Transmission Imbalance Research Articles

Advances in the understanding of the pathophysiology of schizophrenia and bipolar disorder through induced pluripotent stem cell models.

The pathophysiology of schizophrenia and bipolar disorder involves a complex interaction between genetic and environmental factors that begins in the early stages of neurodevelopment. Recent advancements in the field of induced pluripotent stem cells (iPSCs) offer a promising tool for understanding the neurobiological alterations involved in these disorders and, potentially, for developing new treatment options. In this review, we summarize the results of iPSC-based research on schizophrenia and bipolar disorder, showing disturbances in neurodevelopmental processes, imbalance in glutamatergic-GABAergic transmission and neuromorphological alterations. The limitations of the reviewed literature are also highlighted, particularly the methodological heterogeneity of the studies, the limited number of studies developing iPSC models of both diseases simultaneously, and the lack of in-depth clinical characterization of the included samples. Further studies are needed to advance knowledge on the common and disease-specific pathophysiological features of schizophrenia and bipolar disorder and to promote the development of new treatment options.

Characterization of sensory and motor dysfunction and morphological alterations in late stages of type 2 diabetic mice.

Diabetic neuropathy is the most common complication of diabetes and lacks effective treatments. Although sensory dysfunction during the early stages of diabetes has been extensively studied in various animal models, the functional and morphological alterations in sensory and motor systems during late stages of diabetes remain largely unexplored. In the current work, we examined the influence of diabetes on sensory and motor function as well as morphological changes in late stages of diabetes. The obese diabetic Leprdb/db mice (db/db) were used for behavioral assessments and subsequent morphological examinations. The db/db mice exhibited severe sensory and motor behavioral defects at the age of 32 weeks, including significantly higher mechanical withdrawal threshold and thermal latency of hindpaws compared with age-matched nondiabetic control animals. The impaired response to noxious stimuli was mainly associated with the remarkable loss of epidermal sensory fibers, particularly CGRP-positive nociceptive fibers. Unexpectedly, the area of CGRP-positive terminals in the spinal dorsal horn was dramatically increased in diabetic mice, which was presumably associated with microglial activation. In addition, the db/db mice showed significantly more foot slips and took longer time during the beam-walking examination compared with controls. Meanwhile, the running duration in the rotarod test was markedly reduced in db/db mice. The observed sensorimotor deficits and motor dysfunction were largely attributed to abnormal sensory feedback and muscle atrophy as well as attenuated neuromuscular transmission in aged diabetic mice. Morphological analysis of neuromuscular junctions (NMJs) demonstrated partial denervation of NMJs and obvious fragmentation of acetylcholine receptors (AChRs). Intrafusal muscle atrophy and abnormal muscle spindle innervation were also detected in db/db mice. Additionally, the number of VGLUT1-positive excitatory boutons on motor neurons was profoundly increased in aged diabetic mice as compared to controls. Nevertheless, inhibitory synaptic inputs onto motor neurons were similar between the two groups. This excitation-inhibition imbalance in synaptic transmission might be implicated in the disturbed locomotion. Collectively, these results suggest that severe sensory and motor deficits are present in late stages of diabetes. This study contributes to our understanding of mechanisms underlying neurological dysfunction during diabetes progression and helps to identify novel therapeutic interventions for patients with diabetic neuropathy.

COSMOGLOBE DR1 results

We present COSMOGLOBEData Release 1, which implements the first joint analysis of WMAP andPlanckLFI time-ordered data, processed within a single Bayesian end-to-end framework. This framework directly builds on a similar analysis of the LFI measurements by the BEYONDPLANCKcollaboration, and approaches the cosmic microwave background (CMB) analysis challenge through Gibbs sampling of a global posterior distribution, simultaneously accounting for calibration, mapmaking, and component separation. The computational cost of producing one complete WMAP+LFI Gibbs sample is 812 CPU-h, of which 603 CPU-h are spent on WMAP low-level processing; this demonstrates that end-to-end Bayesian analysis of the WMAP data is computationally feasible. We find that our WMAP posterior mean temperature sky maps and CMB temperature power spectrum are largely consistent with the official WMAP9 results. Perhaps the most notable difference is that our CMB dipole amplitude is 3366.2 ± 1.4 μK, which is 11 μK higher than the WMAP9 estimate and 2.5σhigher than BEYONDPLANCK; however, it is in perfect agreement with the HFI-dominatedPlanckPR4 result. In contrast, our WMAP polarization maps differ more notably from the WMAP9 results, and in general exhibit significantly lower large-scale residuals. We attribute this to a better constrained gain and transmission imbalance model. It is particularly noteworthy that theW-band polarization sky map, which was excluded from the official WMAP cosmological analysis, for the first time appears visually consistent with theV-band sky map. Similarly, the long standing discrepancy between the WMAPK-band and LFI 30 GHz maps is finally resolved, and the difference between the two maps appears consistent with instrumental noise at high Galactic latitudes. Relatedly, these updated maps allowed us for the first time to combine WMAP and LFI polarization data into a single coherent model of large-scale polarized synchrotron emission. Still, we identified a few issues that require additional work, including (1) low-level noise modeling; (2) large-scale temperature residuals at the 1–2 μK level; and (3) a strong degeneracy between the absoluteK-band calibration and the dipole of the anomalous microwave emission component. We conclude that leveraging the complementary strengths of WMAP and LFI has allowed the mitigation of both experiments’ weaknesses, and resulted in new state-of-the-art WMAP sky maps. All maps and the associated code are made publicly available through the COSMOGLOBEweb page.

From BEYONDPLANCK to COSMOGLOBE: Preliminary WMAP Q-band analysis

We present the first application of the COSMOGLOBE analysis framework by analyzing nine-year WMAP time-ordered observations that uses similar machinery to that of BEYONDPLANCK for the Planck Low Frequency Instrument (LFI). We analyzed only the Q-band (41 GHz) data and report on the low-level analysis process based on uncalibrated time-ordered data to calibrated maps. Most of the existing BEYONDPLANCK pipeline may be reused for WMAP analysis with minimal changes to the existing codebase. The main modification is the implementation of the same preconditioned biconjugate gradient mapmaker used by the WMAP team. Producing a single WMAP Q1-band sample requires 22 CPU-hrs, which is slightly more than the cost of a Planck 44 GHz sample of 17 CPU-hrs; this demonstrates that a full end-to-end Bayesian processing of the WMAP data is computationally feasible. In general, our recovered maps are very similar to the maps released by the WMAP team, although with two notable differences. In terms of temperature, we find a ∼2 μK quadrupole difference that most likely is caused by different gain modeling, while in polarization we find a distinct 2.5 μK signal that has been previously referred to as poorly measured modes by the WMAP team. In the COSMOGLOBE processing, this pattern arises from temperature-to-polarization leakage from the coupling between the CMB Solar dipole, transmission imbalance, and sidelobes. No traces of this pattern are found in either the frequency map or TOD residual map, suggesting that the current processing has succeeded in modeling these poorly measured modes within the assumed parametric model by using Planck information to break the sky-synchronous degeneracies inherent in the WMAP scanning strategy.

Dopamine Transmission Imbalance in Neuroinflammation: Perspectives on Long-Term COVID-19.

Dopamine (DA) is a key neurotransmitter in the basal ganglia, implicated in the control of movement and motivation. Alteration of DA levels is central in Parkinson's disease (PD), a common neurodegenerative disorder characterized by motor and non-motor manifestations and deposition of alpha-synuclein (α-syn) aggregates. Previous studies have hypothesized a link between PD and viral infections. Indeed, different cases of parkinsonism have been reported following COVID-19. However, whether SARS-CoV-2 may trigger a neurodegenerative process is still a matter of debate. Interestingly, evidence of brain inflammation has been described in postmortem samples of patients infected by SARS-CoV-2, which suggests immune-mediated mechanisms triggering the neurological sequelae. In this review, we discuss the role of proinflammatory molecules such as cytokines, chemokines, and oxygen reactive species in modulating DA homeostasis. Moreover, we review the existing literature on the possible mechanistic interplay between SARS-CoV-2-mediated neuroinflammation and nigrostriatal DAergic impairment, and the cross-talk with aberrant α-syn metabolism.

Fairness-Based Multi-AP Coordination Using Federated Learning in Wi-Fi 7.

Federated learning is a type of distributed machine learning in which models learn by using large-scale decentralized data between servers and devices. In a short-range wireless communication environment, it can be difficult to apply federated learning because the number of devices in one access point (AP) is small, which can be small enough to perform federated learning. Therefore, it means that the minimum number of devices required to perform federated learning cannot be matched by the devices included in one AP environment. To do this, we propose to obtain a uniform global model regardless of data distribution by considering the multi-AP coordination characteristics of IEEE 802.11be in a decentralized federated learning environment. The proposed method can solve the imbalance in data transmission due to the non-independent and identically distributed (non-IID) environment in a decentralized federated learning environment. In addition, we can also ensure the fairness of multi-APs and determine the update criteria for newly elected primary-APs by considering the learning training time of multi-APs and energy consumption of grouped devices performing federated learning. Thus, our proposed method can determine the primary-AP according to the number of devices participating in the federated learning in each AP during the initial federated learning to consider the communication efficiency. After the initial federated learning, fairness can be guaranteed by determining the primary-AP through the training time of each AP. As a result of performing decentralized federated learning using the MNIST and FMNIST dataset, the proposed method showed up to a 97.6% prediction accuracy. In other words, it can be seen that, even in a non-IID multi-AP environment, the update of the global model for federated learning is performed fairly.

Further delineation and long-term evolution of electroclinical phenotype in Mowat Wilson Syndrome. A longitudinal study in 40 individuals

BackgroundEpilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population. MethodsForty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0–4; t2 = 5–12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed. ResultsThirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5–13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures.Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam. ConclusionsEpilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.

Enabling Wavelength-Dependent Adjoint-Based Methods for Process Variation Sensitivity Analysis in Silicon Photonics

To reach its potential as an emerging technology platform, integrated silicon photonics needs accompanying design-for-manufacturability (DFM) methods and tools to assist the design of silicon photonic devices and circuits. Here, we explore spatial sampling in adjoint-based methods for analysis of the sensitivity of photonic components against key fabrication process variations. We apply and test these spatial sampling adjoint analysis methods to examine the impact of line edge roughness (LER) on a passive Y-branch at a given operating wavelength, achieving about 3% relative error. We extend the approach to also study LER variation sensitivity across a range of wavelengths and validate our results with ensemble virtual fabrication and FDTD simulations. The adjoint sensitivity and variance estimation of Y-branch transmission imbalance is seen to be highly efficient in comparison to direct ensemble simulation, with consistent results in the 95% confidence interval.

Anxiolytic Effects of 8-O-Acetyl Shanzhiside Methylester on Acute and Chronic Anxiety via Inflammatory Response Inhibition and Excitatory/Inhibitory Transmission Imbalance

Anxiety leads to a global decline in quality of life and increase in social burden. However, treatments are limited, because the molecular mechanisms underlying complex emotional disorders are poorly understood. We explored the anxiolytic effects of 8-O-acetyl shanzhiside methylester (8-OaS), an active component in Lamiophlomis rotata (L. rotata; Benth.) or Kudo, a traditional herb that has been shown to be effective in the clinical treatment of chronic pain syndromes in China. Two mouse anxiety models were used: forced swimming stress (FSS)–induced anxiety and complete Freund’s adjuvant (CFA)–induced chronic inflammatory pain. All animal behaviors were analyzed on the elevated plus maze and in the open-field test. 8-OaS significantly ameliorated anxiety-like behaviors in both anxiety models and inhibited the translation enhancement of GluN2A, GluN2B, and PSD95. Moreover, a reduction in GABA receptors disrupted the excitatory/inhibitory (E/I) balance in the basolateral amygdala (BLA), indicated by increased excitatory and decreased inhibitory presynaptic release. 8-OaS also blocked microglia activation and reduced the phosphorylation of p38, c-Jun N-terminal kinase (JNK), NF-κB p65, and tumor necrosis factor alpha (TNF-α) in the BLA of anxiety mice. 8-OaS exhibits obvious anxiolytic effects by regulating the excitatory/inhibitory (E/I) synaptic transmission and attenuating inflammatory responses in the BLA.

Afferent-efferent connectivity between auditory brainstem and cortex accounts for poorer speech-in-noise comprehension in older adults

Speech-in-noise (SIN) comprehension deficits in older adults have been linked to changes in both subcortical and cortical auditory evoked responses. However, older adults' difficulty understanding SIN may also be related to an imbalance in signal transmission (i.e., functional connectivity) between brainstem and auditory cortices. By modeling high-density scalp recordings of speech-evoked responses with sources in brainstem (BS) and bilateral primary auditory cortices (PAC), we show that beyond attenuating neural activity, hearing loss in older adults compromises the transmission of speech information between subcortical and early cortical hubs of the speech network. We found that the strength of afferent BS→PAC neural signaling (but not the reverse efferent flow; PAC→BS) varied with mild declines in hearing acuity and this “bottom-up” functional connectivity robustly predicted older adults’ performance in a SIN identification task. Connectivity was also a better predictor of SIN processing than unitary subcortical or cortical responses alone. Our neuroimaging findings suggest that in older adults (i) mild hearing loss differentially reduces neural output at several stages of auditory processing (PAC > BS), (ii) subcortical-cortical connectivity is more sensitive to peripheral hearing loss than top-down (cortical-subcortical) control, and (iii) reduced functional connectivity in afferent auditory pathways plays a significant role in SIN comprehension problems.

Compact optical 90° hybrid based on hybrid plasmonic multimode interferometer

This paper presents an optical 90° hybrid based on a general 4×4 multimode interferometer (MMI), which is realized on hybrid plasmonic waveguides (HPW). First, we analyze the propagation characteristics of multi-order hybrid plasmonic modes in the HPW-MMI, and reveal that the optimal positions of self-images would shift from the theoretical ones. By optimizing the thickness of the dielectric interlayer of the HPW structure, the width and length of the multimode section, and especially by adjusting the position of the input and output waveguides, this HPW hybrid shows a maximum phase error of 0.7°, a transmission imbalance of 0.6 dB, and CMRRs of below −20 dB at the wavelength of 1550 nm.

Silicon-nanowire-based optical hybrid with insensitive operation for TE/TM states of polarization

An optical 90° hybrid consisting of a polarization splitter–rotator (PSR) and a multimode interferometer (MMI) is proposed to realize insensitive optical frequency mixing for TE/TM states of polarization. The PSR is based on the mode hybridization and mode coupling between waveguides; input light at a fundamental transverse electric (TE) mode and a transverse magnetic (TM) mode are output at separate ports, but both output signals are in the fundamental TE mode. These two output fields are then guided to the MMI, where the optical frequency mixing with the light of a local oscillator takes place. This mixing is then independent of the state of polarization of the hybrid input light. We designed such an optical hybrid based on silicon-nanowire waveguides. At a wavelength of 1540nm, simulation results for the hybrid show a transmission efficiency of 98.6% or 95.8% for TE- or TM-polarized input light, respectively, while the transmission efficiencies for both polarizations are above 90% in a 30nm wavelength range, namely [1525nm, 1555nm]. Further, in the wavelength range [1510nm, 1565nm], the transmission imbalance between the output fields is below 0.85dB for TE- or TM-polarized input light, respectively, while the phase errors in both cases are less than 4°.

Asymmetry of parental origin in long QT syndrome: preferential maternal transmission of KCNQ1 variants linked to channel dysfunction.

Transmission distortion of disease-causing alleles in long QT syndrome (LQTS) has been reported, suggesting a potential role of KCNQ1 and KCNH2 in reproduction. This study sought to investigate parental transmission in LQTS families according to ethnicity, gene loci (LQT1-3: KCNQ1, KCNH2, and SCN5A) or severity of channel dysfunction. We studied 3782 genotyped members from 679 European and Japanese LQTS families (2748 carriers). We determined grandparental and parental origins of variant alleles in 1903 children and 624 grandchildren, and the grandparental origin of normal alleles in healthy children from 44 three-generation control families. LQTS alleles were more of maternal than paternal origin (61 vs 39%, P<0.001). The ratio of maternally transmitted alleles in LQT1 (66%) was higher than in LQT2 (56%, P<0.001) and LQT3 (57%, P=0.03). Unlike the Mendelian distribution of grandparental alleles seen in control families, variant grandparental LQT1 and LQT2 alleles in grandchildren showed an excess of maternally transmitted grandmother alleles. For LQT1, maternal transmission differs according to the variant level of dysfunction with 68% of maternal transmission for dominant negative or unknown functional consequence variants vs 58% for non-dominant negative and variants leading to haploinsufficiency, P<0.01; however, for LQT2 or LQT3 this association was not significant. An excess of disease-causing alleles of maternal origin, most pronounced in LQT1, was consistently found across ethnic groups. This observation does not seem to be linked to an imbalance in transmission of the LQTS subtype-specific grandparental allele, but to the potential degree of potassium channel dysfunction.

Reduced perceptual exclusivity during object and grating rivalry in autism.

The dynamics of binocular rivalry may be a behavioral footprint of excitatory and inhibitory neural transmission in visual cortex. Given the presence of atypical visual features in Autism Spectrum Conditions (ASC), and the growing evidence in support of the idea of an imbalance in excitatory/inhibitory neural transmission in animal and genetic models of ASC, we hypothesized that binocular rivalry might prove a simple behavioral marker of such a transmission imbalance in the autistic brain. In support of this hypothesis, we previously reported a slower rate of rivalry in ASC, driven by longer transitional states between dominant percepts. We tested whether atypical dynamics of binocular rivalry in ASC are specific to certain stimulus features. 53 participants (26 with ASC, matched for age, sex, and IQ) participated in a binocular rivalry experiment in which the dynamics of rivalry were measured at two levels of stimulus complexity, low (grayscale gratings) and high (colored objects). Individuals with ASC experienced a slower rate of binocular rivalry, driven by longer transitional states between dominant percepts. These exaggerated transitional states were present at both low and high levels of stimulus complexity (gratings and objects), suggesting that atypical binocular dynamics in autism are robust with respect to stimulus choice. Interactions between stimulus properties and rivalry dynamics in autism indicate that achromatic grating stimuli produce stronger group differences. These results confirm the finding of atypical dynamics of binocular rivalry in ASC. These dynamics were present for stimuli of both low and high levels of visual complexity, suggesting a pervasive imbalance in competitive interactions throughout the visual system of individuals with ASC.

Genetic Evidence for the Adhesion Protein IgSF9/Dasm1 to Regulate Inhibitory Synapse Development Independent of its Intracellular Domain

Normal brain function requires balanced development of excitatory and inhibitory synapses. An imbalance in synaptic transmission underlies many brain disorders such as epilepsy, schizophrenia, and autism. Compared with excitatory synapses, relatively little is known about the molecular control of inhibitory synapse development. We used a genetic approach in mice to identify the Ig superfamily member IgSF9/Dasm1 as a candidate homophilic synaptic adhesion protein that regulates inhibitory synapse development. IgSF9 is expressed in pyramidal cells and subsets of interneurons in the CA1 region of hippocampus. Electrophysiological recordings of acute hippocampal slices revealed that genetic inactivation of the IgSF9 gene resulted in fewer functional inhibitory synapses; however, the strength of the remaining synapses was unaltered. These physiological abnormalities were correlated with decreased expression of inhibitory synapse markers in IgSF9(-/-) mice, providing anatomical evidence for a reduction in inhibitory synapse numbers, whereas excitatory synapse development was normal. Surprisingly, knock-in mice expressing a mutant isoform of IgSF9 lacking the entire cytoplasmic domain (IgSF9(ΔC/ΔC) mice) had no defects in inhibitory synapse development, providing genetic evidence that IgSF9 regulates synapse development via ectodomain interactions rather than acting itself as a signaling receptor. Further, we found that IgSF9 mediated homotypic binding and cell aggregation, but failed to induce synapse formation, suggesting that IgSF9 acts as a cell adhesion molecule (CAM) to maintain synapses. Juvenile IgSF9(-/-) mice exhibited increased seizure susceptibility indicative of an imbalance in synaptic excitation and inhibition. These results provide genetic evidence for a specific role of IgSF9 in inhibitory synapse development/maintenance, presumably by its CAM-like activity.

Decreased pain threshold and enhanced synaptic transmission in the anterior cingulate cortex of experimental hypothyroidism mice.

BackgroundThyroid hormones are essential for the maturation and functions of the central nervous system. Pain sensitivity is related to the thyroid status. However, information on how thyroid hormones affect pain processing and synaptic transmission in the anterior cingulate cortex (ACC) is limited. Nociceptive threshold and synaptic transmission in the ACC were detected in the experimental hypothyroidism (HT) mice.ResultsHT was induced by methimazole and potassium perchlorate in distilled drinking water for 4 weeks. The threshold of pain perception to hot insults, but not mechanical ones, decreased in hypothyroid mice. After treatment with tri-iodothyronine (T3) or thyroxine (T4) for 2 weeks, thermal pain threshold recovered. Electrophysiological recordings revealed enhanced glutamatergic synaptic transmission and reduced GABAergic synaptic transmission in the ACC. Supplementation with T3 or T4 significantly rescued this synaptic transmission imbalance. In the same model, HT caused the up-regulation of the GluR1 subunit of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor and NR2B-containing N-methyl-D-aspartate receptors, but it down-regulated γ-aminobutyric acid A receptors in the ACC. Supplementation with T3 or T4 notably recovered the levels of above proteins.ConclusionsThese results suggest that HT promotes hypersensitivity to noxious thermal, and that supplementation with T3 or T4 rescues the imbalance between excitatory and inhibitory transmission in the ACC.

Synaptic plasticity in glutamatergic and GABAergic neurotransmission following chronic memantine treatment in an in vitro model of limbic epileptogenesis

Chronic N-methyl-d-aspartate receptor (NMDAR) blockade with high affinity competitive and uncompetitive antagonists can lead to seizure exacerbation, presumably due to an imbalance in glutamatergic and GABAergic transmission. Acute administration of the moderate affinity NMDAR antagonist memantine in vivo has been associated with pro- and anticonvulsive properties. Chronic treatment with memantine can exacerbate seizures. Therefore, we hypothesized that chronic memantine treatment would increase glutamatergic and decrease GABAergic transmission, similar to high affinity competitive and uncompetitive antagonists. To test this hypothesis, organotypic hippocampal slice culture were treated for 17–21 days with memantine and then subjected to electrophysiological recordings. Whole-cell recordings from dentate granule cells revealed that chronic memantine treatment slightly, but significantly increased sEPSC frequency, mEPSC amplitude and mEPSC charge transfer, consistent with minimally increased glutamatergic transmission. Chronic memantine treatment also increased both sIPSC and mIPSC frequency and amplitude, suggestive of increased GABAergic transmission. Results suggest that a simple imbalance between glutamatergic and GABAergic neurotransmission may not underlie memantine's ictogenic properties. That said, glutamatergic and GABAergic transmission were assayed independently of one another in the current study. More complex interactions between glutamatergic and GABAergic transmission may prevail under conditions of intact circuitry.

Brain inflammation induces post-synaptic changes during early synapse formation in adult-born hippocampal neurons

An inflammatory reaction in the brain is primarily characterized by activation of parenchymal microglial cells. Microglia regulate several aspects of adult neurogenesis, i.e. the continuous production of new neurons in the adult brain. Hippocampal neurogenesis is thought to be important for memory formation, but its role in brain diseases is not clear. We have previously shown that brain inflammation modulates the functional integration of newly formed hippocampal neurons. Here, we explored whether there is a defined time period during synaptic development when new neurons are susceptible to brain inflammation. Newly formed hippocampal neurons, born in an intact environment in the adult mouse brain, were exposed to lipopolysaccharide (LPS)-induced inflammation during either early or late phases of excitatory and inhibitory synaptogenesis. We used intra-hippocampal injections of GFP-retroviral vector (RV-GFP) to label the new neurons and ipsilateral LPS injection at either 1 or 4weeks post-RV-GFP injection. A single intra-hippocampal LPS injection induced an inflammatory response for at least 3weeks, including an acute transient pro-inflammatory cytokine release as well as a sub-acute and sustained change in microglial morphology. The general cytoarchitecture of the hippocampal dentate gyrus, including granule cell layer (GCL) volume, and astrocytic glial fibrillary acidic protein expression was not different compared to vehicle controls, and no Fluoro-Jade-positive cell death was observed. New neurons encountering this inflammatory environment exhibited no changes in their gross morphology. However, when inflammation occurred during early stages of synapse formation, we found a region-specific increase in the number of thin dendritic spines and post-synaptic density-95 (PSD-95) cluster formation on spines, suggesting an enhanced excitatory synaptic connectivity in the newborn neurons. No changes were observed in the expression of N-cadherin, an adhesion molecule primarily associated with excitatory synapses. At the inhibitory synapses, alterations due to inflammation were also evident during early but not later stages of synaptic development. Gephyrin, an inhibitory scaffolding protein, was down-regulated in the somatic region, while the adhesion molecules neuroligin-2 (NL-2) and neurofascin were increased in the somatic region and/or on the dendrites. The GABAA receptor-α2 subunit (GABAAR-α2) was increased, while pre/peri-synaptic GABA clustering remained unaltered. The disproportional changes in post-synaptic adhesion molecules and GABAA receptor compared to scaffolding protein expression at the inhibitory synapses during brain inflammation are likely to cause an imbalance in GABAergic transmission. These changes were specific for the newborn neurons and were not observed when estimating the overall expression of gephyrin, NL-2, and GABAAR-α2 in the hippocampal GCL. The expression of interleukin-1-type 1 receptor (IL-1R1) on preferentially the somatic region of new neurons, often in close apposition to NL-2 clusters, may indicate a direct interaction between brain inflammation and synaptic proteins on newborn neurons. In summary, this study provides evidence that adult-born hippocampal neurons alter their inhibitory and excitatory synaptic integration when encountering an LPS-induced brain inflammation during the initial stages of synapse formation. Changes at this critical developmental period are likely to interfere with the physiological functions of new neurons within the hippocampus.

A compact thermo-optical multimode-interference silicon-based 1×4 nano-photonic switch

An ultra-compact multimode-interference (MMI)-based 1 × 4 nano-photonic switch is demonstrated by employing silicon thermo-optical effect on SOI platform. The device performance is systematically characterized by comprehensively investigating the constituent building blocks, including 1 × 4 power splitter, 4 × 4 MMI coupler and groove-isolated thermo-optical heaters. An instructive model is established to statistically estimate the required power consumption and investigate the influence of the power imbalance of the 4 × 4 MMI coupler on the switching performance. At the designed wavelength of 1550 nm, the average insertion loss of different switching states is 1.7 dB, and the transmission imbalance is 1.05 dB. The worst extinction ratio and crosstalk of all the output ports reach 11.48 dB and -11.38 dB, respectively.

A Similar but Distinctive Pattern of Impaired Cortical Excitability in First-Episode Schizophrenia and ADHD

Background: First-episode schizophrenia (FE-SZ) and attention deficit hyperactivity disorder (ADHD) are both neuropsychiatric disorders associated with an impaired dopaminergic transmission. Though displaying different clinical phenotypes, a common pathophysiological pathway is discussed controversially. Several studies using transcranial magnetic stimulation (TMS) revealed abnormalities in human motor cortex excitability in both schizophrenia and ADHD patients. Studies on cortical excitability comparing these two diseases directly are lacking. Method: In this study, a total of 94 subjects were analyzed. Twenty-five FE-SZ patients were directly compared with 28 ADHD patients and 41 healthy controls (HC). We investigated cortical excitability (inhibitory and facilitatory networks) with single- and paired-pulse TMS to the left and right motor cortex. Results: Compared to HC, FE-SZ/ADHD patients displayed an impaired cortical inhibition over the left hemisphere. Apart from an enhanced intracortical facilitation, FE-SZ patients did not differ compared to ADHD patients in the main outcome measures. Both patient groups presented a dysfunctional hemispheric pattern of cortical inhibition and facilitation in comparison with HC. Conclusion: The results of this study indicate a pattern of cortical disinhibition and abnormal hemispheric balance of intracortical excitability networks in two different psychiatric diseases. These effects might be associated with an imbalance in GABAergic and dopaminergic transmission and might provide evidence for a common pathophysiological pathway of both diseases.