MET receptor tyrosine kinase promotes the generation of functional synapses in adult cortical circuits

Loss of synapse and functional connectivity in brain circuits is associated with aging and neurodegeneration,however,few molecular mechanisms are known to intrinsically promote synaptogenesis or enhance synapse function.We have previously shown that MET receptor tyrosine kinase in the developing cortical circuits promotes dendritic growth and dendritic spine morphogenesis.To investigate whether enhancing MET in adult cortex has synapse regenerating potential,we created a knockin mouse line,in which the human MET gene expression and signaling can be turned on in adult(10–12 months)cortical neurons through doxycycline-containing chow.We found that similar to the developing brain,turning on MET signaling in the adult cortex activates small GTPases and increases spine density in prefrontal projection neurons.These findings are further corroborated by increased synaptic activity and transient generation of immature silent synapses.Prolonged MET signaling resulted in an increasedα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-Daspartate(AMPA/NMDA)receptor current ratio,indicative of enhanced synaptic function and connectivity.Our data reveal that enhancing MET signaling could be an interventional approach to promote synaptogenesis and preserve functional connectivity in the adult brain.These findings may have implications for regenerative therapy in aging and neurodegeneration conditions.

Optoelectronic Synapses Based on MXene/Violet Phosphorus van der Waals Heterojunctions for Visual‑Olfactory Crossmodal Perception

The crossmodal interaction of different senses,which is an important basis for learning and memory in the human brain,is highly desired to be mimicked at the device level for developing neuromorphic crossmodal perception,but related researches are scarce.Here,we demonstrate an optoelectronic synapse for vision-olfactory crossmodal perception based on MXene/violet phosphorus(VP)van der Waals heterojunctions.Benefiting from the efficient separation and transport of photogenerated carriers facilitated by conductive MXene,the photoelectric responsivity of VP is dramatically enhanced by 7 orders of magnitude,reaching up to 7.7 A W^(−1).Excited by ultraviolet light,multiple synaptic functions,including excitatory postsynaptic currents,pairedpulse facilitation,short/long-term plasticity and“learning-experience”behavior,were demonstrated with a low power consumption.Furthermore,the proposed optoelectronic synapse exhibits distinct synaptic behaviors in different gas environments,enabling it to simulate the interaction of visual and olfactory information for crossmodal perception.This work demonstrates the great potential of VP in optoelectronics and provides a promising platform for applications such as virtual reality and neurorobotics.

Resilience to structural and molecular changes in excitatory synapses in the hippocampus contributes to cognitive function recovery in Tg2576 mice

Plaques of amyloid-β(Aβ)and neurofibrillary tangles are the main pathological characteristics of Alzheimer’s disease(AD).However,some older adult people with AD pathological hallmarks can retain cognitive function.Unraveling the factors that lead to this cognitive resilience to AD offers promising prospects for identifying new therapeutic targets.Our hypothesis focuses on the contribution of resilience to changes in excitatory synapses at the structural and molecular levels,which may underlie healthy cognitive performance in aged AD animals.Utilizing the Morris Water Maze test,we selected resilient(asymptomatic)and cognitively impaired aged Tg2576 mice.While the enzyme-linked immunosorbent assay showed similar levels of Aβ42 in both experimental groups,western blot analysis revealed differences in tau pathology in the pre-synaptic supernatant fraction.To further investigate the density of synapses in the hippocampus of 16-18 month-old Tg2576 mice,we employed stereological and electron microscopic methods.Our findings indicated a decrease in the density of excitatory synapses in the stratum radiatum of the hippocampal CA1 in cognitively impaired Tg2576 mice compared with age-matched resilient Tg2576 and non-transgenic controls.Intriguingly,through quantitative immunoelectron microscopy in the hippocampus of impaired and resilient Tg2576 transgenic AD mice,we uncovered differences in the subcellular localization of glutamate receptors.Specifically,the density of GluA1,GluA2/3,and mGlu5 in spines and dendritic shafts of CA1 pyramidal cells in impaired Tg2576 mice was significantly reduced compared with age-matched resilient Tg2576 and non-transgenic controls.Notably,the density of GluA2/3 in resilient Tg2576 mice was significantly increased in spines but not in dendritic shafts compared with impaired Tg2576 and non-transgenic mice.These subcellular findings strongly support the hypothesis that dendritic spine plasticity and synaptic machinery in the hippocampus play crucial roles in the mechanisms of cognitive resilience in Tg2576 mice.

Therapies for Tau-associated neurodegenerative disorders:targeting molecules,synapses,and cells

Advances in experimental and computational technologies continue to grow rapidly to provide novel avenues for the treatment of neurodegenerative disorders. Despite this, there remain only a handful of drugs that have shown success in late-stage clinical trials for Tau-associated neurodegenerative disorders. The most commonly prescribed treatments are symptomatic treatments such as cholinesterase inhibitors and N-methyl-D-aspartate receptor blockers that were approved for use in Alzheimer's disease. As diagnostic screening can detect disorders at earlier time points, the field needs pre-symptomatic treatments that can prevent, or significantly delay the progression of these disorders(Koychev et al., 2019). These approaches may be different from late-stage treatments that may help to ameliorate symptoms and slow progression once symptoms have become more advanced should early diagnostic screening fail. This mini-review will highlight five key avenues of academic and industrial research for identifying therapeutic strategies to treat Tau-associated neurodegenerative disorders. These avenues include investigating(1) the broad class of chemicals termed “small molecules”;(2) adaptive immunity through both passive and active antibody treatments;(3) innate immunity with an emphasis on microglial modulation;(4) synaptic compartments with the view that Tau-associated neurodegenerative disorders are synaptopathies. Although this mini-review will focus on Alzheimer's disease due to its prevalence, it will also argue the need to target other tauopathies, as through understanding Alzheimer's disease as a Tau-associated neurodegenerative disorder, we may be able to generalize treatment options. For this reason, added detail linking back specifically to Tau protein as a direct therapeutic target will be added to each topic.

Two-Terminal Lithium-Mediated Artificial Synapses with Enhanced Weight Modulation for Feasible Hardware Neural Networks

Recently,artificial synapses involving an electrochemical reaction of Li-ion have been attributed to have remarkable synaptic properties.Three-terminal synaptic transistors utilizing Li-ion intercalation exhibits reliable synaptic characteristics by exploiting the advantage of nondistributed weight updates owing to stable ion migrations.However,the three-terminal configurations with large and complex structures impede the crossbar array implementation required for hardware neuromorphic systems.Meanwhile,achieving adequate synaptic performances through effective Li-ion intercalation in vertical two-terminal synaptic devices for array integration remains challenging.Here,two-terminal Au/LixCoO_(2)/Pt artificial synapses are proposed with the potential for practical implementation of hardware neural networks.The Au/LixCoO_(2)/Pt devices demonstrated extraordinary neuromorphic behaviors based on a progressive dearth of Li in LixCoO_(2)films.The intercalation and deintercalation of Li-ion inside the films are precisely controlled over the weight control spike,resulting in improved weight control functionality.Various types of synaptic plasticity were imitated and assessed in terms of key factors such as nonlinearity,symmetricity,and dynamic range.Notably,the LixCoO_(2)-based neuromorphic system outperformed three-terminal synaptic transistors in simulations of convolutional neural networks and multilayer perceptrons due to the high linearity and low programming error.These impressive performances suggest the vertical two-terminal Au/LixCoO_(2)/Pt artificial synapses as promising candidates for hardware neural networks.

Organic Optoelectronic Synapses for Sound Perception

The neuromorphic systems for sound perception is under highly demanding for the future bioinspired electronics and humanoid robots.However,the sound perception based on volume,tone and timbre remains unknown.Herein,organic optoelectronic synapses(OOSs)are constructed for unprecedented sound recognition.The volume,tone and timbre of sound can be regulated appropriately by the input signal of voltages,frequencies and light intensities of OOSs,according to the amplitude,frequency,and waveform of the sound.The quantitative relation between recognition factor(ζ)and postsynaptic current(I=I_(light)−I_(dark))is established to achieve sound perception.Interestingly,the bell sound for University of Chinese Academy of Sciences is recognized with an accuracy of 99.8%.The mechanism studies reveal that the impedance of the interfacial layers play a critical role in the synaptic performances.This contribution presents unprecedented artificial synapses for sound perception at hardware levels.

Changes in Synapses and Axons Demonstrated by Synaptophysin Immunohistochemistry Following Spinal Cord Compression Trauma in the Rat and Mouse

Objective and methods To evaluate synaptic changes using synaptophysin immunohistochemstry in rat and mouse, which spinal cords were subjected to graded compression trauma at the level of Th8-9. Results Normal animals showed numerous fine dots of synaptophysin immunoreactivity in the gray matter. An increase in synaptophysin immunoreactivity was observed in the neuropil and synapses at the surface of motor neurons of the anterior horns in the ThS-9 segments lost immunoreactivity at 4-hour point after trauma. The immunoreactive synapses reappeared around motor neurons at 9-day point. Unexpected accumulation of synaptophysin immunoreactivity occurred in injured axons of the white matter of the compressed spinal cord. Conclusion Synaptic changes were important components of secondary injuries in spinal cord trauma. Loss of synapses on motor neurons may be one of the factors causing motor dysfunction of hind limbs and formation of new synapses may play an import,ant role in recovery of motor function. Synaptophysin immunohistochemistry is also a good tool for studies of axonal swellings in spinal cord injuries.

Impacts of increased α-synuclein on clathrin-mediated endocytosis at synapses:implications for neurodegenerative diseases

α-Synuclein causes synaptic pathologies in several neurodegenerative diseases：Parkinson’s disease（PD）is a neurodegenerative disease that impacts the lives of millions of people worldwide.A pathological hallmark of PD,as well as dementia with Lewy bodies（DLB）and several Alzheimer’s disease variants,is the appearanceof intracellular inclusions called Lewy bodies, which contain high levels of aggregated α-synuclein,

Two types of auditory glutamatergic synapses and their implications for repairing damaged central auditory pathways

For the mammalian brain to process and decipher the rich panoply of sounds that abound in the world, nature has evolved an elegant collection of neural circuits dedicated to this task. Indeed, the complexity, variety and number of neural pathways devoted to computing auditory information is unique among sensory modalities （Kaas, 2008）. After the initial sensorineural encoding of sound at the level of the cochlea, auditory information is processed in several lower brainstem centers and eventually converges in the midbrain, at the level of the inferior colliculus （Wenstrup, 2005）, Subsequently, auditory information is transferred through the thalamus, the medial geniculate body, and then the auditory cortex （Winer et al., 2005; Razak and Fuzessery, 2010; Hackett, 2011; Lee and Sherman, 2011; Lee and Winer, 2011;

Structural changes in pyramidal cell dendrites and synapses in the unaffected side of the sensorimotor cortex following transcranial magnetic stimulation and rehabilitation training in a rat model of focal cerebral infarct

Very little is known about the effects of transcranial magnetic stimulation and rehabilitation training on pyramidal cell dendrites and synapses of the contralateral, unaffected sensorimotor cortex in a rat model of focal cerebral infarct. The present study was designed to explore the mechanisms underlying improved motor function via transcranial magnetic stimulation and rehabilitation training following cerebral infarction. Results showed that rehabilitation training or transcranial magnetic stimulation alone reduced neurological impairment in rats following cerebral infarction, as well as significantly increased synaptic curvatures and post-synaptic density in the non-injured cerebral hemisphere sensorimotor cortex and narrowed the synapse cleft width. In addition, the percentage of perforated synapses increased. The combination of transcranial magnetic stimulation and rehabilitation resulted in significantly increased total dendritic length, dendritic branching points, and dendritic density in layer V pyramidal cells of the non-injured cerebral hemisphere motor cortex. These results demonstrated that transcranial magnetic stimulation and rehabilitation training altered structural parameters of pyramidal cell dendrites and synapses in the non-injured cerebral hemisphere sensorimotor cortex, thereby improving the ability to compensate for neurological functions in rats following cerebral infarction.

Extrinsic sound stimulations and development of periphery auditory synapses

The development of auditory synapses is a key process for the maturation of heating function. However, it is still on debate regaralng wnemer the development of auditory synapses is dominated by acquired sound stimulations. In this review, we summarize relevant publications in recent decades to address this issue. Most reported data suggest that extrinsic sound stimulations do affect, but not govern the development of periphery auditory synapses. Overall, periphery auditory synapses develop and mature according to its intrinsic mechanism to build up the synaptic connections between sensory neurons and/or interneurons.

Effects of electromagnetic radiation on spatial memory and synapses in rat hippocampal CA1

In this study, we investigated the effects of mobile phone radiation on spatial learning, reference memory, and morphology in related brain regions. After the near-field radiation （0.52 1.08 W/kg） was delivered to 8-week-old Wistar rats 2 hours per day for 1 month, behavioral changes were examined using the Morris water maze. Compared with the sham-irradiated rats, the irradiated rats exhibited impaired performance. Morphological changes were investigated by examining synaptic ultrastructural changes in the hippocampus. Using the physical dissector technique, the number of pyramidal neurons, the synaptic profiles, and the length of postsynaptic densities in the CA1 region were quantified stereologically. The morphological changes included mitochondrial degenerations, fewer synapses, and shorter postsynaptic densities in the radiated rats. These findings indicate that mobile phone radiation can significantly impair spatial learning and reference memory and induce morphological changes in the hippocampal CA1 region.

Recent advances, perspectives, and challenges inferroelectric synapses

The multiple ferroelectric polarization tuned by external electric field could be used to simulate the biological synaptic weight. Ferroelectric synaptic devices have two advantages compared with other reported ones: One is that the intrinsic switching of ferroelectric domains without invoking of defect migration as in resistive oxides, contributes reliable performance in these ferroelectric synapses. Another tremendous advantage is the extremely low energy consumption because the ferroelectric polarization is manipulated by electric field which eliminates the Joule heating by current as in magnetic and phase change memories. Ferroelectric synapses have potential for the construction of low-energy and effective brain-like intelligent networks. Here we summarize recent pioneering work of ferroelectric synapses involving the structure of ferroelectric tunnel junctions (FTJs), ferroelectric diodes (FDs), and ferroelectric field effect transistors (FeFETs), respectively, and shed light on future work needed to accelerate their application for efficient neural network.

Astrocyte-Synapse Receptor Coupling in Tripartite Synapses: A Mechanism for Self-Observing Robots

A model of an intentional self-observing system is proposed based on the structure and functions of astrocyte-synapse interactions in tripartite synapses. Astrocyte-synapse interactions are cyclically organized and operate via feedforward and feedback mechanisms, formally described by proemial counting. Synaptic, extrasynaptic and astrocyte receptors are interpreted as places with the same or different quality of information processing described by the combinatorics of tritograms. It is hypothesized that receptors on the astrocytic membrane may embody intentional programs that select corresponding synaptic and extrasynaptic receptors for the formation of receptor-receptor complexes. Basically, the act of self-observation is generated if the actual environmental information is appropriate to the intended observation processed by receptor-receptor complexes. This mechanism is implemented for a robot brain enabling the robot to experience environmental information as “its own”. It is suggested that this mechanism enables the robot to generate matches and mismatches between intended observations and the observations in the environment, based on the cyclic organization of the mechanism. In exploring an unknown environment the robot may stepwise construct an observation space, stored in memory, commanded and controlled by the intentional self-observing system. Finally, the role of self-observation in machine consciousness is shortly discussed.

The functional properties of synapses made by regenerated axons across spinal cord lesion sites in lamprey

While the anatomical properties of regenerated axons across spinal cord lesion sites have been studied extensively,little is known of how the functional properties of regenerated synapses compared to those in unlesioned animals.This study aims to compare the properties of synapses made by regenerated axons with unlesioned axons using the lamprey,a model system for spinal injury research,in which functional locomotor recovery after spinal cord lesions is associated with axonal regeneration across the lesion site.Regenerated synapses below the lesion site did not differ from synapses from unlesioned axons with respect to the amplitude and duration of single excitatory postsynaptic potentials.They also showed the same activity-dependent depression over spike trains.However,regenerated synapses did differ from unlesioned synapses as the estimated number of synaptic vesicles was greater and there was evidence for increased postsynaptic quantal amplitude.For axons above the lesion site,the amplitude and duration of single synaptic inputs also did not differ significantly from unlesioned animals.However,in this case,there was evidence of a reduction in release probability and inputs facilitated rather than depressed over spike trains.Synaptic inputs from single regenerated axons below the lesion site thus do not increase in amplitude to compensate for the reduced number of descending axons after functional recovery.However,the postsynaptic input was maintained at the unlesioned level using different synaptic properties.Conversely,the facilitation from the same initial amplitude above the lesion site made the synaptic input over spike trains functionally stronger.This may help to increase propriospinal activity across the lesion site to compensate for the lesion-induced reduction in supraspinal inputs.The animal experiments were approved by the Animal Ethics Committee of Cambridge University.

Beyond vertebrates:the amphioxus as a relevant model system to explore the formation,organization,and regeneration of neuromuscular synapses

The neuromuscular junction(NMJ)is the peripheral synapse controlling muscle contraction and coordinated movement in a wide variety of animals.In humans,the mature NMJ is the primary target of morphological disassembly and functional decline in several physiological and pathological conditions,such as aging and motor diseases。

Electronic synapses based on ultrathin quasi-two-dimensional gallium oxide memristor

Synapse emulation is very important for realizing neuromorphic computing, which could overcome the energy and throughput limitations of today's computing architectures. Memristors have been extensively studied for using in nonvolatile memory storage and neuromorphic computing. In this paper, we report the fabrication of vertical sandwiched memristor device using ultrathin quasi-two-dimensional gallium oxide produced by squeegee method. The as-fabricated two-terminal memristor device exhibited the essential functions of biological synapses, such as depression and potentiation of synaptic weight, transition from short time memory to long time memory, spike-timing-dependent plasticity, and spike-rate-dependent plasticity. The synaptic weight of the memristor could be tuned by the applied voltage pulse, number,width, and frequency. We believe that the injection of the top Ag cations should play a significant role for the memristor phenomenon. The ultrathin of medium layer represents an advance to integration in vertical direction for future applications and our results provide an alternative way to fabricate synaptic devices.

Distinct effect of potassium 2-(l-hydroxypentyl) - benzoate on hippocampal neurons, synapses and dystrophic axons in APP/PS1 mice

OBJECTIVE To study the protective effect of potassium 2-(l-hydroxypentyl)-benzoate(PHPB) on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice.METHODS Ten-month-old male APP/PS1 transgenic mice and age-matched wild-type mice were randomly divided into three groups:wild-type group(WT Con group,n=10),APP/PS1 group(Tg Con group,n=10) and PHPB treated APP/PS1 group(PHPB group,n=10).PHPB group received 30 mg · kg-1 PHPB by oral gavage once daily for 3 months.WT Con group and Tg Con group received the same volume of water.Three months later,mice were sacrificed for biochemical and pathological testing such as transmission electron microscopy,Golgi staining and Western boltting analysis.RESULTS Under the transmission electron microscope,most hippocampal neurons and subcel ular organel es in WT Con group exhibited normal morphology.However,the degenerative changes were observed in Tg Con group such as nuclear fragmentation,mitochondrial swelling,ribosomes detachment and autophagic vacuoles accumulation.The hippocampal synapses number and the thickness of postsynaptic density(PSD) were significantly decreased in Tg Con group compared with the WT Con group(P<0.05).After PHPB treatment,the degenerative changes in APP/PS1 mice were alleviated to some extent.The synapse number has been elevated significantly(P<0.05) and the PSD has been thickened as well.Golgi staining showed that the spine density of secondary and tertiary apical dendritic branches was significantly decreased in CA1 and DG areas of Tg Con group(P<0.05).Sholl analysis revealed a decrease of dendritic complexity in Tg Con group compared with WT Con group(P<0.05).These abnormalities were alleviated to some extent after PHPB treatment.Western blotting study showed that the protein levels of synaptic marker PSD-95 and synaptophysin were significantly decreased in the hippocampus of Tg Con group(P<0.05).A significant increase of PSD-95(P<0.05) and a slight increase of SYP were observed after the PHPB treatment.Besides,we found a significant increase in the ratio of LC3-Ⅱ/LC3-Ⅰ in Tg Con group compared with the WT Con group(P<0.01) and the relevant improvement after PHPB treatment(P<0.05),which showed the regulatory effect of PHPB on autophagy impairment.CONCLUSION PHPB showed protective effects on hippocampal neurons,synapses and dystrophic axons in APP/PS1 mice,which might help explain its role on cognitive improvement in Alzheimer disease treatment.

Plastic Changes of Synapses and Excitatory Neurotransmitter Receptors in Facial Nucleus Following Facial-facial Anastomosis

The remodeling process of synapses and neurotransmitter receptors of facial nucleus were observed. Models were set up by facial-facial anastomosis in rat. At post-surgery day （PSD） 0,7,21and 60, synaptophysin （p38）, NMDA receptor subunit 2A and AMPA receptor subunit 2 （GluR2） were observed by immunohistochemical method and semi-quantitative RT-PCR, respectively. Mean-while, the synaptic structure of the facial motorneurons was observed under a transmission electron microscope （TEM）. The intensity of p38 immunoreactivity was decreased, reaching the lowest value at PSD day 7, and then increased slightly at PSD 21. Ultrastructurally, the number of synapses in nucleus of the operational side decreased, which was consistent with the change in P38 immunoreactivity. NMDAR2A mRNA was down-regulated significantly in facial nucleus after the operation （P〈0.05）, whereas AMPAR2 mRNA levels remained unchanged （P〉0.05）. The synapses innervation and the expression of NMDAR2A and AMPAR2 mRNA in facial nucleus might be modified to suit for the new motor tasks following facial-facial anastomosis, and influenced facial nerve regeneration and recovery.

ICAM-1 depletion in the center of immunological synapses is important for calcium releasing in T-cells

T-cell activation requires the formation of the immunological sy napse(IS)bet ween a T-cll and anantigen-presenting cell(AP C)to control the development of the adaptive immune response.How-ever,calcium release,an initial signal of T-cell activation,has been found to occur before IS for-mation.The mechanism for triggering the calcium signaling and relationship bet ween calciumrelease and IS format ion remains unclear.Herein,using live-cell imaging,we found that int ercellularadhesion molecule 1(ICAM-1),an essential mdlecule for IS formation,accumulated and then wasdepleted at the center of the synapse before complete IS formation.During the proces of ICAM1depletion,calcium was released.if ICAM-1 failed to be depleted from the center of the synapse,thesustained calcium signaling could not be induced.Moreover,depletion of ICAM-1 in ISs preferen-tially ccurred with the contact of antigen-specific T-cels and dendritic clls(DCs).Blocking thebinding ofICA M-1 and lymphocy te finction-associated antigen 1(LFA-1),ICAM-1 failed to depleteat the center of the synapse,and calcium release in T-clls decreased.In studying the mechanism ofhow the depletion ofiCA M1 could influence calcium release in T-clls,we found that the movementof ICAM-1 was associat ed with the localization of LFA-1 in the IS,which afected the localization ofcalcium microdomains,ORAIl and mitochondria in IS.Therefore,the depletion of ICAM-1 in the center of the synapse is an important factor for an initial sust ained calcium release in T-cells.