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Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro‐cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long‐term potentiation (LTP1) into the stronger long‐lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long‐term memory. D3R effects were mainly mediated by post‐synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR‐mediated currents, mEPSC amplitude, and the expression of the post‐synaptic proteins PSD‐95, phospho(p)GluA1 and p‐CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post‐synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post‐synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post‐synaptic protein expression, and PSD length. Notably, aged D3‐KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age‐related hippocampal cognitive decline. [ABSTRACT FROM AUTHOR]

Throughout our evolutionary history, physical activity has played a significant role in shaping our physiology. Advances in exercise science have further reinforced this concept by highlighting how exercise can change gene expression and molecular signaling to achieve various beneficial outcomes. Several studies have shown that exercise can alter neuronal functions to prevent neurodegenerative conditions like Parkinson's and Alzheimer's diseases. However, individual genotypes, phenotypes, and varying exercise protocols hinder the prescription of exercise as standard therapy. Moreover, exercise-induced molecular signaling targets can be double-edged swords, making it difficult to use exercise as the primary candidate for beneficial effects. For example, activating PGC-1 alpha and BDNF through exercise could produce several benefits in maintaining brain health, such as plasticity, neuronal survival, memory formation, cognition, and synaptic transmission. However, higher expression of BDNF might playa negative role in bipolar disorder. Therefore, further understanding of a specific mechanistic approach is required. This review focuses on how exercise-induced activation of these molecules could support brain health and discusses the potential underlying mechanisms of the effect of exercise-induced PGC-1 alpha and BDNF on brain health. [ABSTRACT FROM AUTHOR]

Background and objectives: There is an urgent need to discover blood-based biomarkers of multiple sclerosis (MS) to better define the underlying biology of relapses and monitor disease progression. The main goal of this study is to search for candidate biomarkers of MS relapses associated with circulating extracellular vesicles (EVs), an emerging tool for biomarker discovery. Methods: EVs, purified from unpaired plasma and CSF samples of RRMS patients by size-exclusion chromatography (SEC), underwent proteomic analysis to discover novel biomarkers associated with MS relapses. The candidate biomarkers of disease activity were detected by comparison approach between plasma- and CSF-EV proteomes associated with relapses. Among them, a selected potential biomarker was evaluated in a cohort of MS patients, using a novel and highly reproducible flow cytometry-based approach in order to detect low abundant EV subsets in a complex body fluid such as plasma. Results: The proteomic profiles of both SEC-purified plasma EVs (from 6 patients in relapse and 5 patients in remission) and SEC-purified CSF EVs (from 4 patients in relapse and 3 patients in remission) revealed a set of proteins associated with MS relapses significant enriched in the synaptic transmission pathway. Among common proteins, excitatory amino-acid transporter 2, EAAT2, responsible for the majority of the glutamate uptake in CNS, was worthy of further investigation. By screening plasma samples from 110 MS patients, we found a significant association of plasma EV-carried EAAT2 protein (EV-EAAT2) with MS relapses, regardless of disease-modifying therapies. This finding was confirmed by investigating the presence of EV-EAAT2 in plasma samples collected longitudinally from 10 RRMS patients, during relapse and remission. Moreover, plasma EV-EAAT2 levels correlated positively with Expanded Disability Status Scale (EDSS) score in remitting MS patients but showed a negative correlation with age in patients with secondary progressive (SPMS). Conclusion: Our results emphaticize the usefulness of plasma EVs as a source of accessible biomarkers to remotely analyse the CNS status. Plasma EV-EAAT2 showed to be a promising biomarker for MS relapses. Further studies are required to assess the clinical relevance of this biomarker also for disability progression independent of relapse activity and transition from RRMS towards SPMS. [ABSTRACT FROM AUTHOR]

FKBP51, also known as FK506‐binding protein 51, is a molecular chaperone and scaffolding protein with significant roles in regulating hormone signaling and responding to stress. Genetic variants in FKBP5, which encodes FKBP51, have been implicated in a growing number of neuropsychiatric disorders, which has spurred efforts to target FKBP51 therapeutically. However, the molecular mechanisms and sub‐anatomical regions influenced by FKBP51 in these disorders are not fully understood. In this study, we aimed to examine the impact of Fkbp5 ablation using circadian phenotyping and molecular analyses. Our findings revealed that the lack of FKBP51 did not significantly alter circadian rhythms, as detected by wheel‐running activity, but did offer protection against stress‐mediated disruptions in rhythmicity in a sex‐dependent manner. Protein changes in Fkbp5 KO mice, as measured by histology and proteomics, revealed alterations in a brain region‐ and sex‐dependent manner. Notably, regardless of sex, aged Fkbp5 KOs showed elevated MYCBP2, FBXO45, and SPRYD3 levels, which are associated with neuronal‐cell adhesion and synaptic integrity. Additionally, pathways such as serotonin receptor signaling and S100 family signaling were differentially regulated in Fkbp5 KO mice. Weighted protein correlation network analysis identified protein networks linked with synaptic transmission and neuroinflammation. The information generated by this work can be used to better understand the molecular changes in the brain during aging and in the absence of Fkbp5, which has implications for the continued development of FKBP51‐focused therapeutics for stress‐related disorders. [ABSTRACT FROM AUTHOR]

Introduction Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents. Methods A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases. Results Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function. Discussion Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia. [ABSTRACT FROM AUTHOR]

Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17β‐estradiol (E2) can rapidly enhance excitatory synaptic transmission in the hippocampus and facilitate excitatory synaptic transmission in rat lateral entorhinal cortex via activation of the G protein‐coupled estrogen receptor‐1 (GPER1). To assess the mechanisms through which GPER1 activation facilitates synaptic transmission, we assessed the effects of acute 10 nM E2 administration on pharmacologically isolated evoked excitatory and inhibitory synaptic currents in layer II/III entorhinal neurons. Female Long‐Evans rats were ovariectomized between postnatal day (PD) 63 and 74 and implanted with a subdermal E2 capsule to maintain continuous low levels of E2. Electrophysiological recordings were obtained between 7 and 20 days after ovariectomy. Application of E2 for 20 min did not significantly affect AMPA or NMDA receptor‐mediated excitatory synaptic currents. However, GABA receptor‐mediated inhibitory synaptic currents (IPSCs) were markedly reduced by E2 and returned towards baseline levels during the 20‐min washout period. The inhibition of GABA‐mediated IPSCs was blocked in the presence of the GPER1 receptor antagonist G15. GPER1 can modulate protein kinase A (PKA), but blocking PKA with intracellular KT5720 did not prevent the E2‐induced reduction in IPSCs. GPER1 can also stimulate extracellular signal‐regulated kinase (ERK), a negative modulator of GABAA receptors, and blocking activation of ERK with PD90859 prevented the E2‐induced reduction of IPSCs. E2 can therefore result in a rapid GPER1 and ERK signaling‐mediated reduction in GABA‐mediated IPSCs. This provides a novel mechanism through which E2 can rapidly modulate synaptic excitability in entorhinal layer II/III neurons and may also contribute to E2 and ERK‐dependent alterations in synaptic transmission in other brain areas. [ABSTRACT FROM AUTHOR]

Purpose: Prior evidence has shown that neural factors contribute to the loss of muscle force after skeletal muscle disuse. However, little is known about the specific neural mechanisms altered by disuse. Persistent inward current (PIC) is an intrinsic property of motoneurons responsible for prolonging and amplifying the synaptic input, proportionally to the level of neuromodulation, thus influencing motoneuron discharge rate and force production. Here, we hypothesized that short-term unilateral lower limb suspension (ULLS) would reduce the neuromodulatory input associated with PIC, contributing to the reduction of force generation capacity. In addition, we tested whether physical exercise would restore the force generation capacity by reestablishing the initial level of neuromodulatory input. Methods: In 12 young adults, we assessed maximal voluntary contraction pre- and post-10 d of ULLS and after 21 d of active recovery (AR) based on resistance exercise. PIC was estimated from high-density surface electromyograms of the vastus lateralis muscle as the delta frequency (ΔF) of paired motor units calculated during isometric ramped contractions. Results: The values of ΔF were reduced after 10 d of ULLS (-33%, P < 0.001), but were fully reestablished after the AR (+29.4%, P < 0.001). The changes in estimated PIC values were correlated (r = 0.63, P = 0.004) with the reduction in maximal voluntary contraction after ULLS (-29%, P = 0.002) and its recovery after the AR (+28.5%, P = 0.003). Conclusions: Our findings suggest that PIC estimates are reduced by muscle disuse and may contribute to the loss of force production and its recovery with exercise. Overall, this is the first study demonstrating that, in addition to peripheral neuromuscular changes, central neuromodulation is a major contributor to the loss of force generation capacity after disuse, and can be recovered after resistance exercise. [ABSTRACT FROM AUTHOR]

Understanding the endocannabinoid system in C. elegans may offer insights into basic biological processes and potential therapeutic targets for managing pain and inflammation in human. It is well established that anandamide modulates pain perception by binding to cannabinoid and vanilloid receptors, regulating neurotransmitter release and neuronal activity. One objective of this study was to demonstrate the suitability of C. elegans as a model organism for assessing the antinociceptive properties of bioactive compounds and learning about the role of endocannabinoid system in C. elegans. The evaluation of the compound anandamide (AEA) revealed antinociceptive activity by impeding C. elegans nocifensive response to noxious heat. Proteomic and bioinformatic investigations uncovered several pathways activated by AEA. Enrichment analysis unveiled significant involvement of ion homeostasis pathways, which are crucial for maintaining neuronal function and synaptic transmission, suggesting AEA's impact on neurotransmitter release and synaptic plasticity. Additionally, pathways related to translation, protein synthesis, and mTORC1 signaling were enriched, highlighting potential mechanisms underlying AEA's antinociceptive effects. Thermal proteome profiling identified NPR-32 and NPR-19 as primary targets of AEA, along with OCR-2, Cathepsin B, Progranulin, Transthyretin, and ribosomal proteins. These findings suggest a complex interplay between AEA and various cellular processes implicated in nociceptive pathways and inflammation modulation. Further investigation into these interactions could provide valuable insights into the therapeutic potential of AEA and its targets for the management of pain-related conditions. [ABSTRACT FROM AUTHOR]

Our group previously showed that genetic or pharmacological inhibition of the cystine/glutamate antiporter, system xc−, mitigates excitotoxicity after anoxia by increasing latency to anoxic depolarization, thus attenuating the ischaemic core. Hypoxia, however, which prevails in the ischaemic penumbra, is a condition where neurotransmission is altered, but excitotoxicity is not triggered. The present study employed mild hypoxia to further probe ischaemia‐induced changes in neuronal responsiveness from wild‐type and xCT KO (xCT−/−) mice. Synaptic transmission was monitored in hippocampal slices from both genotypes before, during and after a hypoxic episode. Although wild‐type and xCT−/− slices showed equal suppression of synaptic transmission during hypoxia, mutant slices exhibited a persistent potentiation upon re‐oxygenation, an effect we termed 'post‐hypoxic long‐term potentiation (LTP)'. Blocking synaptic suppression during hypoxia by antagonizing adenosine A1 receptors did not preclude post‐hypoxic LTP. Further examination of the induction and expression mechanisms of this plasticity revealed that post‐hypoxic LTP was driven by NMDA receptor activation, as well as increased calcium influx, with no change in paired‐pulse facilitation. Hence, the observed phenomenon engaged similar mechanisms as classical LTP. This was a remarkable finding as theta‐burst stimulation‐induced LTP was equivalent between genotypes. Importantly, post‐hypoxic LTP was generated in wild‐type slices pretreated with system xc− inhibitor, S‐4‐carboxyphenylglycine, thereby confirming the antiporter's role in this phenomenon. Collectively, these data indicate that system xc− interference enables neuroplasticity in response to mild hypoxia, and, together with its regulation of cellular damage in the ischaemic core, suggest a role for the antiporter in post‐ischaemic recovery of the penumbra. What is the central question of this study?Does glutamate antiporter system xc− influence recovery in the ischemic penumbra?What is the main finding and its importance?Our data reveal that mild hypoxia elicits a persistent potentiation of synaptic transmission in hippocampus when system xc− is genetically deleted or pharmacologically inhibited. This 'post‐hypoxic long‐term potentiation (LTP)' engages similar mechanims as classical NMDAR‐dependent LTP induced by theta‐burst stimulation (TBS). Because this neuroplasticity potentially fosters recovery in penumbral tissue, these findings portend system xc− antagonism as a post‐stroke therapeutic intervention. [ABSTRACT FROM AUTHOR]

Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter required for excitation/inhibition balance is synthesized by the glutamic acid decarboxylases (GADs) in GABAergic neurons. The levels and activity of GADs are strongly correlated with GABA and neural transmission. Dysregulation of GADs and GABA is associated with various neurological disorders. The study used psoralidin, found in the seeds of Psoralea corylifolia, to investigate its effect on GAD levels and regulatory mechanisms in primary cortical neurons. Psoralidin reduced GAD67 through transcriptional regulation. The reduction was not mediated by the N-methyl-D-aspartate receptor. Additionally, psoralidin attenuated the formation of inhibitory synapses in primary hippocampal neurons. [ABSTRACT FROM AUTHOR]

Background and Purpose: Many medications taste intensely bitter. The innate aversion to bitterness affects medical compliance, especially in children. There is a clear need to develop bitter blockers to suppress the bitterness of vital medications. Bitter taste is mediated by TAS2R receptors. Because different pharmaceutical compounds activate distinct sets of TAS2Rs, targeting specific receptors may only suppress bitterness for certain, but not all, bitter‐tasting compounds. Alternative strategies are needed to identify universal bitter blockers that will improve the acceptance of every medication. Taste cells in the mouth transmit signals to afferent gustatory nerve fibres through the release of ATP, which activates the gustatory nerve‐expressed purine receptors P2X2/P2X3. We hypothesized that blocking gustatory nerve transmission with P2X2/P2X3 inhibitors (e.g. 5‐(5‐iodo‐4‐methoxy‐2‐propan‐2‐ylphenoxy)pyrimidine‐2,4‐diamine [AF‐353]) would reduce bitterness for all medications and bitter compounds. Experimental Approach: Human sensory taste testing and mouse behavioural analyses were performed to determine if oral application of AF‐353 blocks perception of bitter taste and other taste qualities but not non‐gustatory oral sensations (e.g. tingle). Key Results: Rinsing the mouth with AF‐353 in humans or oral swabbing it in mice suppressed the bitter taste and avoidance behaviours of all compounds tested. We further showed that AF‐353 suppressed other taste qualities (i.e. salt, sweet, sour and savoury) but had no effects on other oral or nasal sensations (e.g, astringency and oral tingle). Conclusion and Implications: This is the first time a universal, reversible taste blocker in humans has been reported. Topical application of P2X2/P2X3 inhibitor to suppress bitterness may improve medical compliance. [ABSTRACT FROM AUTHOR]

Despite extensive research efforts aimed at discovering novel antipsychotic compounds, a satisfactory pharmacological strategy for schizophrenia treatment remains elusive. All the currently available drugs act by modulating dopaminergic neurotransmission, leading to insufficient management of the negative and cognitive symptoms of the disorder. Due to these challenges, several attempts have been made to design agents with innovative, non‐dopaminergic mechanisms of action. Consequently, a number of promising compounds are currently progressing through phases 2 and 3 of clinical trials. This review aims to examine the rationale behind the most promising of these strategies while simultaneously providing a comprehensive survey of study results. We describe the versatility behind the cholinergic neurotransmission modulation through the activation of M1 and M4 receptors, exemplified by the prospective drug candidate KarXT. Our discussion extends to the innovative approach of activating TAAR1 receptors via ulotaront, along with the promising outcomes of iclepertin, a GlyT‐1 inhibitor with the potential to become the first treatment option for cognitive impairment associated with schizophrenia. Finally, we evaluate the 5‐HT2A antagonist paradigm, assessing two recently developed serotonergic agents, pimavanserin and roluperidone. We present the latest advancements in developing novel solutions to the complex challenges posed by schizophrenia, offering an additional perspective on the diverse investigated drug candidates. [ABSTRACT FROM AUTHOR]

• The estrous cycle does not affect the innate startle but influences fear learning. • In high-anxious females, hormonal increase during proestrus reduces learned fear. • In BLA, 5-HT reduces potentiated startle by combining with estrous cycle hormones. • In BLA, 5-HT interacts with female hormones likely through 5-HT1A receptors. • DPAG stimulation of high-anxious females increases the response to stressful stimuli. Despite significant advances in the study of fear and fear memory formation, little is known about fear learning and expression in females. This omission has been proven surprising, as normal and pathological behaviors are highly influenced by ovarian hormones, particularly estradiol and progesterone. In the current study, we investigated the joint influence of serotonin (5-HT) neurotransmission and estrous cycle phases (low or high levels of estradiol and progesterone) on the expression of conditioned fear in a group of female rats that were previously divided according to their response to stressful stimuli into low or high anxiety-like subjects. The baseline amplitude of the unconditioned acoustic startle responses was high in high-anxiety female rats, with no effect on the estrous cycle observed. Data collected during the proestrus-estrus phase revealed that low-anxiety rats had startle amplitudes similar to those of high-anxiety rats. It is supposed that high-anxiety female rats benefit from increased estradiol and progesterone levels to achieve comparable potentiated startle amplitudes. In contrast, female rats experienced a significant decrease in hormone levels during the Diestrus phase. This decrease is believed to play a role in preventing them from displaying a heightened startle response when faced with strongly aversive stimuli. Data collected after 5-HT and 8-OH-DPAT were administered into the basolateral nuclei and dorsal periaqueductal gray suggest that 5-HT neurotransmission works with progesterone and estrogen to reduce startle potentiation, most likely by activating the serotonin-1A receptor subtype. [ABSTRACT FROM AUTHOR]

• Physical activity upregulates serotonin via increased synthesis substrates. • Physical activity upregulates serotonin via increased gut microbiota diversity. • Serotonin regulates children's cognitive function and social-emotional abilities. • Serotonin plays a pivotal role in early neurogenesis and synaptic plasticity. Early childhood serves as a critical period for neural development and skill acquisition when children are extremely susceptible to the external environment and experience. As a crucial experiential stimulus, physical activity is believed to produce a series of positive effects on brain development, such as cognitive function, social-emotional abilities, and psychological well-being. The World Health Organization recommends that children engage in sufficient daily physical activity, which has already been strongly advocated in the practice of preschool education. However, the mechanisms by which physical activity promotes brain development are still unclear. The role of neurotransmitters, especially serotonin, in promoting brain development through physical activity has received increasing attention. Physical activity has been shown to stimulate the secretion of serotonin by increasing the bioavailability of free tryptophan and enriching the diversity of gut microbiota. Due to its important role in modulating neuronal proliferation, differentiation, synaptic morphogenesis, and synaptic transmission, serotonin can regulate children's explicit cognitive and social interaction behavior in the early stages of life. Therefore, we hypothesized that serotonin emerges as a pivotal transmitter that mediates the relationship between physical activity and brain development during early childhood. Further systematic reviews and meta -analyses are needed to specifically explore whether the type, intensity, dosage, duration, and degree of voluntariness of PA may affect the role of serotonin in the relationship between physical activity and brain function. This review not only helps us understand the impact of exercise on development but also provides a solid theoretical basis for increasing physical activity during early childhood. [ABSTRACT FROM AUTHOR]

How does alcohol consumption alter synaptic transmission across time, and do these alcohol-induced neuroadaptations occur similarly in both male and female mice? Previously we identified that anterior insular cortex (AIC) projections to the dorsolateral striatum (DLS) are uniquely sensitive to alcohol-induced neuroadaptations in male, but not female mice, and play a role in governing binge alcohol consumption in male mice (Haggerty et al., 2022). Here, by using high-resolution behavior data paired with in-vivo fiber photometry, we show how similar levels of alcohol intake are achieved via different behavioral strategies across sexes, and how inter-drinking session thirst states predict future alcohol intakes in females, but not males. Furthermore, we show how presynaptic calcium activity recorded from AIC synaptic inputs in the DLS across 3 weeks of water consumption followed by 3 weeks of binge alcohol consumption changes across, fluid, time, sex, and brain circuit lateralization. By time-locking presynaptic calcium activity from AIC inputs to the DLS to peri-initiation of drinking events we also show that AIC inputs into the left DLS robustly encode binge alcohol intake behaviors relative to water consumption. These findings suggest a fluid-, sex-, and lateralization-dependent role for the engagement of AIC inputs into the DLS that encode binge alcohol consumption behaviors and further contextualize alcohol-induced neuroadaptations at AIC inputs to the DLS. [ABSTRACT FROM AUTHOR]

The anterior cingulate cortex (ACC) is a key cortical region for pain perception and emotion. Different forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), have been reported in the ACC. Synaptic tagging of LTP plays an important role in hippocampus-related associative memory. In this study, we demonstrate that synaptic tagging of LTD is detected in the ACC of adult male and female mice. This form of tagged LTD requires the activation of metabotropic glutamate receptor subtype 1 (mGluR1). The induction of tagged LTD is time-related with the strongest tagged LTD appearing when the interval between two independent stimuli is 30 min. Inhibitors of mGluR1 blocked the induction of tagged LTD; however, blocking N-methyl-d-aspartate receptors did not affect the induction of tagged LTD. Nimodipine, an inhibitor of L-type voltage–gated calcium channels, also blocked tagged LTD. In an animal model of amputation, we found that tagged LTD was either reduced or completely blocked. Together with our previous report of tagged LTP in the ACC, this study strongly suggests that excitatory synapses in the adult ACC are highly plastic. The biphasic tagging of synaptic transmission provides a new form of heterosynaptic plasticity in the ACC which has functional and pathophysiological significance in phantom pain. [ABSTRACT FROM AUTHOR]

For a subset of individuals known as sign‐trackers, discrete Pavlovian cues associated with rewarding stimuli can acquire incentive properties and exert control over behaviour. Because responsiveness to cues is a feature of various neuropsychiatric conditions, rodent models of sign‐tracking may prove useful for exploring the neurobiology of individual variation in psychiatric vulnerabilities. Converging evidence points towards the involvement of dopaminergic neurotransmission in the nucleus accumbens core (NAc) in the development of sign‐tracking, yet whether this phenotype is associated with specific accumbal postsynaptic properties is unknown. Here, we examined dendritic spine structural organisation, as well as presynaptic and postsynaptic markers of activity, in the NAc core of male and female rats following a Pavlovian‐conditioned approach procedure. In contrast to our prediction that cue re‐exposure would increase spine density, experiencing the discrete lever‐cue without reward delivery resulted in lower spine density than control rats for which the lever was unpaired with reward during training; this effect was tempered in the most robust sign‐trackers. Interestingly, this same behavioural test (lever presentation without reward) resulted in increased levels of a marker of presynaptic activity (synaptophysin), and this effect was greatest in female rats. Whilst some behavioural differences were observed in females during initial Pavlovian training, final conditioning scores did not differ from males and were unaffected by the oestrous cycle. This work provides novel insights into how conditioning impacts the neuronal plasticity of the NAc core, whilst highlighting the importance of studying the behaviour and neurobiology of both male and female rats. [ABSTRACT FROM AUTHOR]

The synapses between parallel fibers and Purkinje cells play a pivotal role in cerebellar function. They are intricately governed by a variety of presynaptic receptors, notably by type 4metabotropic glutamate (mGlu4) receptors and type 1 adenosine (A1) receptors both of which curtail glutamate release upon activation. Despite their pivotal role in regulating synaptic transmission within the cerebellar cortex, functional interactions between mGlu4 and A1 receptors have remained relatively unexplored. To bridge this gap, our study delves into how mGlu4 receptor activity influences A1 receptor-mediated alterations in excitatory transmission. Employing a combination of whole-cell patch clamp recordings of Purkinje cells and parallel fiber presynaptic fluorometric calcium measurements in acute rat andmouse cerebellar cortical slices, our results reveal functional interactions between these receptor types. These findings hold implications for understanding potential roles of these presynaptic receptors in neuroprotection during pathophysiological conditions characterized by elevated glutamate and adenosine levels. [ABSTRACT FROM AUTHOR]

Temporal discounting, in which the recipient of a reward perceives the value of that reward to decrease with delay in its receipt, is associated with impulsivity and psychiatric disorders such as depression. Here, we investigate the role of the serotonin 5-HT4 receptor (5-HT4R) in modulating temporal discounting in the macaque dorsal caudate nucleus (dCDh), the neurons of which have been shown to represent temporally discounted value. We first mapped the 5-HT4R distribution in macaque brains using positron emission tomography (PET) imaging and confirmed dense expression of 5-HT4R in the dCDh. We then examined the effects of a specific 5-HT4R antagonist infused into the dCDh. Blockade of 5-HT4R significantly increased error rates in a goal-directed delayed reward task, indicating an increase in the rate of temporal discounting. This increase was specific to the 5-HT4R blockade because saline controls showed no such effect. The results demonstrate that 5-HT4Rs in the dCDh are involved in reward-evaluation processes, particularly in the context of delay discounting, and suggest that serotonergic transmission via 5-HT4R may be a key component in the neural mechanisms underlying impulsive decisions, potentially contributing to depressive symptoms. [ABSTRACT FROM AUTHOR]

Glutamate is one of the most important excitatory neurotransmitters within the mammalian central nervous system. The role of glutamate in regulating neural network signaling transmission through both synaptic and extra‐synaptic paths highlights the importance of the real‐time and continuous monitoring of its concentration and dynamics in living organisms. Progresses in multidisciplinary research have promoted the development of electrochemical glutamate sensors through the co‐design of materials, interfaces, electronic devices, and integrated systems. This review summarizes recent works reporting various electrochemical sensor designs and their applicability as miniaturized neural probes to in vivo sensing within biological environments. We start with an overview of the role and physiological significance of glutamate, the metabolic routes, and its presence in various bodily fluids. Next, we discuss the design principles, commonly employed validation models/protocols, and successful demonstrations of multifunctional, compact, and bio‐integrated devices in animal models. The final section provides an outlook on the development of the next generation glutamate sensors for neuroscience and neuroengineering, with the aim of offering practical guidance for future research. [ABSTRACT FROM AUTHOR]

The Venus flytrap sea anemone Actinoscyphia liui inhabits the nutrient‐limited deep ocean in the tropical western Pacific. Compared with most other sea anemones, it has undergone a distinct modification of body shape similar to that of the botanic flytrap. However, the molecular mechanism by which such a peculiar sea anemone adapts to a deep‐sea oligotrophic environment is unknown. Here, we report the chromosomal‐level genome of A. liui constructed from PacBio and Hi‐C data. The assembled genome is 522 Mb in size and exhibits a continuous scaffold N50 of 58.4 Mb. Different from most other sea anemones, which typically possess 14–18 chromosomes per haplotype, A. liui has only 11. The reduced number of chromosomes is associated with chromosome fusion, which likely represents an adaptive strategy to economize energy in oligotrophic deep‐sea environments. Comparative analysis with other deep‐sea sea anemones revealed adaptive evolution in genes related to cellular autophagy (TMBIM6, SESN1, SCOCB and RPTOR) and mitochondrial energy metabolism (MDH1B and KAD2), which may aid in A. liui coping with severe food scarcity. Meanwhile, the genome has undergone at least two rounds of expansion in gene families associated with fast synaptic transmission, facilitating rapid responses to water currents and prey. Positive selection was detected on putative phosphorylation sites of muscle contraction‐related proteins, possibly further improving feeding efficiency. Overall, the present study provides insights into the molecular adaptation to deep‐sea oligotrophic environments and sheds light upon potential effects of a novel morphology on the evolution of Cnidaria. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1β in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1β expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1β-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1β-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Neuroprotection aims to safeguard neurons from damage caused by various factors like stress, potentially leading to the rescue, recovery, or regeneration of the nervous system and its functions [J Clin Neurosci. 2002;9(1):4–8]. Conversely, neuroplasticity refers to the brain’s ability to adapt and change throughout life, involving structural and functional alterations in cells and synaptic transmission [Neural Plast. 2014;2014:541870]. Neuroprotection is a broad and multidisciplinary field encompassing various approaches and strategies aimed at preserving and promoting neuronal health. It is a critical area of research in neuroscience and neurology, with the potential to lead to new therapies for a wide range of neurological disorders and conditions. Neuroprotection can take various forms and may involve pharmacological agents, lifestyle modifications, or behavioral interventions. Accordingly, also the perspective and the meaning of neuroprotection differs due to different angles of interpretation. The primary interpretation is from the pharmacological point of view since the most consistent data come from this field. In addition, we will discuss also alternative, yet less considered, perspectives on neuroprotection, focusing on specific neuroprotective targets, interactions with surrounding microglia, different levels of neuroprotective effects, the reversive/adaptative dimension, and its use as anticipatory/prophylactic intervention. [ABSTRACT FROM AUTHOR]

One of the puzzling aspects of sporadic Alzheimer's disease (AD) is how it commences. Changes in one key brain peptide, amyloid-beta (Aß), accompany disease progression, but whether this comprises a trigger or a consequence of AD is still a topic of debate. It is clear however that the cerebral presence of oligomeric Aß (1-42) is a key factor in early AD-pathogenesis. Furthermore, treatment of rodent brains with oligomeric Aß (1-42) either in vitro or in vivo, acutely impairs hippocampal synaptic plasticity, creating a link between Aß-pathology and learning impairments. Here, we show that a once-off inoculation of the brains of healthy adult rats with oligomeric Aß (1-42) exerts debilitating effects on the long-term viability of the hippocampus, one of the primary targets of AD. Changes are progressive: months after treatment, synaptic plasticity, neuronal firing and spatial learning are impaired and expression of plasticityrelated proteins are changed, in the absence of amyloid plaques. Early changes relate to activation of microglia, whereas later changes are associated with a reconstruction of astroglial morphology. These data suggest that a disruption of Aß homeostasis may suffice to trigger an irreversible cascade, underlying progressive loss of hippocampal function, that parallels the early stages of AD. [ABSTRACT FROM AUTHOR]

AMPA-type receptors (AMPARs) are rapidly inserted into synapses undergoing plasticity to increase synaptic transmission, but it is not fully understood if and how AMPAR-containing vesicles are selectively trafficked to these synapses. Here, we developed a strategy to label AMPAR GluA1 subunits expressed from their endogenous loci in cultured rat hippocampal neurons and characterized the motion of GluA1-containing vesicles using single-particle tracking and mathematical modeling. We find that GluA1-containing vesicles are confined and concentrated near sites of stimulation-induced structural plasticity. We show that confinement is mediated by actin polymerization, which hinders the active transport of GluA1-containing vesicles along the length of the dendritic shaft by modulating the rheological properties of the cytoplasm. Actin polymerization also facilitates myosin-mediated transport of GluA1-containing vesicles to exocytic sites. We conclude that neurons utilize F-actin to increase vesicular GluA1 reservoirs and promote exocytosis proximal to the sites of synaptic activity. [ABSTRACT FROM AUTHOR]

The encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem are well suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that reduce MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation (“wedge-slice”). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The “in vivo-like” timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivolike timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hypersuppression of cochlear activity. [ABSTRACT FROM AUTHOR]

Key points Dynamins are GTPases required for pinching vesicles off the plasma membrane once a critical curvature is reached during endocytosis. Here, we probed dynamin function in central synapses by depleting all three dynamin isoforms in postnatal hippocampal neurons down to negligible levels. We found a decrease in the propensity of evoked neurotransmission as well as a reduction in synaptic vesicle numbers. Recycling of synaptic vesicles during spontaneous or low levels of evoked activity were largely impervious to dynamin depletion, while retrieval of synaptic vesicle components at higher levels of activity was partially arrested. These results suggest the existence of balancing dynamin‐independent mechanisms for synaptic vesicle recycling at central synapses. Classical dynamin‐dependent mechanisms are not essential for retrieval of synaptic vesicle proteins after quantal single synaptic vesicle fusion, but they become more relevant for membrane retrieval during intense, sustained neuronal activity. Loss of dynamin 2 does not impair synaptic transmission. Loss of all three dynamin isoforms mostly affects evoked neurotransmission. Excitatory synapse function is more susceptible to dynamin loss. Spontaneous neurotransmission is only mildly affected by loss of dynamins. Single synaptic vesicle endocytosis is largely dynamin independent. [ABSTRACT FROM AUTHOR]

Neurons rely on mitochondrial energy metabolism for essential functions like neurogenesis, neurotransmission, and synaptic plasticity. Mitochondrial dysfunctions are associated with neurodevelopmental disorders including Fragile X syndrome (FXS), the most common cause of inherited intellectual disability, which also presents with motor skill deficits. However, the precise role of mitochondria in the pathophysiology of FXS remains largely unknown. Notably, previous studies have linked the serotonergic system and mitochondrial activity to FXS. Our study investigates the potential therapeutic role of serotonin receptor 1A (5-HT1A) in FXS. Using the Drosophila model of FXS, we demonstrated that treatment with eltoprazine, a 5-HT1A agonist, can ameliorate synaptic transmission, correct mitochondrial deficits, and ultimately improve motor behavior. While these findings suggest that the 5-HT1A-mitochondrial axis may be a promising therapeutic target, further investigation is needed in the context of FXS. [ABSTRACT FROM AUTHOR]

Background and Purpose: Transient hypofunction of the NMDA receptor represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant pathway synapses, have barely been explored in this pathological condition. Experimental Approach: We identified a series of synaptic alterations of the lateral and medial perforant paths in animals postnatally treated with the NMDA antagonist MK‐801. This dysregulation suggests decreased cognitive performance, for which the dentate gyrus is critical. Key Results: We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in slices from MK‐801‐treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of long‐term potentiation (LTP) and CB1 receptor‐mediated long‐term depression (LTD). Remarkably, by inhibiting the degradation of 2‐arachidonoylglycerol (2‐AG), an endogenous ligand of the CB1 receptor, we restored the LTD in animals treated with MK‐801. Additionally, we showed for the first time, that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDA receptors. Conclusion and Implications: Dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus has been demonstrated, which may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia. [ABSTRACT FROM AUTHOR]

Background and Purpose: Methamphetamine (METH) use disorder has risen dramatically over the past decade, and there are currently no FDA‐approved medications due, in part, to gaps in our understanding of the pharmacological mechanisms related to METH action in the brain. Experimental Approach: Here, we investigated whether transient receptor potential ankyrin 1 (TRPA1) mediates each of several METH abuse‐related behaviours in rodents: self‐administration, drug‐primed reinstatement, acquisition of conditioned place preference, and hyperlocomotion. Additionally, METH‐induced molecular (i.e., neurotransmitter and protein) changes in the brain were compared between wild‐type and TRPA1 knock‐out mice. Finally, the relationship between TRPA1 and the dopamine transporter was investigated through immunoprecipitation and dopamine reuptake assays. Key Results: TRPA1 antagonism blunted METH self‐administration and drug‐primed reinstatement of METH‐seeking behaviour. Further, development of METH‐induced conditioned place preference and hyperlocomotion were inhibited by TRPA1 antagonist treatment, effects that were not observed in TRPA1 knock‐out mice. Similarly, molecular studies revealed METH‐induced increases in dopamine levels and expression of dopamine system‐related proteins in wild‐type, but not in TRPA1 knock‐out mice. Furthermore, pharmacological blockade of TRPA1 receptors reduced the interaction between TRPA1 and the dopamine transporter, thereby increasing dopamine reuptake activity by the transporter. Conclusion and Implications: This study demonstrates that TRPA1 is involved in the abuse‐related behavioural effects of METH, potentially through its modulatory role in METH‐induced activation of dopaminergic neurotransmission. Taken together, these data suggest that TRPA1 may be a novel therapeutic target for treating METH use disorder. [ABSTRACT FROM AUTHOR]

The mechanisms utilized by neurons to regulate the efficacy of phasic and tonic inhibition and their impacts on synaptic plasticity and behavior are incompletely understood. Cleft lip and palate transmembrane protein 1 (Clptm1) is a membrane-spanning protein that interacts with multiple γ-aminobutyric acid type A receptor (GABAAR) subunits, trapping them in the endoplasmic reticulum and Golgi network. Overexpression and knock-down studies suggest that Clptm1 modulates GABAAR-mediated phasic inhibition and tonic inhibition as well as activity-induced inhibitory synaptic homeostasis in cultured hippocampal neurons. To investigate the role of Clptm1 in the modulation of GABAARs in vivo, we generated Clptm1 knock-out (KO) mice. Here, we show that genetic KO of Clptm1 elevated phasic and tonic inhibitory transmission in both male and female heterozygous mice. Although basal excitatory synaptic transmission was not affected, Clptm1 haploinsufficiency significantly blocked high-frequency stimulation-induced long–term potentiation (LTP) in hippocampal CA3→CA1 synapses. In the hippocampus-dependent contextual fear-conditioning behavior task, both male and female Clptm1 heterozygous KO mice exhibited impairment in contextual fear memory. In addition, LTP and contextual fear memory were rescued by application of L-655,708, a negative allosteric modulator of the extrasynaptic GABAAR α5 subunit. These results suggest that haploinsufficiency of Clptm1 contributes to cognitive deficits through altered synaptic transmission and plasticity by elevation of inhibitory neurotransmission, with tonic inhibition playing a major role. [ABSTRACT FROM AUTHOR]

Recent work demonstrated that activation of spinal D1 and D5 dopamine receptors (D1/D5Rs) facilitates non-Hebbian long-term potentiation (LTP) at primary afferent synapses onto spinal projection neurons. However, the cellular localization of the D1/D5Rs driving non-Hebbian LTP in spinal nociceptive circuits remains unknown, and it is also unclear whether D1/D5R signaling must occur concurrently with sensory input in order to promote non-Hebbian LTP at these synapses. Here we investigate these issues using cell-type–selective knockdown of D1Rs or D5Rs from lamina I spinoparabrachial neurons, dorsal root ganglion (DRG) neurons, or astrocytes in adult mice of either sex using Cre recombinase-based genetic strategies. The LTP evoked by low-frequency stimulation of primary afferents in the presence of the selective D1/D5R agonist SKF82958 persisted following the knockdown of D1R or D5R in spinoparabrachial neurons, suggesting that postsynaptic D1/D5R signaling was dispensable for non-Hebbian plasticity at sensory synapses onto these key output neurons of the superficial dorsal horn (SDH). Similarly, the knockdown of D1Rs or D5Rs in DRG neurons failed to influence SKF82958-enabled LTP in lamina I projection neurons. In contrast, SKF82958-induced LTP was suppressed by the knockdown of D1R or D5R in spinal astrocytes. Furthermore, the data indicate that the activation of D1R/D5Rs in spinal astrocytes can either retroactively or proactively drive non-Hebbian LTP in spinoparabrachial neurons. Collectively, these results suggest that dopaminergic signaling in astrocytes can strongly promote activity-dependent LTP in the SDH, which is predicted to significantly enhance the amplification of ascending nociceptive transmission from the spinal cord to the brain. [ABSTRACT FROM AUTHOR]

The nonlinear Fitzhugh–Nagumo (FN) model is a well-known nonlinear reaction-diffusion model, which is a simplified form of the Hodgkin–Huxley (HH) model. Several important phenomena are analyzed via the FN model, such as nerve impulse transmission through the neurons, biological population genetics, noise formations in circuit theory, intercellular trigger wave propagation, and others. The FN model is definitely an important mathematical model in the domain of neurobiological sciences and engineering applications. In this paper, we study the nonlinear fractional FN model, computationally and numerically using the auxiliary equation (AE) method through the conformable derivative. We have established numerous fresh, useful, efficient and wide-ranging closed-form traveling wave solutions of the model. Additionally, we examine the influence of fractional parameter on the signal transmission through the nerve system and other related wave propagation by sketching the three-dimensional graphs of the solutions with the aid of the Mathematica program. The established results authenticate the efficiency and reliability of the considered method. [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) denotes damage to both the structure and function of the spinal cord, primarily manifesting as sensory and motor deficits caused by disruptions in neural transmission pathways, potentially culminating in irreversible paralysis. Its pathophysiological processes are complex, with numerous molecules and signaling pathways intricately involved. Notably, the pronounced upregulation of the Wnt signaling pathway post-SCI holds promise for neural regeneration and repair. Activation of the Wnt pathway plays a crucial role in neuronal differentiation, axonal regeneration, local neuroinflammatory responses, and cell apoptosis, highlighting its potential as a therapeutic target for treating SCI. However, excessive activation of the Wnt pathway can also lead to negative effects, highlighting the need for further investigation into its applicability and significance in SCI. This paper provides an overview of the latest research advancements in the Wnt signaling pathway in SCI, summarizing the recent progress in treatment strategies associated with the Wnt pathway and analyzing their advantages and disadvantages. Additionally, we offer insights into the clinical application of the Wnt signaling pathway in SCI, along with prospective avenues for future research direction. [ABSTRACT FROM AUTHOR]

Introduction: Pseudomyxoma peritonei (PMP) is a disease characterized by progressive accumulation of intraperitoneal mucinous ascites produced by neoplasms in the abdominal cavity. Since the prognosis of patients with PMP remains unsatisfactory, the development of effective therapeutic drug(s) is a matter of pressing concern. Genetic analyses of PMP have clarified the frequent activation of GNAS and/or KRAS. However, the involvement of global epigenetic alterations in PMPs has not been reported. Methods: To clarify the genetic background of the 15 PMP tumors, we performed genetic analysis using AmpliSeq Cancer HotSpot Panel v2. We further investigated global DNA methylation in the 15 tumors and eight noncancerous colonic epithelial tissues using MethylationEPIC array BeadChip (Infinium 850k) containing a total of 865,918 probes. Results: This is the first report of comprehensive DNA methylation profiles of PMPs in the world. We clarified that the 15 PMPs could be classified into at least two epigenotypes, unique methylation epigenotype (UME) and normal-like methylation epigenotype (NLME), and that genes associated with neuronal development and synaptic signaling may be involved in the development of PMPs. In addition, we identified a set of hypermethylation marker genes such as HOXD1 and TSPYL5 in the 15 PMPs. Conclusions: These findings may help the understanding of the molecular mechanism(s) of PMP and contribute to the development of therapeutic strategies for this life-threatening disease. [ABSTRACT FROM AUTHOR]

The excitatory monosynaptic activation of hippocampal CA1 pyramidal cells is spatially segregated such that the proximal part of the apical dendritic tree in stratum radiatum (SR) receives input from the hippocampal CA3 region while the distal part in the stratum‐lacunosum‐moleculare (SLM) receives input mainly from the entorhinal cortex. The AMPA receptor‐mediated (AMPA) signalling of SLM synapses in slices from neonatal rats was previously found to considerably differ from that of the SR synapses. In the present study, AMPA signalling of SLM synapses in 1‐month‐old rats has been examined, that is, when the hippocampus is essentially functionally mature. For the SR synapses, this time is characterized by a facilitatory shift in short‐term plasticity, in the disappearance of labile postsynaptic AMPA signalling, a property thought to be important for early activity‐dependent organization of neural circuits, and the expression of an adult form of long‐term potentiation. We found that the SLM synapses alter their short‐term plasticity similarly to that of the SR synapses. However, the labile postsynaptic AMPA signalling was not only maintained but substantially enhanced in the SLM synapses. The long‐term potentiation observed was not of the adult form but like that of the neonatal SR synapses based on unsilencing of AMPA labile synapses. We propose that these features of the SLM synapses in the mature hippocampus will help to produce a flexible map of the multimodal sensory input reaching the SLM required for its conjunctive operation with the SR input to generate a proper functional output from the CA1 region. The SLM and SR regions of the hippocampus follow distinct developmental paths as they mature functionally. During maturation, the SLM synapses become more postsynaptically AMPA labile, a property thought to be a developmental feature adapted for the early activity‐dependent topographical organization of cortical areas. We propose that the AMPA lability presently observed allows for synaptic flexibility required for the adult SLM region to represent this complex multimodal sensory input. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease. Unfortunately, efficient and affordable treatments are still lacking for this neurodegenerative disorder, it is therefore urgent to identify new pharmacological targets. Astrocytes are playing a crucial role in the tuning of synaptic transmission and several studies have pointed out severe astrocyte reactivity in AD. Reactive astrocytes show altered physiology and function, suggesting they could have a role in the early pathophysiology of AD. Objective: We aimed to characterize early synaptic impairments in the AppNL-F knock-in mouse model of AD, especially to understand the contribution of astrocytes to early brain dysfunctions. Methods: The AppNL-F mouse model carries two disease-causing mutations inserted in the amyloid precursor protein gene. This strain does not start to develop amyloid-β plaques until 9 months of age. Thanks to electrophysiology, we investigated synaptic function, at both neuronal and astrocytic levels, in 6-month-old animals and correlate the synaptic activity with emotional behavior. Results: Electrophysiological recordings in the hippocampus revealed an overall synaptic mistuning at a pre-plaque stage of the pathology, associated to an intact social memory but a stronger depressive-like behavior. Astrocytes displayed a reactive-like morphology and a higher tonic GABA current compared to control mice. Interestingly, we here show that the synaptic impairments in hippocampal slices are partially corrected by a pre-treatment with the monoamine oxidase B blocker deprenyl or the fast-acting antidepressant ketamine (5 mg/kg). Conclusions: We propose that reactive astrocytes can induce synaptic mistuning early in AD, before plaques deposition, and that these changes are associated with emotional symptoms. [ABSTRACT FROM AUTHOR]

Acetylcholine is the main neurotransmitter at the vertebrate neuromuscular junctions (NMJs). ACh exocytosis is precisely modulated by co-transmitter ATP and its metabolites. It is assumed that ATP/ADP effects on ACh release rely on activation of presynaptic Gi protein-coupled P2Y13 receptors. However, downstream signaling mechanism of ATP/ADP-mediated modulation of neuromuscular transmission remains elusive. Using microelectrode recording and fluorescent indicators, the mechanism underlying purinergic regulation was studied in the mouse diaphragm NMJs. Pharmacological stimulation of purinoceptors with ADP decreased synaptic vesicle exocytosis evoked by both low and higher frequency stimulation. This inhibitory action was suppressed by antagonists of P2Y13 receptors (MRS 2211), Ca2+ mobilization (TMB8), protein kinase C (chelerythrine) and NADPH oxidase (VAS2870) as well as antioxidants. This suggests the participation of Ca2+ and reactive oxygen species (ROS) in the ADP-triggered signaling. Indeed, ADP caused an increase in cytosolic Ca2+ with subsequent elevation of ROS levels. The elevation of [Ca2+]in was blocked by MRS 2211 and TMB8, whereas upregulation of ROS was prevented by pertussis toxin (inhibitor of Gi protein) and VAS2870. Targeting the main components of lipid rafts, cholesterol and sphingomyelin, suppressed P2Y13 receptor-dependent attenuation of exocytosis and ADP-induced enhancement of ROS production. Inhibition of P2Y13 receptors decreased ROS production and increased the rate of exocytosis during intense activity. Thus, suppression of neuromuscular transmission by exogenous ADP or endogenous ATP can rely on P2Y13 receptor/Gi protein/Ca2+/protein kinase C/NADPH oxidase/ROS signaling, which is coordinated in a lipid raft-dependent manner. [ABSTRACT FROM AUTHOR]

Secreted microRNAs (miRNAs) have been detected in various body fluids including the cerebrospinal fluid, yet their direct role in regulating synaptic transmission remains uncertain. We found that intrathecal injection of low dose of let-7b (1 mg) induced shortterm (,24 hours) mechanical allodynia and heat hyperalgesia, a response that is compromised in Tlr7-/- or Trpa1-/- mice. Ex vivo and in vivo calcium imaging in GCaMP6-report mice revealed increased calcium signal in spinal cord afferent terminals and doral root ganglion/dorsal root ganglia neurons following spinal perfusion and intraplantar injection of let-7b. Patch-clamp recordings also demonstrated enhanced excitatory synaptic transmission (miniature excitatory postsynaptic currents [EPSCs]) in spinal nociceptive neurons following let-7b perfusion or optogenetic activation of axonal terminals. The elevation in spinal calcium signaling and EPSCs was dependent on the presence of toll-like receptor-7 (TLR7) and transient receptor potential ion channel subtype A1 (TRPA1). In addition, endogenous let-7b is enriched in spinal cord synaptosome, and peripheral inflammation increased let-7b in doral root ganglion/dorsal root ganglia neurons, spinal cord tissue, and the cerebrospinal fluid. Notably, let-7b antagomir inhibited inflammatory pain and inflammation-induced synaptic plasticity (EPSC increase), suggesting an endogenous role of let-7b in regulating pain and synaptic transmission. Furthermore, intrathecal injection of let-7b, at a higher dose (10 mg), induced persistent mechanical allodynia for .2 weeks, which was abolished in Tlr7-/- mice. The high dose of let-7b also induced microgliosis in the spinal cord. Of interest, intrathecal minocycline only inhibited let-7b-induced mechanical allodynia in male but not female mice. Our findings indicate that the secreted microRNA let-7b has the capacity to provoke pain through both neuronal and glial signaling, thereby establishing miRNA as an emerging neuromodulator. [ABSTRACT FROM AUTHOR]

Pulse-coupled spiking neural networks are a powerful tool to gain mechanistic insights into how neurons self-organize to produce coherent collective behavior. These networks use simple spiking neuron models, such as the θ -neuron or the quadratic integrate-and-fire (QIF) neuron, that replicate the essential features of real neural dynamics. Interactions between neurons are modeled with infinitely narrow pulses, or spikes, rather than the more complex dynamics of real synapses. To make these networks biologically more plausible, it has been proposed that they must also account for the finite width of the pulses, which can have a significant impact on the network dynamics. However, the derivation and interpretation of these pulses are contradictory, and the impact of the pulse shape on the network dynamics is largely unexplored. Here, I take a comprehensive approach to pulse coupling in networks of QIF and θ -neurons. I argue that narrow pulses activate voltage-dependent synaptic conductances and show how to implement them in QIF neurons such that their effect can last through the phase after the spike. Using an exact low-dimensional description for networks of globally coupled spiking neurons, I prove for instantaneous interactions that collective oscillations emerge due to an effective coupling through the mean voltage. I analyze the impact of the pulse shape by means of a family of smooth pulse functions with arbitrary finite width and symmetric or asymmetric shapes. For symmetric pulses, the resulting voltage coupling is not very effective in synchronizing neurons, but pulses that are slightly skewed to the phase after the spike readily generate collective oscillations. The results unveil a voltage-dependent spike synchronization mechanism at the heart of emergent collective behavior, which is facilitated by pulses of finite width and complementary to traditional synaptic transmission in spiking neuron networks. [ABSTRACT FROM AUTHOR]

Autoantibodies directed against the N -methyl- D- aspartate receptor (NMDAR-Ab) are pathogenic immunoglobulins detected in patients suffering from NMDAR encephalitis. NMDAR-Ab alter the receptor membrane trafficking, synaptic transmission and neuronal network properties, leading to neurological and psychiatric symptoms in patients. Patients often have very little neuronal damage but rapid and massive (treatment-responsive) brain dysfunctions related to an unknown early mechanism of NMDAR-Ab. Our understanding of this early molecular cascade remains surprisingly fragmented. Here, we used a combination of single molecule-based imaging of membrane proteins to unveil the spatiotemporal action of NMDAR-Ab on live hippocampal neurons. We first demonstrate that different clones of NMDAR-Ab primarily affect extrasynaptic (and not synaptic) NMDARs. In the first minutes, NMDAR-Ab increase extrasynaptic NMDAR membrane dynamics, declustering its surface interactome. NMDAR-Ab also rapidly reshuffle all membrane proteins located in the extrasynaptic compartment. Consistent with this alteration of multiple proteins, effects of NMDAR-Ab were not mediated through the sole interaction between the NMDAR and EphB2 receptor. In the long term, NMDAR-Ab reduce the NMDAR synaptic pool by slowing down receptor membrane dynamics in a cross-linking-independent manner. Remarkably, exposing only extrasynaptic NMDARs to NMDAR-Ab was sufficient to produce their full-blown effect on synaptic receptors. Collectively, we demonstrate that NMDAR-Ab initially impair extrasynaptic proteins, then the synaptic ones. These data thus shed new and unsuspected light on the mode of action of NMDAR-Ab and, probably, our understanding of (extra)synaptopathies. [ABSTRACT FROM AUTHOR]

Recently, we showed that while atogepant—a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist—does not fully prevent activation of meningeal nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C fibres and late response probability in Aδ fibres. The current study investigates atogepant effect on CSD-induced activation and sensitization of high threshold (HT) and wide dynamic range (WDR) central dura-sensitive trigeminovascular neurons. In anaesthetized male rats, single-unit recordings were used to assess effects of atogepant (5 mg/kg) versus vehicle on CSD-induced activation and sensitization of HT and WDR trigeminovascular neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus revealed the ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 versus 1/10 activated neurons in the control versus treated groups, P = 0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 versus 5/10 activated neurons in the control versus treated groups, P = 0.64). Unexpectedly however, in spite of atogepant's inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant' ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly myelinated Aδ fibres. Atogepant's inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibres. Molecular and physiological processes that govern neuronal activation versus sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the spinal trigeminal nucleus can prevent their sensitization but not activation. [ABSTRACT FROM AUTHOR]

Objective: Given its key homeostatic role affecting mitochondria, ionotropic and metabotropic receptors, and voltage‐gated ion channels, sigma‐1 receptor (Sig1R) represents an interesting target for epilepsy management. Antiseizure effects of the positive allosteric modulator E1R have already been reported in acute seizure models. Although modulation of serotonergic neurotransmission is considered the main mechanism of action of fenfluramine, its interaction with Sig1R may be of additional relevance. Methods: To further explore the potential of Sig1R as a target, we assessed the efficacy and tolerability of E1R and fenfluramine in two chronic mouse models, including an amygdala kindling paradigm and the intrahippocampal kainate model. The relative contribution of the interaction with Sig1R was analyzed using combination experiments with the Sig1R antagonist NE‐100. Results: Whereas E1R exerted pronounced dose‐dependent antiseizure effects at well‐tolerated doses in fully kindled mice, only limited effects were observed in response to fenfluramine, without a clear dose dependency. In the intrahippocampal kainate model, E1R failed to influence electrographic seizure activity. In contrast, fenfluramine significantly reduced the frequency of electrographic seizure events and their cumulative duration. Pretreatment with NE‐100 reduced the effects of E1R and fenfluramine in the kindling model. Surprisingly, pre‐exposure to NE‐100 in the intrahippocampal kainate model rather enhanced and prolonged fenfluramine's antiseizure effects. Significance: In conclusion, the kindling data further support Sig1R as an interesting target for novel antiseizure medications. However, it is necessary to further explore the preclinical profile of E1R in chronic epilepsy models with spontaneous seizures. Despite the rather limited effects in the kindling paradigm, the findings from the intrahippocampal kainate model suggest that it is of interest to further assess a possible broad‐spectrum potential of fenfluramine. [ABSTRACT FROM AUTHOR]

Following exocytosis, the recapture of plasma membrane‐stranded vesicular proteins into recycling synaptic vesicles (SVs) is essential for sustaining neurotransmission. Surface clustering of vesicular proteins has been proposed to act as a ‘pre‐assembly’ mechanism for endocytosis that ensures high‐fidelity retrieval of SV cargo. Here, we used single‐molecule imaging to examine the nanoclustering of synaptotagmin‐1 (Syt1) and synaptic vesicle protein 2A (SV2A) in hippocampal neurons. Syt1 forms surface nanoclusters through the interaction of its C2B domain with SV2A, which are sensitive to mutations in this domain (Syt1K326A/K328A) and SV2A knockdown. SV2A co‐clustering with Syt1 is reduced by blocking SV2A's cognate interaction with Syt1 (SV2AT84A). Surprisingly, impairing SV2A‐Syt1 nanoclustering enhanced the plasma membrane recruitment of key endocytic protein dynamin‐1, causing accelerated Syt1 endocytosis, altered intracellular sorting and decreased trafficking of Syt1 to Rab5‐positive endocytic compartments. Therefore, SV2A and Syt1 are segregated from the endocytic machinery in surface nanoclusters, limiting dynamin recruitment and negatively regulating Syt1 entry into recycling SVs. [ABSTRACT FROM AUTHOR]

The melanocortin-4 receptor (MC4R) is a G protein-coupled receptor (GPCR) that is expressed in several brain locations encompassing the hypothalamus and the brainstem, where the receptor controls several body functions, including metabolism. In a well-defined pathway to decrease appetite, hypothalamic proopiomelanocortin (POMC) neurons localized in the arcuate nucleus (Arc) project to MC4R neurons in the paraventricular nuclei (PVN) to release the natural MC4R agonist α-melanocyte-stimulating hormone (α-MSH). Arc neurons also project excitatory glutamatergic fibers to the MC4R neurons in the PVN for a fast synaptic transmission to regulate a satiety pathway potentiated by α-MSH. By using super-resolution microscopy, we found that in hypothalamic neurons in a primary culture, postsynaptic density protein 95 (PSD95) colocalizes with GluN1, a subunit of the ionotropic N-methyl-D-aspartate receptor (NMDAR). Thus, hypothalamic neurons form excitatory postsynaptic specializations. To study the MC4R distribution at these sites, tagged HA-MC4R under the synapsin promoter was expressed in neurons by adeno-associated virus (AAV) gene transduction. HA-MC4R immunofluorescence peaked at the center and in proximity to the PSD95- and NMDAR-expressing sites. These data provide morphological evidence that MC4R localizes together with glutamate receptors at postsynaptic and peri-postsynaptic sites. [ABSTRACT FROM AUTHOR]

Forgetting is often viewed as a human frailty. However, over the years, it has been considered an adaptive process that allows people to avoid retrieval of undesirable memories, preventing them from suffering and discomfort. Evidence shows that the ability to suppress memories is affected by several psychopathological conditions characterized by persistent unwanted thoughts, including anxiety and posttraumatic stress disorders. Nevertheless, memory suppression (MS) mechanisms in addiction—a clinical condition characterized by recurrent drug‐related thoughts that contribute to repeated drug use—have received little attention so far. Addiction theories reveal that drugs change behavior by working on memory systems, particularly on declarative memory, which is related to the retrieval and encoding of drug‐related memories. In this review, the main behavioral and neurofunctional findings concerning the Think/No‐Think task—an adaptation of the classical Go/No‐Go tasks typically used to evaluate the suppression of motor response—are presented. We then show how the memory system can be involved in the craving or anticipation/preoccupation stage of the addiction cycle. Subsequently, the study of MS in the context of addictive behaviors is highlighted as a promising approach for gaining knowledge about the mechanisms contributing to the continuation of addiction. Finally, we discuss how interventions aiming to strengthen this ability could impact the anticipation/preoccupation stage by (i) reducing the accessibility of drug‐related memories, (ii) decreasing craving and attention toward drug‐related stimuli, and (iii) improving overall inhibition abilities. In conclusion, this review aims to illustrate how the study of MS may be a valuable approach to enhance our understanding of substance use disorders by unveiling the underlying cognitive and neural mechanisms involved, which could have important implications for addiction treatment. [ABSTRACT FROM AUTHOR]

Background and Purpose Experimental Approach Key Results Conclusion and Implications Clozapine is an effective antipsychotic for treatment‐resistant schizophrenia, but its discontinuation leads to discontinuation syndrome/catatonia complicated by benzodiazepine‐resistance and rhabdomyolysis.This study determined time‐dependent effects of exposure and subsequent discontinuation of clozapine on expression of connexin43, 5‐HT receptors, intracellular L‐β‐aminoisobutyrate (L‐BAIBA) and 2nd‐messengers and signalling of AMPK, PP2A and Akt in cultured astrocytes and rat frontal cortex.Intracellular L‐BAIBA levels increased during clozapine exposure but immediately recovered after discontinuation. Both exposure to clozapine and L‐BAIBA increased connexin43 and signalling of AMPK/Akt time‐dependently, but reduced PP2A signalling, 5‐HT receptor expression and IP3 level. These changes recovered within 2 weeks after discontinuation, while 5‐HT receptors and IP3 transiently increased during the recovery process. L‐BAIBA activated AMPK signalling, leading to attenuated PP2A signalling. Astroglial D‐serine release was increased by clozapine exposure but continued to increase within 1 week after discontinuation via activation of IP3 receptor function.Clozapine discontinuation restored PP2A signalling due to decreased L‐BAIBA, increased 5‐HT receptor expression via probably enhanced 5‐HT receptor recycling, but increased astroglial D‐serine release persisted by transiently activated IP3 receptors via transiently increased IP3 level. Decreased L‐BAIBA caused by clozapine discontinuation is, at least partially, involved in the transiently increased 5‐HT receptor and astroglial D‐serine release. [ABSTRACT FROM AUTHOR]

Polymorphisms in the gene encoding for metabotropic glutamate receptor 3 (mGlu 3) are associated with an increased likelihood of schizophrenia diagnosis and can predict improvements in negative symptoms following treatment with antipsychotics. However, the mechanisms by which mGlu 3 can regulate brain circuits involved in schizophrenia pathophysiology are not clear. We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, slice optogenetics, and fiber photometry to investigate the effects of mGlu 3 activation on phencyclidine (PCP)-induced impairments in thalamo-accumbal transmission and sociability deficits. A chemogenetic approach was used to evaluate the role of thalamo-accumbal transmission in PCP-induced sociability deficits. We first established that PCP treatment augmented excitatory transmission onto dopamine D 1 receptor–expressing medium spiny neurons (D1-MSNs) in the nucleus accumbens (NAc) and induced sociability deficits. Our studies revealed a selective increase in glutamatergic synaptic transmission from thalamic afferents to D1-MSNs in the NAc shell. Chemogenetic silencing of thalamo-accumbal inputs rescued PCP-induced sociability deficits. Pharmacological activation of mGlu 3 normalized PCP-induced impairments in thalamo-accumbal transmission and sociability deficits. Mechanistic studies revealed that mGlu 3 activation induced robust long-term depression at synapses from the thalamic projections onto D1-MSNs in the NAc shell. These data demonstrate that activation of mGlu 3 decreases thalamo-accumbal transmission and thereby rescues sociability deficits in mouse modeling schizophrenia-like symptoms. These findings provide novel insights into the NAc-specific mechanisms and suggest that agents modulating glutamatergic signaling in the NAc may provide a promising approach for treating negative symptoms in schizophrenia. [ABSTRACT FROM AUTHOR]

Synaptically localized NMDA receptors (NMDARs) play a crucial role in important cognitive functions by mediating synaptic transmission and plasticity. In contrast, a tonic NMDAR current, thought to be mediated by extrasynaptic NMDARs, has a less clear function. This review provides a comprehensive overview of tonic NMDAR currents, focusing on their roles in synaptic transmission/plasticity and their impact on cognitive functions and psychiatric disorders. We discuss the roles of 3 endogenous ligands (i.e., glutamate, glycine, and D-serine) and receptors in mediating tonic NMDAR currents and explore the diverse mechanisms that regulate tonic NMDAR currents. In light of recent controversies surrounding the source of D-serine, we highlight the recent findings suggesting that astrocytes release D-serine to modulate tonic NMDAR currents and control cognitive flexibility. Furthermore, we propose distinct roles of neuronal and astrocytic D-serine in different locations and their implications for synaptic regulation and cognitive functions. The potential roles of tonic NMDAR currents in various psychiatric disorders, such as schizophrenia and autism spectrum disorder, are discussed in the context of the NMDAR hypofunction hypothesis. By presenting the mechanisms by which various cells, particularly astrocytes, regulate tonic NMDAR currents, we aim to stimulate future research in NMDAR hypofunction- or hyperfunction-related psychiatric disorders. This review not only provides a better understanding of the complex interplay between tonic NMDAR currents and cognitive functions but also sheds light on its potential therapeutic target for the treatment of various psychiatric disorders. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic neurodegenerative disease (NDD) due to the degeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). PD is characterized by diverse motor symptoms such as rigidity, resting tremors, and bradykinesia, and non-motor symptoms such as cognitive dysfunction and sleep disturbances. Vitamin D (VD), VD receptor (VDR), and VD metabolites are present in the brain and play a role in maintaining the development, differentiation, and functions of the DNs. VDRs exert protective effects against PD neuropathology by modulating functional capacity and DNs neurotransmission in the SN. In virtue of its anti-inflammatory and antioxidant activities, VD could be effective in the prevention and treatment of PD. VD exerts a neuroprotective effect by reducing oxidative stress and mitochondrial dysfunction, and by increasing autophagy and brain-derived neurotrophic factor (BDNF). Low VD serum level is connected with cognitive dysfunction and the development of dementia in PD. The VD-mediated cognitive augmenting effect is interrelated to the safeguarding of synaptic plasticity and modulation of neurotransmitter release. VD deficiency is linked with the severity of olfactory dysfunction which precedes the progression of symptomatic PD. However, the precise role of VD in PD remains unidentified, and there is a conflict about whether treatment with VD can ameliorate PD or not. [ABSTRACT FROM AUTHOR]