission and inward rectification. ELS-TRAPed neurons, but not non-TRAPed surrounding neurons, exhibited enduring decreases in Gria2 mRNA, responsible for encoding the GluA2 subunit of the AMPARs. This was paralleled by decreased synaptic GluA2 protein expression and heightened phosphorylated GluA2 at Ser880 in dendrites, indicative of GluA2 internalization. Consistent with increased GluA2-lacking AMPARs, ELS-TRAPed neurons showed premature silent synapse depletion, impaired long-term potentiation, and impaired long-term depression. In vivo postseizure treatment with IEM-1460, an inhibitor of GluA2-lacking AMPARs, markedly mitigated ELS-induced changes in TRAPed neurons. These findings show that enduring modifications of AMPARs occur in a subpopulation of ELS-activated neurons, contributing to synaptic dysplasticity and network hyperexcitability, but are reversible with early IEM-1460 intervention. [ABSTRACT FROM AUTHOR]

Objective: Biomarkers predicting risk of type 1 diabetes (stage 3) among children with islet autoantibodies are greatly needed to prevent diabetic ketoacidosis and facilitate prevention therapies.Research Design and Methods: Children in the prospective The Environmental Determinants of Diabetes in the Young (TEDDY) study (n = 707) with confirmed diabetes-associated autoantibodies (GAD antibody, IA-2A, and/or insulin autoantibody) and two or more HbA1c measurements were followed to diabetes or median age 11.1 years. Once confirmed autoantibody positive, HbA1c was measured quarterly. Cox models and receiver operative characteristic curve analyses revealed the prognostic utility for risk of stage 3 on a relative HbA1c increase from the baseline visit or an oral glucose tolerance test (OGTT) 2-h plasma glucose (2-hPG). This HbA1c approach was then validated in the Type 1 Diabetes TrialNet Pathway to Prevention Study (TrialNet) (n = 1,190).Results: A 10% relative HbA1c increase from baseline best marked the increased risk of stage 3 in TEDDY (74% sensitive; 88% specific). Significant predictors of risk for HbA1c change were age and HbA1c at the baseline test, genetic sex, maximum number of autoantibodies, and maximum rate of HbA1c increase by time of change. The multivariable model featuring a HbA1c ≥10% increase and these additional factors revealed increased risk of stage 3 in TEDDY (hazard ratio [HR] 12.74, 95% CI 8.7-18.6, P < 0.0001) and TrialNet (HR 5.09, 95% CI 3.3-7.9, P < 0.0001). Furthermore, the composite model using HbA1c ≥10% increase performed similarly to an OGTT 2-hPG composite model (TEDDY area under the curve [AUC] 0.88 and 0.85, respectively) and to the HbA1c model in TrialNet (AUC 0.82).Conclusions: An increase of ≥10% in HbA1c from baseline is as informative as OGTT 2-hPG in predicting risk of stage 3 in youth with genetic risk and diabetes-associated autoantibodies. [ABSTRACT FROM AUTHOR]

Objective: To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children.Research Design and Methods: Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3-12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models.Results: Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes.Conclusions: Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes. [ABSTRACT FROM AUTHOR]

Objective: The Environmental Determinants of Diabetes in the Young (TEDDY) study is uniquely capable of investigating age-specific differences associated with type 1 diabetes. Because age is a primary driver of heterogeneity in type 1 diabetes, we sought to characterize by age metabolic derangements prior to diagnosis and clinical features associated with diabetic ketoacidosis (DKA).Research Design and Methods: The 379 TEDDY children who developed type 1 diabetes were grouped by age at onset (0-4, 5-9, and 10-14 years; n = 142, 151, and 86, respectively) with comparisons of autoantibody profiles, HLAs, family history of diabetes, presence of DKA, symptomatology at onset, and adherence to TEDDY protocol. Time-varying analysis compared those with oral glucose tolerance test data with TEDDY children who did not progress to diabetes.Results: Increasing fasting glucose (hazard ratio [HR] 1.09 [95% CI 1.04-1.14]; P = 0.0003), stimulated glucose (HR 1.50 [1.42-1.59]; P < 0.0001), fasting insulin (HR 0.89 [0.83-0.95]; P = 0.0009), and glucose-to-insulin ratio (HR 1.29 [1.16-1.43]; P < 0.0001) were associated with risk of progression to type 1 diabetes. Younger children had fewer autoantibodies with more symptoms at diagnosis. Twenty-three children (6.1%) had DKA at onset, only 1 (0.97%) of 103 with and 22 (8.0%) of 276 children without a first-degree relative (FDR) with type 1 diabetes (P = 0.008). Children with DKA were more likely to be nonadherent to study protocol (P = 0.047), with longer duration between their last TEDDY evaluation and diagnosis (median 10.2 vs. 2.0 months without DKA; P < 0.001).Conclusions: DKA at onset in TEDDY is uncommon, especially for FDRs. For those without familial risk, metabolic monitoring continues to provide a primary benefit of reduced DKA but requires regular follow-up. Clinical and laboratory features vary by age at onset, adding to the heterogeneity of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: Participants' study satisfaction is important for both compliance with study protocols and retention, but research on parent study satisfaction is rare. This study sought to identify factors associated with parent study satisfaction in The Environmental Determinants of Diabetes in the Young (TEDDY) study, a longitudinal, multinational (US, Finland, Germany, Sweden) study of children at risk for type 1 diabetes. The role of staff consistency to parent study satisfaction was a particular focus. Methods: Parent study satisfaction was measured by questionnaire at child-age 15 months (5579 mothers, 4942 fathers) and child-age four years (4010 mothers, 3411 fathers). Multiple linear regression analyses were used to identify sociodemographic factors, parental characteristics, and study variables associated with parent study satisfaction at both time points. Results: Parent study satisfaction was highest in Sweden and the US, compared to Finland. Parents who had an accurate perception of their child's type 1 diabetes risk and those who believed they can do something to prevent type 1 diabetes were more satisfied. More educated parents and those with higher depression scores had lower study satisfaction scores. After adjusting for these factors, greater study staff change frequency was associated with lower study satisfaction in European parents (mothers at child-age 15 months: − 0.30,95% Cl − 0.36, − 0.24, p < 0.001; mothers at child-age four years: -0.41, 95% Cl − 0.53, − 0.29, p < 0.001; fathers at child-age 15 months: -0.28, 95% Cl − 0.34, − 0.21, p < 0.001; fathers at child-age four years: -0.35, 95% Cl − 0.48, − 0.21, p < 0.001). Staff consistency was not associated with parent study satisfaction in the US. However, the number of staff changes was markedly higher in the US compared to Europe. Conclusions: Sociodemographic factors, parental characteristics, and study-related variables were all related to parent study satisfaction. Those that are potentially modifiable are of particular interest as possible targets of future efforts to improve parent study satisfaction. Three such factors were identified: parent accuracy about the child's type 1 diabetes risk, parent beliefs that something can be done to reduce the child's risk, and study staff consistency. However, staff consistency was important only for European parents. Trial registration: NCT00279318. [ABSTRACT FROM AUTHOR]

The risk of seizures is 10-fold higher in patients with Alzheimer's disease than the general population, yet the mechanisms underlying this susceptibility and the effects of these seizures are poorly understood. To elucidate the proposed bidirectional relationship between Alzheimer's disease and seizures, we studied human brain samples (n = 34) from patients with Alzheimer's disease and found that those with a history of seizures (n = 14) had increased amyloid-β and tau pathology, with upregulation of the mechanistic target of rapamycin (mTOR) pathway, compared with patients without a known history of seizures (n = 20). To establish whether seizures accelerate the progression of Alzheimer's disease, we induced chronic hyperexcitability in the five times familial Alzheimer's disease mouse model by kindling with the chemoconvulsant pentylenetetrazol and observed that the mouse model exhibited more severe seizures than the wild-type. Furthermore, kindled seizures exacerbated later cognitive impairment, Alzheimer's disease neuropathology and mTOR complex 1 activation. Finally, we demonstrated that the administration of the mTOR inhibitor rapamycin following kindled seizures rescued enhanced remote and long-term memory deficits associated with earlier kindling and prevented seizure-induced increases in Alzheimer's disease neuropathology. These data demonstrated an important link between chronic hyperexcitability and progressive Alzheimer's disease pathology and suggest a mechanism whereby rapamycin may serve as an adjunct therapy to attenuate progression of the disease. [ABSTRACT FROM AUTHOR]

Significant progress has been made in elucidating genetic risk factors influencing Type 1 diabetes (T1D); however, features other than genetic variants that initiate and/or accelerate islet autoimmunity that lead to the development of clinical T1D remain largely unknown. We hypothesized that genetic and environmental risk factors can both contribute to T1D through dynamic alterations of molecular interactions in physiologic networks. To test this hypothesis, we utilized longitudinal blood transcriptomic profiles in The Environmental Determinants of Diabetes in the Young (TEDDY) study to generate gene co-expression networks. In network modules that contain immune response genes associated with T1D, we observed highly dynamic differences in module connectivity in the 600 days (~ 2 years) preceding clinical diagnosis of T1D. Our results suggest that gene co-expression is highly plastic and that connectivity differences in T1D-associated immune system genes influence the timing and development of clinical disease. [ABSTRACT FROM AUTHOR]

Objective: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study.Research Design and Methods: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.Results: There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282, or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88-1.42; P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78-10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10-29.29; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.Conclusions: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) neuropathology is largely driven by two pathological proteins, tau, and ß‐amyloid, both of which induce neuronal hyperexcitability and are thought to play a role in the high comorbidity between AD and epilepsy. Central to the progression of AD is the spread of tau along neuronal networks likely via neuronal activity. Our previous work suggests a bidirectional relationship between AD and epilepsy with seizures inducing AD pathology and vice versa (Gourmaud et al. Brain, 2021; awab268). Additionally, there is evidence of excitatory‐inhibitory (E:I) imbalance in AD reminiscent of E:I imbalances involved in epileptogenesis. Thus, we hypothesized that seizures can exacerbate E:I imbalance in AD models and that this enhanced hyperexcitability promotes the propagation of pathological tau. Method: We utilized the Five times familial AD (5XFAD) model and an established pentylenetetrazol (PTZ) kindling method to induce seizures in these and WT littermates. To model pathological tau spread seen in AD, a cohort of animals also underwent intracerebral injection of human AD‐derived tau (AD‐tau) into the hippocampus and overlying cortex prior to seizure induction. Western blots were performed for the Cl− transporters, K+‐ Cl−cotransporter 2 (KCC2) and Na+‐K+‐Cl− cotransporter 1 (NKCC1), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) subunits, GluA2 and GluA1, and GABAAR subunits α1 and α3, given their roles in E:I balance. AD‐tau injected mice were also examined by western blot for phospho‐tau AT8 [Ser202; Thr205] and phospho‐tau AT180 [Thr231] in sites proximal (hippocampus) and distal (frontal cortex) to injection site to determine the effects of seizures on tau propagation. Result: PTZ‐kindling enhanced the dysregulation of Cl‐ transporters, NKCC1 and KCC2 (p<0.05, n = 12‐19) and GluA2/GluA1 ratios (p<0.05, n = 12‐19) in 5XFAD mice, while 5XFAD mice showed decreased GABAARα1 (p<0.05, n = 12‐19). No significant changes were seen in the hippocampus for AT8 nor AT180, but seizure induction elevated AT8 levels in the frontal cortex across genotypes (p<0.05, n = 5‐9). Conclusion: Our data suggest that seizures exacerbate E:I imbalance in 5XFAD mice and tau propagation in both WT and 5XFAD mice. Thus, drugs targeting mechanisms involved in E:I balance or controlling seizures with antiseizure medication shows therapeutic efficacy for AD patients with comorbid seizures. [ABSTRACT FROM AUTHOR]

The risk of seizures is 10-fold higher in patients with Alzheimer's disease than the general population, yet the mechanisms underlying this susceptibility and the effects of these seizures are poorly understood. To elucidate the proposed bidirectional relationship between Alzheimer's disease and seizures, we studied human brain samples (n = 34) from patients with Alzheimer's disease and found that those with a history of seizures (n = 14) had increased amyloid-β and tau pathology, with upregulation of the mechanistic target of rapamycin (mTOR) pathway, compared with patients without a known history of seizures (n = 20). To establish whether seizures accelerate the progression of Alzheimer's disease, we induced chronic hyperexcitability in the five times familial Alzheimer's disease mouse model by kindling with the chemoconvulsant pentylenetetrazol and observed that the mouse model exhibited more severe seizures than the wild-type. Furthermore, kindled seizures exacerbated later cognitive impairment, Alzheimer's disease neuropathology and mTOR complex 1 activation. Finally, we demonstrated that the administration of the mTOR inhibitor rapamycin following kindled seizures rescued enhanced remote and long-term memory deficits associated with earlier kindling and prevented seizure-induced increases in Alzheimer's disease neuropathology. These data demonstrated an important link between chronic hyperexcitability and progressive Alzheimer's disease pathology and suggest a mechanism whereby rapamycin may serve as an adjunct therapy to attenuate progression of the disease., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fragile X syndrome (FXS) is the leading monogenic form of intellectual disability and autism, with patients exhibiting numerous auditory-related phenotypes during their developmental period, including communication, language development, and auditory processing deficits. Despite FXS studies describing excitatory-inhibitory (E-I) imbalance in the auditory circuit and an impaired auditory critical period, evaluation of E-I circuitry maturation in the auditory cortex of FXS models remains limited. Here, we examined GABAA receptor (GABAAR)-mediated inhibitory synaptic transmission within the auditory cortex, characterizing normal intracortical circuit development patterns in wild-type (WT) mice and examining their dysregulation in developing Fmr1 knock-out (KO) mice. Electrophysiological recordings revealed gradual developmental shifts in WT L4-L2/3 connectivity, where circuit excitability significantly increased after critical period onset. KO mice exhibited accelerated developmental shifts related to aberrant GABAergic signaling. Specifically, Fmr1 KO L2/3 pyramidal neurons have enhanced developmental sensitivity to pharmacological GABAAR modulators, altered maturation of GABAAR voltage-dependent conductance, with additional presynaptic GABA release alterations. These differences are further accompanied by alterations in developmental long-term potentiation. Together, our results suggest that altered GABAergic signaling within developing Fmr1 KOs impairs the normal patterning of E-I circuit and synaptic plasticity maturation to contribute to the impaired auditory cortex critical period and functional auditory deficits in FXS., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Approximately half of people infected with HIV (PWH) exhibit HIV-associated neuropathology (neuroHIV), even when receiving combined antiretroviral therapy. Opiate use is widespread in PWH and exacerbates neuroHIV. While neurons themselves are not infected, they incur sublethal damage and GABAergic disruption is selectively vulnerable to viral and inflammatory factors released by infected/affected glia. Here, we demonstrate diminished K + -Cl - cotransporter 2 (KCC2) levels in primary human neurons after exposure to HIV-1 or HIV-1 proteins ± morphine. Resulting disruption of GABA A R-mediated hyperpolarization/inhibition was shown using genetically-encoded voltage (Archon1) and calcium (GCaMP6f) indicators. The HIV proteins Tat (acting through NMDA receptors) and R5-gp120 (acting via CCR5) but not X4-tropic gp120 (acting via CXCR4), and morphine (acting through μ-opioid receptors) all induced KCC2 loss. We demonstrate that modifying KCC2 levels or function, or antagonizing NMDAR, CCR5 or MOR rescues KCC2 and GABA A R-mediated hyperpolarization/inhibition in HIV, Tat, or gp120 ± morphine-exposed neurons. Using an inducible, Tat-transgenic mouse neuroHIV model, we found that chronic exposure to Tat also reduces KCC2. Our results identify KCC2 as a novel therapeutic target for ameliorating the pathobiology of neuroHIV, including PWH exposed to opiates., Competing Interests: Declaration of Competing Interest No competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)