Synaptic Function Research Articles

Differential functions of phosphatidylinositol 4-kinases in neurotransmission and synaptic development.

Phosphoinositides, such as PI(4,5)P2, are known to function as structural components of membranes, signalling molecules, markers of membrane identity, mediators of protein recruitment and regulators of neurotransmission and synaptic development. Phosphatidylinositol 4-kinases (PI4Ks) synthesize PI4P, which are precursors for PI(4,5)P2, but may also have independent functions. The roles of PI4Ks in neurotransmission and synaptic development have not been studied in detail. Previous studies on PI4KII and PI4KIIIβ at the Drosophila larval neuromuscular junction have suggested that PI4KII and PI4KIIIβ enzymes may serve redundant roles, where single PI4K mutants yielded mild or no synaptic phenotypes. However, the precise synaptic functions (neurotransmission and synaptic growth) of these PI4Ks have not been thoroughly studied. Here, we used PI4KII and PI4KIIIβ null mutants and presynaptic-specific knockdowns of these PI4Ks to investigate their roles in neurotransmission and synaptic growth. We found that PI4KII and PI4KIIIβ appear to have non-overlapping functions. Specifically, glial PI4KII functions to restrain synaptic growth, whereas presynaptic PI4KIIIβ promotes synaptic growth. Furthermore, loss of PI4KIIIβ or presynaptic PI4KII impairs neurotransmission. The data presented in this study uncover new roles for PI4K enzymes in neurotransmission and synaptic growth.

Linking activation of synaptic NMDA receptors-induced CREB signaling to brief exposure of cortical neurons to oligomeric amyloid-beta peptide.

Amyloid-beta peptide oligomers (AβO) have been considered "primum movens" for a cascade of events that ultimately cause selective neuronal death in Alzheimer's disease (AD). However, initial events triggered by AβO have not been clearly defined. Synaptic (Syn) N-methyl-d-aspartate receptors (NMDAR) are known to activate cAMP response element-binding protein (CREB), a transcriptional factor involved in gene expression related to cell survival, memory formation and synaptic plasticity, whereas activation of extrasynaptic (ESyn) NMDARs was linked to excitotoxic events. In AD brain, CREB phosphorylation/activation was shown to be altered, along with dyshomeostasis of intracellular Ca2+ (Ca2+ i). Thus, in this work, we analyze acute/early and long-term AβO-mediated changes in CREB activation involving Syn or ESyn NMDARs in mature rat cortical neurons. Our findings show that acute AβO exposure produce early increase in phosphorylated CREB, reflecting CREB activity, in a process occurring through Syn NMDAR-mediated Ca2+ influx. Data also demonstrate that AβO long-term (24 h) exposure compromises synaptic function related to Ca2+-dependent CREB phosphorylation/activation and nuclear CREB levels and related target genes, namely Bdnf, Gadd45γ, and Btg2. Data suggest a dual effect of AβO following early or prolonged exposure in mature cortical neurons through the activation of the CREB signaling pathway, linked to the activation of Syn NMDARs.

Solution-Processed Polymer Memcapacitors with Stimulus-Controlled and Evolvable Synaptic Functionalities: From Short-Term Plasticity to Long-Term Plasticity to Metaplasticity.

In the vanguard of neuromorphic engineering, we develop a paradigm of biocompatible polymer memcapacitors using a seamless solution process, unleashing comprehensive synaptic capabilities depending on both the stimulation form and history. Like the human brain to learn and adapt, the memcapacitors exhibit analogue-type and evolvable capacitance shifts that mirror the complex flexibility of synaptic strengthening and weakening. With increasing frequency and intensity of the stimulation, the memcapacitors demonstrate an evolution from short-term plasticity (STP) to long-term plasticity (LTP), and even to metaplasticity (MP) at a higher level. A physical picture, featuring the stimulus-controlled spatiotemporal ion redistribution in the polymer, elaborates the origin of the memcapacitive prowess and resultant versatile synaptic plasticity. The distinctive MP behavior endows the memcapacitors with a dynamic learning rate (LR), which is utilized in an artificial neural network. The superiority of implementing a dynamic LR compared with conventional practices of using constant LR shines light on the potential of the memcapacitors to exploit organic neuromorphic computing hardware.

A Peptide Motif Covering Splice Site B in Neuroligin-1 Binds to Aβ and Acts as a Neprilysin Inhibitor.

The most common cause of dementia among elderly people is Alzheimer's disease (AD). The typical symptom of AD is the decline of cognitive abilities, which is caused by loss of synaptic function. Amyloid-β (Aβ) oligomers play a significant role in the development of this synaptic dysfunction. Neuroligin-(NL)1 is a postsynaptic cell-adhesion molecule located in excitatory synapses and involved in the maintenance and modulation of synaptic contacts. A recent study has found that Aβ interacts with the soluble N-terminal fragment of NL1. The present study aimed to elucidate the role of NL1 in Aβ-induced neuropathology. Employing surface plasmon resonance and competitive ELISA, we confirmed the high-affinity binding of NL1 to the Aβ peptide. We also identified a sequence motif representing the NL1-binding site for the Aβ peptide and showed that a synthetic peptide modeled after this motif, termed neurolide, binds to the Aβ peptide with high affinity, comparable to the NL1-Aβ interaction. To assess the effect of neurolide in vivo, wild-type and 5XFAD mice were subcutaneously treated with this peptide for 10weeks. We observed an increase in Aβ plaque formation in the cortex of neurolide-treated 5XFAD mice. Furthermore, we showed that neurolide reduces the activity of neprilysin, the predominant Aβ-degrading enzyme in the brain. Accordingly, we suggest that neurolide is the NL1-binding site for Aβ peptide, and acts as an inhibitor of neprilysin activity. Based on these data, we confirm the involvement of NL1 in the development of AD and suggest a mechanism for NL1-induced Aβ plaque formation.

Mitigation of synaptic and memory impairments via F-actin stabilization in Alzheimer’s disease

BackgroundSynaptic dysfunction, characterized by synapse loss and structural alterations, emerges as a prominent correlate of cognitive decline in Alzheimer’s disease (AD). Actin cytoskeleton, which serves as the structural backbone of synaptic architecture, is observed to be lost from synapses in AD. Actin cytoskeleton loss compromises synaptic integrity, affecting glutamatergic receptor levels, neurotransmission, and synaptic strength. Understanding these molecular changes is crucial for developing interventions targeting synaptic dysfunction, potentially mitigating cognitive decline in AD.MethodsIn this study, we investigated the synaptic actin interactome using mass spectrometry in a mouse model of AD, APP/PS1. Our objective was to explore how alterations in synaptic actin dynamics, particularly the interaction between PSD-95 and actin, contribute to synaptic and cognitive impairment in AD. To assess the impact of restoring F-actin levels on synaptic and cognitive functions in APP/PS1 mice, we administered F-actin stabilizing agent, jasplakinolide. Behavioral deficits in the mice were evaluated using the contextual fear conditioning paradigm. We utilized primary neuronal cultures to study the synaptic levels of AMPA and NMDA receptors and the dynamics of PSD-95 actin association. Furthermore, we analyzed postmortem brain tissue samples from subjects with no cognitive impairment (NCI), mild cognitive impairment (MCI), and Alzheimer’s dementia (AD) to determine the association between PSD-95 and actin.ResultsWe found a significant reduction in PSD-95-actin association in synaptosomes from middle-aged APP/PS1 mice compared to wild-type (WT) mice. Treatment with jasplakinolide, an actin stabilizer, reversed deficits in memory recall, restored PSD-95-actin association, and increased synaptic F-actin levels in APP/PS1 mice. Additionally, actin stabilization led to elevated synaptic levels of AMPA and NMDA receptors, enhanced dendritic spine density, suggesting improved neurotransmission and synaptic strength in primary cortical neurons from APP/PS1 mice. Furthermore, analysis of postmortem human tissue with NCI, MCI and AD subjects revealed disrupted PSD-95-actin interactions, underscoring the clinical relevance of our preclinical studies.ConclusionOur study elucidates disrupted PSD-95 actin interactions across different models, highlighting potential therapeutic targets for AD. Stabilizing F-actin restores synaptic integrity and ameliorates cognitive deficits in APP/PS1 mice, suggesting that targeting synaptic actin regulation could be a promising therapeutic strategy to mitigate cognitive decline in AD.

Artificial pain-perceptual nociceptor emulation based on graphene oxide synaptic transistors

Pain-perceptual nociceptors play a crucial role as sensory neurons, detecting noxious stimuli and enabling the human body to respond effectively while accurately perceiving atypical or hazardous situations in reality. Hence, the utilization of emerging devices in hardware to incorporate pain-perceptual nociceptors can significantly enhance the effectiveness of bionic devices by providing them with varying sensitivities towards external stimuli based on specific objectives. In this study, we have developed a pain-perceptive nociceptor by combining a temperature sensor with a synaptic transistor. To emulate synaptic functions and features of nociceptors, a graphene oxide synaptic transistor with sodium alginate electrolyte as gate dielectric is utilized. This device has the ability to replicate significant attributes of pain-perceptive nociceptors, including the threshold for pain, memory of prior injury, and modulation of pain sensitivity. For the purpose of perceiving pain, temperature sensing is achieved by employing a MoS2 temperature sensor for the pain-perceptual nociceptors. The suggested device has the potential to create novel possibilities for the applications of advanced neuromorphic brain-like systems, like electronic skins, wearable sensing and implantable bioelectronics.

Phosphoproteomic analysis reveals CDK5-Mediated phosphorylation of MTDH inhibits protein synthesis in microglia

CDK5 plays a crucial role in maintaining normal central nervous system (CNS) development and synaptic function, while microglia are the primary immune cells present in the CNS and play vital physiological roles in CNS development, immune surveillance, and regulation of synaptic plasticity. Despite this, our understanding of both the substrate proteins and functional mechanisms of CDK5 in microglia remains limited. To address this, we utilized CRISPR-Cas9 knockout of Cdk5 in BV2 cells and conducted quantitative phosphoproteomics analysis to systematically screen potential CDK5 substrates in microglia. Our findings identified 335 phosphorylation sites on 234 proteins as potential CDK5 substrates in microglia based on the reported sequence motif. Through in vitro kinase assay and intracellular inhibition and knockout of CDK5 experiments, we confirmed that ER proteins MTDH (protein LYRIC) and Calnexin are novel substrate proteins of CDK5. Moreover, we demonstrated for the first time a critical mechanism for regulating protein synthesis in microglia, that the phosphorylation of S565 site on MTDH, a key protein mediating cell growth, by CDK5 inhibits protein synthesis. Our data provide valuable insights for the discovery of new substrate proteins of CDK5 and the in-depth investigation of the function and mechanism of CDK5 in microglia.

Behavioral regression in shank3Δex4-22 mice during early adulthood corresponds to cerebellar granule cell glutamatergic synaptic changes.

Shank3, a gene encoding a synaptic scaffolding protein, is implicated in autism spectrum disorder (ASD) and is disrupted in Phelan-McDermid syndrome (PMS). Despite evidence of regression or worsening of ASD-like symptoms in individuals with PMS, the underlying mechanisms remain unclear. Although shank3 is highly expressed in the cerebellar cortical granule cells, its role in cerebellar function and contribution to behavioral deficits in ASD models are unknown. This study investigates behavioral changes and cerebellar synaptic alterations in shank3 Δex4-22 mice at two developmental stages. Shank3 Δex4-22 wildtype, heterozygous, and homozygous knockout mice lacking exons 4-22 (all functional isoforms) were subjected to a behavioral battery in both juvenile (5-7 weeks old) and adult (3-5 months old) mouse cohorts of both sexes. Immunostaining was used to show the expression of SHANK3 in the cerebellar cortex. Spontaneous excitatory postsynaptic currents (sEPSCs) from cerebellar granule cells (CGCs) were recorded by whole-cell patch-clamp electrophysiology. Deletion of shank3 ex4-22 caused deficits in motor function, heightened anxiety, and repetitive behaviors. These genotype-dependent behavioral alterations were more prominent in adult mice than in juveniles. Reduced social preference was only identified in adult shank3 Δex4-22 knockout mice and self-grooming was uniquely elevated only in males across both age groups. Immunofluorescence staining indicates the presence of SHANK3 predominantly in the dendrite-containing rosette-like structures in CGCs, colocalizing with presynaptic markers of glutamatergic mossy fiber. Electrophysiological findings identify a parallel relationship between the age-related exacerbation of behavioral impairments and the enhancement of sEPSC amplitude in CGCs. Other behavioral tests of muscle strength (grip strength test), memory (Barnes/water maze), and communication (ultrasonic vocalization), were not performed. Further study is necessary to elucidate how SHANK3 modulates synaptic function at the mossy fiber-granule cell synapse in the cerebellum. Our findings reveal an age-related exacerbation of behavioral impairments in shank3 Δex4-22 mutant mice. These results suggest that SHANK3 may play a role in maintaining glutamatergic receptors and synapses in CGCs, as well as the potential involvement of the cerebellum in ASD.

Tactile sensory synapse based on organic electrochemical transistors with ionogel triboelectric layer

Recent advancements in artificial tactile sensory systems have significantly improved their ability to replicate the sensory functions of biological systems by integrating various sensory and synaptic components, yet these configurations often lack the efficiency and seamless integration seen in nature. To address these limitations, we introduce a monolithic artificial mechanoreceptor that combines an organic electrochemical transistor with an ionogel (IG), serving as both a mechano-responsive triboelectric sensing layer and a gate electrolyte. Triboelectrification upon mechanical stimulation using different materials produces an output voltage of the triboelectric generator which drives the movement of ions within the tribo-negative IG based on 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ionic liquid and poly(vinylidene fluoride-co-hexafluoropropylene), modulating de-doping of the poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS) channel. This enhances synaptic functionalities such as spike number-dependent plasticity (SNDP) and spike duration-dependent plasticity (SDDP) during mechanical stimulation, allowing the device to mimic biological mechanoreceptors by sensing and converting external mechanical signals, including the number, force, and duration of touches, into synaptic plasticity. Furthermore, the device shows potential for material recognition using machine learning techniques, marking a significant advancement towards efficient artificial tactile systems.

Genetic advances in neurodevelopmental disorders

Abstract Neurodevelopmental disorders (NDDs) are a group of highly heterogeneous diseases that affect children’s social, cognitive, and emotional functioning. The etiology is complicated with genetic factors playing an important role. During the past decade, large-scale whole exome sequencing (WES) and whole genome sequencing (WGS) have vastly advanced the genetic findings of NDDs. Various forms of variants have been reported to contribute to NDDs, such as de novo mutations (DNMs), copy number variations (CNVs), rare inherited variants (RIVs), and common variation. By far, over 200 high-risk NDD genes have been identified, which are involved in biological processes including synaptic function, transcriptional and epigenetic regulation. In addition, monogenic, oligogenic, polygenetic, and omnigenic models have been proposed to explain the genetic architecture of NDDs. However, the majority of NDD patients still do not have a definitive genetic diagnosis. In the future, more types of risk factors, as well as noncoding variants, are await to be identified, and including their interplay mechanisms are key to resolving the etiology and heterogeneity of NDDs.

Impact of KDM6B mosaic brain knockout on synaptic function and behavior

Autism spectrum disorders (ASD) are complex neurodevelopmental conditions characterized by impairments in social communication, repetitive behaviors, and restricted interests. Epigenetic modifications serve as critical regulators of gene expression playing a crucial role in controlling brain function and behavior. Lysine (K)-specific demethylase 6B (KDM6B), a stress-inducible H3K27me3 demethylase, has emerged as one of the highest ASD risk genes, but the precise effects of KDM6B mutations on neuronal activity and behavioral function remain elusive. Here we show the impact of KDM6B mosaic brain knockout on the manifestation of different autistic-like phenotypes including repetitive behaviors, social interaction, and significant cognitive deficits. Moreover, KDM6B mosaic knockout display abnormalities in hippocampal excitatory synaptic transmission decreasing NMDA receptor mediated synaptic transmission and plasticity. Understanding the intricate interplay between epigenetic modifications and neuronal function may provide novel insights into the pathophysiology of ASD and potentially inform the development of targeted therapeutic interventions.

Postnatal Neuronal Nogo-A Knockdown Decreased the Message of Glutamatergic Synaptic Proteins.

It is well known that oligodendrocyte-associated Nogo-A protein is an important regulator of axonal outgrowth and an important inhibitor of functional recovery and anatomical plasticity after central nervous system (CNS) injury. Abundant studies of oligodendrocyte-associated Nogo-A function in the uninjured rodent have suggested a role in neuronal development and synaptic function. On the other hand, the roles of neuron-associated (i.e., neuronal) Nogo-A have not been fully investigated. We have previously shown that neuronal Nogo-A influence dendritic spine density and morphology in pyramidal neurons of the intact neocortex. To further examine the role of neuronal Nogo-A in this synaptic population, we designed an RNAi directed against Nogo-A, delivered to the developing rat sensorimotor cortex using a neurotropic viral vector adeno-associated virus (AAV) 2/8. We examined the transduced neocortex for molecules important for synaptic plasticity, including N-Methyl-D-Aspartate (NMDA) receptor subunits GRIN2A; glutamate receptor subunit epsilon-1 (NR2A), and GRIN2B; glutamate receptor subunit epsilon-2 (NR2B), as well as postsynaptic density-95 (PSD-95). Furthermore, we also determined the density of excitatory synapses by examining the presynaptic protein vesicular glutamate transporter 1 (vGLut1) as a marker for potential excitatory synapses. Our results showed that neuronal Nogo-A knockdown in postnatal pyramidal neurons of the sensorimotor cortex led to a significant decrease in NMDA receptor subunits NR2A and NR2B messenger RNA when examined as adults. However, there was no difference in PSD-95 expression in comparison to controls. In addition, the decrease in the number of vGlut1(+) puncta on branches of apical dendrites of pyramidal neurons indicated the loss of synapses that have a strong influence on direct current entering the dendrite. Taken together, these results indicate that neuronal Nogo-A may regulate synaptic plasticity by modulating the components of excitatory synapses. This finding represents a novel role in excitatory synaptic formation for neuronal Nogo-A in developing neurons of the uninjured CNS.

The Effect of N52R Mutation at the SPN-ARR Interface on the Conformational Dynamics of SHANK3

Background: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition. The genetic basis of ASD involves numerous loci converging on neural pathways, particularly affecting excitatory synapses. SHANK3, an essential protein in the post-synaptic neurons, has been implicated in ASD, with mutations affecting its N-terminal, including the SPN domain. Objective: This study aims to investigate the impact of the N52R mutation on SHANK3 and assess the dynamics, stability, flexibility, and compactness of the N52R mutant compared to SHANK3 WT. Methods: Molecular dynamics simulations were conducted to investigate the structural dynamics of SHANK3 WT and the N52R mutant. The simulations involved heating dynamics, density equilibrium, and production dynamics. The trajectories were analyzed for RMSD, RMSF, Rg, hydrogen bond analysis, and secondary structure. Results: The simulations revealed that the N52R mutant disrupts the stability and folding of SHANK3, affecting intramolecular contacts between SPN and ARR. This disruption opens up the distance between SPN and ARR domains, potentially influencing the protein's interactions with partners, including αCaMKII and α-Fodrin. The altered conformation of the SPN-ARR tandem in the N52R mutant suggests a potential impact on dendritic spine shape and synaptic plasticity. Conclusion: The findings shed light on the structural consequences of the N52R mutation in SHANK3, emphasizing its role in influencing intramolecular interactions and potential effects on synaptic function. Understanding these molecular dynamics contributes to unraveling the intricate relationship between genetic variations in SHANK3 and clinical traits associated with ASD. Further investigations are warranted to explore the physiological implications of these structural alterations in vivo.

ProSAAS is preferentially up-regulated during homeostatic scaling and reduces amyloid plaque burden in the 5xFAD mouse hippocampus.

The accumulation of β-amyloid in Alzheimer's disease greatly impacts neuronal health and synaptic function. To maintain network stability in the face of altered synaptic activity, neurons engage a feedback mechanism termed homeostatic scaling; however, this process is thought to be disrupted during disease progression. Previous proteomics studies have shown that one of the most highly regulated proteins in cell culture models of homeostatic scaling is the small secretory chaperone proSAAS. Our prior work has shown that proSAAS exhibits anti-aggregant behavior against alpha-synuclein and β-amyloid fibrillation invitro and is up-regulated in cell models of proteostatic stress. However, the specific role that this protein might play in homeostatic scaling, and its anti-aggregant role in Alzheimer's progression, is not clear. To learn more about the role of proSAAS in maintaining hippocampal proteostasis, we compared its expression in a primary neuron model of homeostatic scaling to other synaptic components using western blotting and qPCR, revealing that proSAAS protein responses to homeostatic up- and down-regulation were significantly higher than those of two other synaptic vesicle components, 7B2 and carboxypeptidase E. However, proSAAS mRNA expression was static, suggesting translational control and/or altered protein degradation. ProSAAS was readily released upon depolarization of differentiated hippocampal cultures, supporting its synaptic localization. Immunohistochemical analysis demonstrated abundant proSAAS within the mossy fiber layer of the hippocampus in both wild-type and 5xFAD mice; in the latter, proSAAS was also concentrated around amyloid plaques. Importantly, overexpression of proSAAS in the CA1 region via stereotaxic injection of proSAAS-encoding AAV2/1 significantly decreased amyloid plaque burden in 5xFAD mice. We hypothesize that dynamic changes in proSAAS expression play a critical role in hippocampal proteostatic processes, both in the context of normal homeostatic plasticity and in the control of protein aggregation during Alzheimer's disease progression.

PLASTAMINATION: Outcomes on the Central Nervous System and Reproduction.

Environmental exposures to non-biodegradable and biodegradable plastics are unavoidable. Microplastics (MPs) and nanoplastics (NPs) from the manufacturing of plastics (primary sources) and the degradation of plastic waste (secondary sources) can enter the food chain directly or indirectly and, passing biological barriers, could target both the brain and the gonads. Hence, the worldwide diffusion of environmental plastic contamination (PLASTAMINATION) in daily life may represent a possible and potentially serious risk to human health. This review provides an overview of the effects of non-biodegradable and the more recently introduced biodegradable MPs and NPs on the brain and brain-dependent reproductive functions, summarizing the molecular mechanisms and outcomes on nervous and reproductive organs. Data from in vitro, ex vivo, non-mammalian and mammalian animal models and epidemiological studies have been reviewed and discussed. MPs and NPs from non-biodegradable plastics affect organs, tissues and cells from sensitive systems such as the brain and reproductive organs. Both MPs and NPs induce oxidative stress, chronic inflammation, energy metabolism disorders, mitochondrial dysfunction and cytotoxicity, which in turn are responsible for neuroinflammation, dysregulation of synaptic functions, metabolic dysbiosis, poor gamete quality, and neuronal and reproductive toxicity. In spite of this mechanistic knowledge gained from studies of non-biodegradable plastics, relatively little is known about the adverse effects or molecular mechanisms of MPs and NPs from biodegradable plastics. The neurological and reproductive health risks of MPs/NPs exposure warrant serious consideration, and further studies on biodegradable plastics are recommended.

Presynaptic Enhancement of Transmission from Nociceptors Expressing Nav1.8 onto Lamina-I Spinothalamic Tract Neurons by Spared Nerve Injury in Mice.

Alteration of synaptic function in the dorsal horn (DH) has been implicated as a cellular substrate for the development of neuropathic pain, but certain details remain unclear. In particular, the lack of information on the types of synapses that undergo functional changes hinders the understanding of disease pathogenesis from a synaptic plasticity perspective. Here, we addressed this issue by using optogenetic and retrograde tracing ex vivo to selectively stimulate first-order nociceptors expressing Nav1.8 (NRsNav1.8) and record the responses of spinothalamic tract neurons in spinal lamina I (L1-STTNs). We found that spared nerve injury (SNI) increased excitatory postsynaptic currents (EPSCs) in L1-STTNs evoked by photostimulation of NRsNav1.8 (referred to as Nav1.8-STTN EPSCs). This effect was accompanied by a significant change in the failure rate and paired-pulse ratio of synaptic transmission from NRsNav1.8 to L1-STTN and in the frequency (not amplitude) of spontaneous EPSCs recorded in L1-STTNs. However, no change was observed in the ratio of AMPA to NMDA receptor-mediated components of Nav1.8-STTN EPSCs or in the amplitude of unitary EPSCs constituting Nav1.8-STTN EPSCs recorded with extracellular Ca2+ replaced by Sr2+ In addition, there was a small increase (approximately 10%) in the number of L1-STTNs showing immunoreactivity for phosphorylated extracellular signal-regulated kinases in mice after SNI compared with sham. Similarly, only a small percentage of L1-STTNs showed a lower action potential threshold after SNI. In conclusion, our results show that SNI induces presynaptic modulation at NRNav1.8 (consisting of both peptidergic and nonpeptidergic nociceptors) synapses on L1-STTNs forming the lateral spinothalamic tract.

Abstract P159: Conditional deletion of ADAM17 (A disintegrin and metalloprotease 17) in microglia attenuates hypertension and associated inflammation.

Microglia, the resident immune cell in the brain, contributes to neuroinflammation and neurogenic hypertension by secreting various cytokines and chemokines. ADAM17 shedding of these signaling molecules) in microglia modulates synaptic function but the consequences of this process have not been studied in neurogenic hypertension. Accordingly, we hypothesize that deletion of ADAM17 in microglia opposes microglia activation and cytokine secretion thus preventing the development of neuroinflammation in salt-sensitive hypertension. To test our hypothesis, a new mouse model (ADAM17::CX3CR1-CreERT2; A17-Mic-/-) amenable for selective deletion of ADAM17 in microglia was developed. Following the initiation of deoxycorticosterone acetate plus salt (DOCA-salt) hypertension, tamoxifen was injected intracerebroventricularly to delete ADAM17 in microglia and blood pressure (BP) monitored over 3 weeks. In A17-Mic-/- mice, lacking ADAM17 in microglia, the BP increase induced by DOCA-salt treatment was blunted compared to control mice (127.4±5 vs. 143.4±4 mmHg, P<0.05). However, it was not abated in iRhom2-/- mice (149.5±3 mmHg), lacking the rhomboid protein involved in ADAM17 maturation in microglia, suggesting possible compensation by iRhom1. Interestingly, A17-Mic-/- mice showed a reduced level of proinflammatory cytokines and chemokines in the plasma, including TNF-α (A17-Mic-/-: 5.21±0.97, iRhom2-/-: 3.867±1 vs. control: 20.72±4 pg/mL), IL-6 (A17-Mic-/-: 36.53±11.33, iRhom2-/-: 91.41±14 vs. control: 79.65±15.72 pg/mL) and G-CSF (A17-Mic-/-: 508.4±98.7, iRhom2-/-: 3523±897 vs. 838.2±238.2 pg/mL) and MCP-1 (A17-Mic-/-: 38.41±9, iRhom2-/-: 51.87±7 vs. control: 75.52±12 pg/mL), respectively (P<0.05). Together, our data suggests that conditional deletion of ADAM17 opposes the activation of microglia and reduces pro-inflammatory cytokine and chemokine expression in hypertension. Overall, our data highlights the pivotal role of microglial ADAM17 in regulating salt-sensitive hypertension and the associated inflammation.

Apolipoprotein E in Alzheimer's Disease: Focus on Synaptic Function and Therapeutic Strategy.

Synaptic dysfunction is a critical pathological feature in the early phase of Alzheimer's disease (AD) that precedes typical hallmarks of AD, including beta-amyloid (Aβ) plaques and neurofibrillary tangles. However, the underlying mechanism of synaptic dysfunction remains incompletely defined. Apolipoprotein E (APOE) has been shown to play a key role in the pathogenesis of AD, and the ε4 allele of APOE remains the strongest genetic risk factor for sporadic AD. Itiswidelyrecognizedthat APOE4 accelerates the development of Aβ andtau pathology in AD. Recent studies have indicated that APOE affects synaptic function through a variety of pathways. Here, we summarize the mechanism of modulating synapses by various APOE isoforms and demonstrate the therapeutic potential by targeting APOE4 for AD treatment.

Reconfigurable dielectric engineered WSe2/HZO mem-transistor

Abstract Hybrid systems coupling 2D semiconductors with functional ferroelectrics are attracting increasing attention due to their excellent electronic/optoelectronic properties and new functionalities through the multiple heterointerface interaction. In our device architecture, interfacial states are introduced on the ferroelectric Hf0.5Zr0.5O2 thin film as gate dielectric layer for charge trapping effect. Utilizing the collaborative effects of charge trapping and ferroelectric polarization behavior, a multifunctional 2D WSe2/HZO memtransistor is demonstrated with ultra-low off-state (dark) current of 10-13 A, high on/off ratio of 106 and linear conductance update. This device exhibits reliable memory properties and tunable synaptic functions including short-term plasticity (STP)/ long-term plasticity (LTP), paired pulse facilitation (PPF), spike-timing dependent plasticity (STDP), synaptic potentiation/depression, and filtering in a single device. Extensive endurance tests ensure robust stability (1000 switching cycles, 2000 s holding time) and the synaptic weight update in the device exhibits excellent linearity. Based on the experimental data, our devices eventually achieve an accuracy of 94.8% in artificial neural network simulations. These results highlight a new approach for constructing hybrid systems coupling 2D semiconductors with functional ferroelectrics in a single device for tuning synaptic weight, optimizing circuit design, and building artificial neuromorphic computing systems.

Properties of layer V pyramidal neurons in the primary motor cortex that represent acquired motor skills

Layer V neurons in primary motor cortex (M1) are required for motor skill learning. We analyzed training-induced plasticity using a whole-cell slice patch-clamp technique with a rotor rod task, and found that training induces diverse changes in intrinsic properties and synaptic plasticity in M1 layer V neurons. Although the causal relationship between specific cellular changes and motor performance is unclear, by linking individual motor performance to cellular/synaptic functions, we identified several cellular and synaptic parameters that represent acquired motor skills. With respect to cellular properties, motor performance was positively correlated with resting membrane potential and fast afterhyperpolarization, but not with the membrane resistance, capacitance, or threshold. With respect to synaptic function, the performance was positively correlated with AMPA receptor-mediated postsynaptic currents, but not with GABAA receptor-mediated postsynaptic currents. With respect to live imaging analysis in Thy1-YFP mice, we further demonstrated a cross-correlation between motor performance, spine head volume, and self-entropy per spine. In the present study, we identified several changes in M1 layer V pyramidal neurons after motor training that represent acquired motor skills. Furthermore, training increased extracellular acetylcholine levels known to promote synaptic plasticity, which is correlated with individual motor performance. These results suggest that systematic control of specific intracellular parameters and enhancement of synaptic plasticity in M1 layer V neurons may be useful for improving motor skills.