Energetic Profiles of the Yo-Yo Intermittent Recovery Tests 1 and 2.

PURPOSE: To analyze the energetic profiles of the Yo-Yo Intermittent Recovery Tests 1 and 2 (YYIR1 and YYIR2). METHODS: Intermittent running distance (IR1D and IR2D), time to exhaustion (IR1T and IR2T), and total recovery time between shuttles (IR1R and IR2R) were measured in 10 well-trained male athletes (age 24.4 [2.0] y, height 182 [1] cm, weight 75.8 [7.9] kg). Respiratory gases and blood lactate (BLC) were obtained preexercise, during exercise, and until 15 min postexercise. Metabolic energy, average metabolic power , and energy share (percentage of aerobic [WAER], anaerobic lactic [WBLC], and anaerobic alactic energy system [WPCr]) were calculated using the PCr-La-O2 method. RESULTS: Peak oxygen consumption was possibly higher in YYIR2 (60.3 [5.1] mL·kg-1·min-1) than in YYIR1 (P = .116, 57.7 [4.5] mL·kg-1·min-1, d = -0.58). IR1D, IR1T, and IR1R were very likely higher than IR2D, IR2T, and IR2R, respectively (P < .001, 1876 [391] vs 672 [132] m, d = -2.83; P < .001, 916 [175] vs 304 [57] s, d = -3.03; and P < .001, 460 [100] vs 150 [40] s, d = -2.83). Metabolic energy was most likely lower in YYIR2 than in YYIR1 (P < .001, 493.5 [118.1] vs 984.8 [171.7] kJ, d = 3.24). Average metabolic power was most likely higher in YYIR2 than in YYIR1 (P < .001, 21.5 [1.7] vs 14.5 [2.2] W·kg-1, d = 3.54). When considering aerobic phosphocreatine restoration during breaks between shuttles, WAER (P = .693, 49% [10%] vs 48% [5%], d = -0.16) was similar, WPCr (P = .165, 47% [11%] vs 42% [6%], d = -0.54) possibly higher, and WBLC (P < .001, 4% [1%] vs 10% [3%], d = 1.95) almost certainly lower in YYIR1 than in YYIR2. CONCLUSIONS: WAER and WPCr are predominant in YYIR1 and YYIR2 with almost identical WAER. Higher IR1D and IR1T in YYIR1 result in higher metabolic energy but lower average metabolic power and slightly lower peak oxygen consumption. Higher IR1R allows for higher reliance on WPCr in YYIR1, while YYIR2 requires a higher fraction of WBLC.

Hyperactivity and Hypermotivation Associated With Increased Striatal mGluR1 Signaling in a Shank2 Rat Model of Autism.

Mutations in the SHANK family of genes have been consistently identified in genetic and genomic screens of autism spectrum disorder (ASD). The functional overlap of SHANK with several other ASD-associated genes suggests synaptic dysfunction as a convergent mechanism of pathophysiology in ASD. Although many ASD-related mutations result in alterations to synaptic function, the nature of those dysfunctions and the consequential behavioral manifestations are highly variable when expressed in genetic mouse models. To investigate the phylogenetic conservation of phenotypes resultant of Shank2 loss-of-function in a translationally relevant animal model, we generated and characterized a novel transgenic rat with a targeted mutation of the Shank2 gene, enabling an evaluation of gene-associated phenotypes, the elucidation of complex behavioral phenotypes, and the characterization of potential translational biomarkers. The Shank2 loss-of-function mutation resulted in a notable phenotype of hyperactivity encompassing hypermotivation, increased locomotion, and repetitive behaviors. Mutant rats also expressed deficits in social behavior throughout development and in the acquisition of operant tasks. The hyperactive phenotype was associated with an upregulation of mGluR1 expression, increased dendritic branching, and enhanced long-term depression (LTD) in the striatum but opposing morphological and cellular alterations in the hippocampus (HP). Administration of the mGluR1 antagonist JNJ16259685 selectively normalized the expression of striatally mediated repetitive behaviors and physiology but had no effect on social deficits. Finally, Shank2 mutant animals also exhibited alterations in electroencephalography (EEG) spectral power and event-related potentials, which may serve as translatable EEG biomarkers of synaptopathic alterations. Our results show a novel hypermotivation phenotype that is unique to the rat model of Shank2 dysfunction, in addition to the traditional hyperactive and repetitive behaviors observed in mouse models. The hypermotivated and hyperactive phenotype is associated with striatal dysfunction, which should be explored further as a targetable mechanism for impairment in ASD.

Energetic Profile of the Basketball Exercise Simulation Test in Junior Elite Players.

PURPOSE: To analyze the energetic profile of the Basketball Exercise Simulation Test (BEST). METHODS: Ten male elite junior basketball players (age 15.5 [0.6] y, height 180 [9] cm, and body mass 66.1 [11.2] kg) performed a modified BEST (20 circuits consisting of jumping, sprinting, jogging, shuffling, and short breaks) simulating professional basketball game play. Circuit time, sprint time, sprint decrement, oxygen uptake (VO2), heart rate, and blood lactate concentration (blc) were obtained. Metabolic energy and metabolic power above rest (Wtot and Ptot), as well as energy share in terms of aerobic (Waer), glycolytic (Wblc), and high-energy phosphates (WPCr), were calculated from VO2 during exercise, net lactate production, and the fast component of postexercise VO2 kinetics, respectively. RESULTS: Waer, Wblc, and WPCr reflect 89% (2%), 5% (1%), and 6% (1%) of total energy needed, respectively. Assuming an aerobic replenishment of PCr energy stores during short breaks, the adjusted energy share yielded Waer 66% (4%), Wblc 5% (1%), and WPCr 29% (1%). Waer and WPCr were negatively correlated (-0.72 and -0.59) with sprint time, which was not the case for Wblc. CONCLUSIONS: Consistent with general findings on energy system interaction during repeated high-intensity exercise bouts, the intermittent profile of the BEST relies primarily on aerobic energy combined with repetitive supplementation by anaerobic utilization of high-energy phosphates.

Neurotrophic Factors in Mouse Models of Autism Spectrum Disorder: Focus on BDNF and IGF-1.

Neurotrophic factors are secreted proteins promoting the development and maintaining the function of neural circuits. Studies in human individuals with autism spectrum disorder (ASD) and corresponding animal models have implicated that alterations of neurotrophic factor levels and the associated signalling pathways might contribute to the underlying pathophysiology. As most of this work has investigated the role of brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) in ASD formation, we focus on these two molecules in this review. We start with reviewing findings on neurotrophic factor levels in human individuals with ASD, continue with providing a broad overview on murine BDNF and IGF-1 in several well-established mouse models of ASD and finally discuss the therapeutic potential of both molecules in the context of translational ASD research.

Proteomic Analysis of Post-synaptic Density Fractions from Shank3 Mutant Mice Reveals Brain Region Specific Changes Relevant to Autism Spectrum Disorder.

Disruption of the human SHANK3 gene can cause several neuropsychiatric disease entities including Phelan-McDermid syndrome, autism spectrum disorder (ASD), and intellectual disability. Although, a wide array of neurobiological studies strongly supports a major role for SHANK3 in organizing the post-synaptic protein scaffold, the molecular processes at synapses of individuals harboring SHANK3 mutations are still far from being understood. In this study, we biochemically isolated the post-synaptic density (PSD) fraction from striatum and hippocampus of adult Shank3Δ11-/- mutant mice and performed ion-mobility enhanced data-independent label-free LC-MS/MS to obtain the corresponding PSD proteomes (Data are available via ProteomeXchange with identifier PXD005192). This unbiased approach to identify molecular disturbances at Shank3 mutant PSDs revealed hitherto unknown brain region specific alterations including a striatal decrease of several molecules encoded by ASD susceptibility genes such as the serine/threonine kinase Cdkl5 and the potassium channel KCa1.1. Being the first comprehensive analysis of brain region specific PSD proteomes from a Shank3 mutant line, our study provides crucial information on molecular alterations that could foster translational treatment studies for SHANK3 mutation-associated synaptopathies and possibly also ASD in general.

Genetic Animal Models for Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects approximately 1 % of the human population and has a strong genetic component. Hence, the recent discovery of major "ASD genes" has subsequently resulted in the generation of several genetic animal models of ASD. Careful analysis of behavioral phenotypes and characterization of the underlying neurobiological mechanisms in these models should further help us to identify novel therapeutic targets and develop more effective strategies in the future to ameliorate or even reverse core symptoms and comorbidities of ASD. In this review, we will focus on the mutant mouse as animal model and outline how to characterize both behavioral and neurobiological phenotypes in this organism. We will further discuss a selection of major ASD mutant mouse lines. Our conclusions will finally address the current goals and perspectives in the field to obtain a more comprehensive and possibly also converging picture of ASD pathogenesis, which could be most useful for the desired bench-to-bedside strategy of translational medicine for this complex disorder.

An Epha4/Sipa1l3/Wnt pathway regulates eye development and lens maturation.

The signal-induced proliferation-associated family of proteins comprises four members, SIPA1 and SIPA1L1-3. Mutations of the human SIPA1L3 gene result in congenital cataracts. In Xenopus, loss of Sipa1l3 function led to a severe eye phenotype that was distinguished by smaller eyes and lenses including lens fiber cell maturation defects. We found a direct interaction between Sipa1l3 and Epha4, building a functional platform for proper ocular development. Epha4 deficiency phenocopied loss of Sipa1l3 and rescue experiments demonstrated that Epha4 acts upstream of Sipa1l3 during eye development, with both Sipa1l3 and Epha4 required for early eye specification. The ocular phenotype, upon loss of either Epha4 or Sipa1l3, was partially mediated by rax We demonstrate that canonical Wnt signaling is inhibited downstream of Epha4 and Sipa1l3 during normal eye development. Depletion of either Sipa1l3 or Epha4 resulted in an upregulation of axin2 expression, a direct Wnt/ß-catenin target gene. In line with this, Sipa1l3 or Epha4 depletion could be rescued by blocking Wnt/ß-catenin or activating non-canonical Wnt signaling. We therefore conclude that this pathomechanism prevents proper eye development and maturation of lens fiber cells, resulting in congenital cataracts.

The Shank3 Interaction Partner ProSAPiP1 Regulates Postsynaptic SPAR Levels and the Maturation of Dendritic Spines in Hippocampal Neurons.

The postsynaptic density or PSD is a submembranous compartment containing a wide array of proteins that contribute to both morphology and function of excitatory glutamatergic synapses. In this study, we have analyzed functional aspects of the Fezzin ProSAP-interacting protein 1 (ProSAPiP1), an interaction partner of the well-known PSD proteins Shank3 and SPAR. Using lentiviral-mediated overexpression and knockdown of ProSAPiP1, we found that this protein is dispensable for the formation of both pre- and postsynaptic specializations per se. We further show that ProSAPiP1 regulates SPAR levels at the PSD and the maturation of dendritic spines. In line with previous findings on the ProSAPiP1 homolog PSD-Zip70, we conclude that Fezzins essentially contribute to the maturation of excitatory spine synapses.

Selective Localization of Shanks to VGLUT1-Positive Excitatory Synapses in the Mouse Hippocampus.

Members of the Shank family of multidomain proteins (Shank1, Shank2, and Shank3) are core components of the postsynaptic density (PSD) of excitatory synapses. At synaptic sites Shanks serve as scaffolding molecules that cluster neurotransmitter receptors as well as cell adhesion molecules attaching them to the actin cytoskeleton. In this study we investigated the synapse specific localization of Shank1-3 and focused on well-defined synaptic contacts within the hippocampal formation. We found that all three family members are present only at VGLUT1-positive synapses, which is particularly visible at mossy fiber contacts. No costaining was found at VGLUT2-positive contacts indicating that the molecular organization of VGLUT2-associated PSDs diverges from classical VGLUT1-positive excitatory contacts in the hippocampus. In light of SHANK mutations in neuropsychiatric disorders, this study indicates which glutamatergic networks within the hippocampus will be primarily affected by shankopathies.

Self-selected intensity exercise in the treatment of major depression: A pragmatic RCT.

OBJECTIVE: The purpose of the study was to determine the therapeutic effect of physical exercise for patients with unipolar depression. Participants took part in an 8-week walking/running aerobic exercise program at a local sports club. METHODS: Forty-six outpatients aged 18-65 years and diagnosed with mild to severe depression (ICD-10 criteria) were randomly assigned to an intervention group or wait list. Treatment as usual was continued. The Hamilton Rating Scale for Depression (HRSD-17) served as the main outcome measure. Secondary outcome measures were Beck Depression Inventory (BDI-II), Fitness Index (FI), and VO(2) max as estimated by Urho Kaleka Kekkonen or UKK 2-km Walk Test. RESULTS: Out of forty-six participants, 24% dropped out. Participants attended 58% of exercise sessions. All randomized participants were included in intention-to-treat (ITT) analysis. Analysis of covariance or ANCOVA showed a large reduction of depressive symptoms in HRSD-17 scores (Cohen's d: 1.8; mean change 8.2, p < .0001). BDI-II (Cohen's d: 0.50; mean change: 4.7, p = 0.09), FI scores (Cohen's d: 0.27; mean change: 5.3, p = 0.08), and VO2 max did not change significantly. CONCLUSIONS: We observed a large and clinically significant change in HRSD-17 scores. Moderate changes in BDI-II scores without clinical significance and small changes in physical fitness assessments were observed.

In-depth protein profiling of the postsynaptic density from mouse hippocampus using data-independent acquisition proteomics.

Located at neuronal terminals, the postsynaptic density (PSD) is a highly complex network of cytoskeletal scaffolding and signaling proteins responsible for the transduction and modulation of glutamatergic signaling between neurons. Using ion-mobility enhanced data-independent label-free LC-MS/MS, we established a reference proteome of crude synaptosomes, synaptic junctions, and PSD derived from mouse hippocampus including TOP3-based absolute quantification values for identified proteins. The final dataset across all fractions comprised 49 491 peptides corresponding to 4558 protein groups. Of these, 2102 protein groups were identified in highly purified PSD in at least two biological replicates. Identified proteins play pivotal roles in neurological and synaptic processes providing a rich resource for studies on hippocampal PSD function as well as on the pathogenesis of neuropsychiatric disorders. All MS data have been deposited in the ProteomeXchange with identifier PXD000590 (http://proteomecentral.proteomexchange.org/dataset/PXD000590).