Receptor and metabolic insights on the ability of caffeine to prevent alcohol-induced stimulation of mesolimbic dopamine transmission.

The consumption of alcohol and caffeine affects the lives of billions of individuals worldwide. Although recent evidence indicates that caffeine impairs the reinforcing properties of alcohol, a characterization of its effects on alcohol-stimulated mesolimbic dopamine (DA) function was lacking. Acting as the pro-drug of salsolinol, alcohol excites DA neurons in the posterior ventral tegmental area (pVTA) and increases DA release in the nucleus accumbens shell (AcbSh). Here we show that caffeine, via antagonistic activity on A2A adenosine receptors (A2AR), prevents alcohol-dependent activation of mesolimbic DA function as assessed, in-vivo, by brain microdialysis of AcbSh DA and, in-vitro, by electrophysiological recordings of pVTA DA neuronal firing. Accordingly, while the A1R antagonist DPCPX fails to prevent the effects of alcohol on DA function, both caffeine and the A2AR antagonist SCH 58261 prevent alcohol-dependent pVTA generation of salsolinol and increase in AcbSh DA in-vivo, as well as alcohol-dependent excitation of pVTA DA neurons in-vitro. However, caffeine also prevents direct salsolinol- and morphine-stimulated DA function, suggesting that it can exert these inhibitory effects also independently from affecting alcohol-induced salsolinol formation or bioavailability. Finally, untargeted metabolomics of the pVTA showcases that caffeine antagonizes alcohol-mediated effects on molecules (e.g. phosphatidylcholines, fatty amides, carnitines) involved in lipid signaling and energy metabolism, which could represent an additional salsolinol-independent mechanism of caffeine in impairing alcohol-mediated stimulation of mesolimbic DA transmission. In conclusion, the outcomes of this study strengthen the potential of caffeine, as well as of A2AR antagonists, for future development of preventive/therapeutic strategies for alcohol use disorder.

Combinatorial accumulation, stress response, detoxification and synaptic transmission effects of cadmium and selenium in clams Ruditapes philippinarum.

This study investigated the toxicological effects and mechanisms of cadmium (Cd) (5 and 50 µg/L) and selenium (Se) (3 and 30 µg/L) at environmentally relevant concentrations on the gills and digestive glands of clams Ruditapes philippinarum. Results indicated that Cd and Se could tissue-specifically impact osmoregulation, energy metabolism, and synaptic transmission in the gills and digestive glands of clams. After exposure to 50 µg/L Cd, the digestive glands of clams up-regulated the expression of methionine-gamma-lyase and metallothionein for detoxification. Clam digestive glands exposed to 3 µg/L Se up-regulated the expression of catalase and glutathione peroxidase to alleviate oxidative stress, and down-regulated the expression of selenide-water dikinase to reduce the conversion of inorganic Se. Additionally, the interaction mode between Cd and Se largely depended on their molar ratio, with a ratio of 11.71 (50 µg/L Cd + 3 µg/L Se) demonstrated to be particularly harmful, as manifested by significantly more lesions, oxidative stress, and detoxification demand in clams than those exposed to Cd or Se alone. Collectively, this study revealed the complex interaction patterns and mechanisms of Cd and Se on clams, providing a reference for exploring their single and combined toxicity.

Penidaleodiolides A and B, Cage-Like Polyketides with Neurotransmission-Regulating Activity from the Soil Fungus Penicillium daleae L3SO.

Penicillium daleae L3SO is a fungus isolated from the rhizospheric soil of the chloroplast-deficient plant Monotropa uniflora. A chemical study on the rice fermentation of this fungus led to the isolation and identification of two cage-like polyketides, penidaleodiolide A (1) and its biosynthetic-related congener penidaleodiolide B (2). The structures of 1 and 2 were determined by a combination of extensive spectroscopic analysis, biosynthetic consideration, chemical derivatization, and computational methods. Compound 1 harbors an unusual tricyclo[4.3.04,9]nonane scaffold, unprecedented in polyketide natural products. The hypothetical biosynthetic pathways for 1 and 2 were postulated and were supported by CRISPR/Cas9 genome editing results. Penidaleodiolide A (1) showed a significant inhibitory effect on the action potentials of murine hippocampal basket neurons and decreased the frequency of spontaneous excitatory postsynaptic currents in a concentration-dependent manner (the inhibition ratios were 0.30 ± 0.02 for 1 µM, 0.37 ± 0.03 for 10 µM, and 0.50 ± 0.07 for 20 µM) while being devoid of cytotoxicity against the nerve cells.

The interplay of brain neurotransmission and mental fatigue: A research protocol.

INTRODUCTION: Mental fatigue (MF) significantly affects both cognitive and physical performance. However, the precise mechanisms, particularly concerning neurotransmission, require further investigation. An implication of the role of dopamine (DA) and noradrenaline (NA) is stated, but empirical evidence for this theory still needs to be provided. To address this gap, we aim to investigate the role of brain neurotransmission in elucidating if, and how prolonged cognitive activity induces MF and its subsequent impact on cognitive performance. METHODS: This study (registration number: G095422N) will adopt a randomized cross-over design with sixteen healthy participants aged 18-35 years. The sessions include a familiarization, two experimental (DA: 20mg Methylphenidate; NA: 8mg Reboxetine) conditions, and one placebo (lactose tablet: 10mg) condition. A 60-minute individualized Stroop task will be used to investigate whether, and how the onset of MF changes under the influence of reuptake inhibitors. Attention and response inhibition will be assessed before and after the MF-inducing task using a Go/NoGo task. The integration of physiological (electroencephalography, heart rate), behavioral (attention, response inhibition), and subjective indicators (scales and questionnaires) will be used to detect the underlying mechanisms holistically. Data analysis will involve linear mixed models with significance at p<0.05. DISCUSSION: The integration of diverse techniques and analyses offers a comprehensive perspective on the onset and impact of MF, introducing a novel approach. Future research plans involve extending this protocol to explore the connection between brain neurotransmission and physical fatigue. This protocol will further advance our understanding of the complex interplay between the brain and fatigue.

Neurotoxicity induced by aged microplastics from plastic bowls: Abnormal neurotransmission in Caenorhabditis elegans.

The use of plastic bowls (PB) has garnered increasing scrutiny due to the inevitable generation of microplastics (MPs) throughout their lifecycle. Despite this concern, there exists a limited understanding of the behaviors, toxicological effects, and mechanisms associated with aged PB (A-PB). This research investigated the photoaging properties of A-PB following ultraviolet irradiation and evaluated the neurotoxic impact of exposure to A-PB at environmentally relevant concentrations (0.001-1 mg/L) on Caenorhabditis elegans. Significant alterations in the crystallinity, elemental composition, and functional groups of A-PB were observed compared to virgin PB (V-PB), along with the emergence of environmentally persistent free radicals and reactive oxygen species. Toxicity assessments revealed that exposure to 0.1-1 mg/L A-PB induced greater neurotoxicity on locomotion behaviors compared to V-PB, as evidenced by marked reductions in head thrashes, body bends, wavelength, and mean amplitude. Exposure to A-PB also altered the fluorescence intensities and neurodegeneration percentage of dopaminergic, serotonergic, and GABAergic neurons, suggesting neuronal damage in the nematodes. Correspondingly, decreases in the levels of dopamine, serotonin, and GABA were noted together with significant drops in the expression of neurotransmitter-related genes (e.g., dat-1, tph-1, and unc-47). Correlation analyses established a significant positive relationship between these genes and locomotion behaviors. Further exploration showed the absence of locomotion behaviors in dat-1 (ok157), tph-1 (mg280), and unc-47 (e307) mutants, underscoring the pivotal roles of the dat-1, tph-1, and unc-47 genes in mediating neurotoxicity in C. elegans. This study sheds light on the photoaging characteristics and heightened toxicity of A-PB, elucidating the mechanisms driving A-PB-induced neurotoxicity.

Long-term saturated fat-enriched diets impair hippocampal learning and memory processes in a sex-dependent manner.

Consumption of saturated fat-enriched diets during adolescence has been closely associated with the reduction of hippocampal synaptic plasticity and the impairment of cognitive function. Nevertheless, the effect of long-term intake of these foods has not yet been studied. In the present study, we have investigated the effect of a treatment, lasting for 40 weeks, with a diet enriched in saturated fat (SOLF) on i) spatial learning and memory, ii) hippocampal synaptic transmission and plasticity, and iii) hippocampal gene expression levels in aged male and female mice. Our findings reveal that SOLF has a detrimental impact on spatial memory and synaptic plasticity mechanisms, such as long-term potentiation (LTP), and downregulates Gria1 expression specifically in males. In females, SOLF downregulates the gene expression of Gria1/2/3 and Grin1/2A/2B glutamate receptor subunits as well as some proinflammatory interleukins. These findings highlight the importance of considering sex-specific factors when assessing the long-term effects of high-fat diets on cognition and brain plasticity.

Maternal fluoxetine impairs synaptic transmission and plasticity in the medial prefrontal cortex and alters the structure and function of dorsal raphe nucleus neurons in offspring mice.

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.

17ß-Estradiol reduces inhibitory synaptic currents in entorhinal cortex neurons through G protein-coupled estrogen receptor-1 activation of extracellular signal-regulated kinase.

Estrogens are believed to modulate cognitive functions in part through the modulation of synaptic transmission in the cortex and hippocampus. Administration of 17ß-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.

Synaptic modulation by coffee compounds: Insights into neural plasticity.

The physiological structure and functioning of the brain are determined by activity-dependent processes and affected by "synapse plasticity." Because chemical transmitters target and regulate synapses, exogenous chemical stimulants and transmitters can alter their physiological functions by interacting with synaptic surface receptors or chemical modulators. Caffeine, a commonly used pharmacologic substance, can target and alter synapses. It impact various biological, chemical, and metabolic processes related to synaptic function. This chapter investigates how caffeine affects fluctuations in structure and function in the hippocampus formation and neocortical structure, regions known for their high synaptic plasticity profile. Specifically, caffeine modulates various synaptic receptors and channel activities by mobilizing intracellular calcium, inhibiting phosphodiesterase, and blocking adenosine and GABA cellular receptors. These caffeine-induced pathways and functions allow neurons to generate plastic modulations in synaptic actions such as efficient and morphological transmission. Moreover, at a network level, caffeine can stimulate neural oscillators in the cortex, resulting in repetitive signals that strengthen long-range communication between cortical areas reliant on N-methyl-d-aspartate receptors. This suggests that caffeine could facilitate the reorganization of cortical network functions through its effects on synaptic mobilization.

Embryonic alcohol exposure alters cholinergic neurotransmission and memory in adult zebrafish.

Alcohol is the most consumed addictive substance worldwide that elicits multiple health problems. Consumption of alcoholic beverages by pregnant women is of great concern because pre-natal exposure can trigger fetal alcohol spectrum disorder (FASD). This disorder can significantly change the embryo's normal development, mainly by affecting the central nervous system (CNS), leading to neurobehavioral consequences that persist until adulthood. Among the harmful effects of FASD, the most reported consequences are cognitive and behavioral impairments. Alcohol interferes with multiple pathways in the brain, affecting memory by impairing neurotransmitter systems, increasing the rate of oxidative stress, or even activating neuroinflammation. Here, we aimed to evaluate the deleterious effects of alcohol on the cholinergic signaling and memory in a FASD zebrafish model, using inhibitory avoidance and novel object recognition tests. Four months after the embryonic exposure to ethanol, the behavioral tests indicated that ethanol impairs memory. While both ethanol concentrations tested (0.5 % and 1 %) disrupted memory acquisition in the inhibitory avoidance test, 1 % ethanol impaired memory in the object recognition test. Regarding the cholinergic system, 0.5 % ethanol decreased ChAT and AChE activities, but the relative gene expression did not change. Overall, we demonstrated that FASD model in zebrafish impairs memory in adult individuals, corroborating the memory impairment associated with embryonic exposure to ethanol. In addition, the cholinergic system was also affected, possibly showing a relation with the cognitive impairment observed.

Activation of the 5-HT1A Receptor by Eltoprazine Restores Mitochondrial and Motor Deficits in a Drosophila Model of Fragile X Syndrome.

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.

Recent advances on the influence of fipronil on insect behavior.

Fipronil, a pesticide widely used to control agricultural and household insect pests, blocks insect GABAA and glutamate (GluCl) ionotropic receptors, resulting in uncontrolled hyperexcitation and paralysis that eventually leads to death. The use of fipronil is controversial because unintentional exposure to this compound may contribute to the ongoing global decline of insect pollinator populations. Although the sublethal effects of fipronil have been linked to aberrant behavior and impaired olfactory learning in insects, the precise mechanisms involved in these responses remain unclear. In this article, we highlight recent studies that have investigated the interaction among different pathways involved in the ability of fipronil to modulate insect behavior, with particular emphasis on the role of GABAergic neurotransmission in fine-tuning the integration of sensorial responses and insect behavior. Recent findings suggest that fipronil can also cause functional alterations that affect synaptic organization and the availability of metal ions in the brain.

Switch to phagocytic microglia by CSFR1 inhibition drives amyloid-beta clearance from glutamatergic terminals rescuing LTP in acute hippocampal slices.

Microglia, traditionally regarded as innate immune cells in the brain, drive neuroinflammation and synaptic dysfunctions in the early phases of Alzheimer disease (AD), acting upstream to Aß accumulation. Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its levels are significantly increased in neurodegenerative diseases, possibly contributing to the chronic inflammatory microglial response. On the other hand, CSF-1R inhibitors confer neuroprotection in preclinical models of neurodegenerative diseases. Here, we determined the effects of the CSF-1R inhibitor PLX3397 on the Aß-mediated synaptic alterations in ex vivo hippocampal slices. Electrophysiological findings show that PLX3397 rescues LTP impairment and neurotransmission changes induced by Aß. In addition, using confocal imaging experiments, we demonstrate that PLX3397 stimulates a microglial transition toward a phagocytic phenotype, which in turn promotes the clearance of Aß from glutamatergic terminals. We believe that the selective pruning of Aß-loaded synaptic terminals might contribute to the restoration of LTP and excitatory transmission alterations observed upon acute PLX3397 treatment. This result is in accordance with the mechanism proposed for CSF1R inhibitors, that is to eliminate responsive microglia and replace it with newly generated, homeostatic microglia, capable of promoting brain repair. Overall, our findings identify a connection between the rapid microglia adjustments and the early synaptic alterations observed in AD, possibly highlighting a novel disease-modifying target.

Adolescent cannabinoid exposure rescues phencyclidine-induced social deficits through modulation of CA2 transmission.

Psychotic disorders entail intricate conditions marked by disruptions in cognition, perception, emotions, and social behavior. Notably, psychotic patients who use cannabis tend to show less severe deficits in social behaviors, such as the misinterpretation of social cues and the inability to interact with others. However, the biological underpinnings of this epidemiological interaction remain unclear. Here, we used the NMDA receptor blocker phencyclidine (PCP) to induce psychotic-like states and to study the impact of adolescent cannabinoid exposure on social behavior deficits and synaptic transmission changes in hippocampal area CA2, a region known to be active during social interactions. In particular, adolescent mice underwent 7 days of subchronic treatment with the synthetic cannabinoid, WIN 55, 212-2 (WIN) followed by one injection of PCP. Using behavioral, biochemical, and electrophysiological approaches, we showed that PCP persistently reduced sociability, decreased GAD67 expression in the hippocampus, and induced GABAergic deficits in proximal inputs from CA3 and distal inputs from the entorhinal cortex (EC) to CA2. Notably, WIN exposure during adolescence specifically restores adult sociability deficits, the expression changes in GAD67, and the GABAergic impairments in the EC-CA2 circuit, but not in the CA3-CA2 circuit. Using a chemogenetic approach to target EC-CA2 projections, we demonstrated the involvement of this specific circuit on sociability deficits. Indeed, enhancing EC-CA2 transmission was sufficient to induce sociability deficits in vehicle-treated mice, but not in animals treated with WIN during adolescence, suggesting a mechanism by which adolescent cannabinoid exposure rescues sociability deficits caused by enhanced EC-CA2 activity in adult mice.

Arginine vasopressin activates serotonergic neurons in the dorsal raphe nucleus during neonatal development in vitro and in vivo.

Birth stress is a risk factor for psychiatric disorders and associated with exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. In perinatal hippocampus, AVP activates GABAergic interneurons which leads to suppression of spontaneous network events and suggests a protective function of AVP on cortical networks during birth. However, the role of AVP in developing subcortical networks is not known. Here we tested the effect of AVP on the dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system in male and female neonatal rats, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. We show that AVP is strongly excitatory in neonatal DRN: it increases excitatory synaptic inputs of 5-HT neurons via V1A receptors in vitro and promotes their action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of these neurons. Furthermore, we identified two major firing patterns of neonatal 5-HT neurons in vivo, tonic regular firing and low frequency oscillations of regular spike trains and confirmed that these neurons are also activated by AVP in vivo. Finally, we show that the sparse vasopressinergic innervation in neonatal DRN originates exclusively from cell groups in medial amygdala and bed nucleus of stria terminalis. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own functional development and affect the maturation of cortical target regions, which may increase the risk for psychiatric conditions later on.

Anandamide-Mediated Modulation of Nociceptive Transmission at the Spinal Cord Level.

Three decades ago, the first endocannabinoid, anandamide (AEA), was identified, and its analgesic effect was recognized in humans and preclinical models. However, clinical trial failures pointed out the complexity of the AEA-induced analgesia. The first synapses in the superficial laminae of the spinal cord dorsal horn represent an important modulatory site in nociceptive transmission and subsequent pain perception. The glutamatergic synaptic transmission at these synapses is strongly modulated by two primary AEA-activated receptors, cannabinoid receptor 1 (CB1) and transient receptor potential vanilloid 1 (TRPV1), both highly expressed on the presynaptic side formed by the endings of primary nociceptive neurons. Activation of these receptors can have predominantly inhibitory (CB1) and excitatory (TRPV1) effects that are further modulated under pathological conditions. In addition, dual AEA-mediated signaling and action may occur in primary sensory neurons and dorsal horn synapses. AEA application causes balanced inhibition and excitation of primary afferent synaptic input on superficial dorsal horn neurons in normal conditions, whereas peripheral inflammation promotes AEA-mediated inhibition. This review focuses mainly on the modulation of synaptic transmission at the spinal cord level and signaling in primary nociceptive neurons by AEA via CB1 and TRPV1 receptors. Furthermore, the spinal analgesic effect in preclinical studies and clinical aspects of AEA-mediated analgesia are considered.

Levetiracetam Prevents Neurophysiological Changes and Preserves Cognitive Function in the Human Immunodeficiency Virus (HIV)-1 Transactivator of Transcription Transgenic Mouse Model of HIV-Associated Neurocognitive Disorder.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the central nervous system and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. SIGNIFICANCE STATEMENT: Approximately half of people living with human immunodeficiency virus (HIV) also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein transactivator of transcription (TAT) causes toxicity that is thought to contribute to HAND. Here, the antiepileptic drug levetiracetam (LEV) prevented synaptic and cognitive impairments in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-mediated neuroprotection in HAND.

Gestational valproic acid exposure enhances facial stimulation-evoked cerebellar mossy fiber-granule cell transmission via GluN2A subunit-containing NMDA receptor in offspring mice.

Valproic acid (VPA) is one of the most effective antiepileptic drugs, and exposing animals to VPA during gestation has been used as a model for autism spectrum disorder (ASD). Numerous studies have shown that impaired synaptic transmission in the cerebellar cortical circuits is one of the reasons for the social deficits and repetitive behavior seen in ASD. In this study, we investigated the effect of VPA exposure during pregnancy on tactile stimulation-evoked cerebellar mossy fiber-granule cell (MF-GC) synaptic transmission in mice anesthetized with urethane. Three-chamber testing showed that mice exposed to VPA mice exhibited a significant reduction in social interaction compared with the control group. In vivo electrophysiological recordings revealed that a pair of air-puff stimulation on ipsilateral whisker pad evoked MF-GC synaptic transmission, N1, and N2. The evoked MF-GC synaptic responses in VPA-exposed mice exhibited a significant increase in the area under the curve (AUC) of N1 and the amplitude and AUC of N2 compared with untreated mice. Cerebellar surface application of the selective N-methyl-D-aspartate (NMDA) receptor blocker D-APV significantly inhibited facial stimulation-evoked MF-GC synaptic transmission. In the presence of D-APV, there were no significant differences between the AUC of N1 and the amplitude and AUC of N2 in the VPA-exposed mice and those of the untreated mice. Notably, blockade of the GluN2A subunit-containing, but not the GluN2B subunit-containing, NMDA receptor, significantly inhibited MF-GC synaptic transmission and decreased the AUC of N1 and the amplitude and AUC of N2 in VPA-exposed mice to levels similar to those seen in untreated mice. In addition, the GluN2A subunit-containing NMDA receptor was expressed at higher levels in the GC layer of VPA-treated mice than in control mice. These results indicate that gestational VPA exposure in mice produces ASD-like behaviors, accompanied by increased cerebellar MF-GC synaptic transmission and an increase in GluN2A subunit-containing NMDA receptor expression in the offspring.

Synaptic Mechanisms of Ethanol Tolerance and Neuroplasticity: Insights from Invertebrate Models.

Alcohol tolerance is a neuroadaptive response that leads to a reduction in the effects of alcohol caused by previous exposure. Tolerance plays a critical role in the development of alcohol use disorder (AUD) because it leads to the escalation of drinking and dependence. Understanding the molecular mechanisms underlying alcohol tolerance is therefore important for the development of effective therapeutics and for understanding addiction in general. This review explores the molecular basis of alcohol tolerance in invertebrate models, Drosophila and C. elegans, focusing on synaptic transmission. Both organisms exhibit biphasic responses to ethanol and develop tolerance similar to that of mammals. Furthermore, the availability of several genetic tools makes them a great candidate to study the molecular basis of ethanol response. Studies in invertebrate models show that tolerance involves conserved changes in the neurotransmitter systems, ion channels, and synaptic proteins. These neuroadaptive changes lead to a change in neuronal excitability, most likely to compensate for the enhanced inhibition by ethanol.

Effects of Cannabis on Glutamatergic Neurotransmission: The Interplay between Cannabinoids and Glutamate.

There has been a significant increase in the consumption of cannabis for both recreational and medicinal purposes in recent years, and its use can have long-term consequences on cognitive functions, including memory. Here, we review the immediate and long-term effects of cannabis and its derivatives on glutamatergic neurotransmission, with a focus on both the presynaptic and postsynaptic alterations. Several factors can influence cannabinoid-mediated changes in glutamatergic neurotransmission, including dosage, sex, age, and frequency of use. Acute exposure to cannabis typically inhibits glutamate release, whereas chronic use tends to increase glutamate release. Conversely, the postsynaptic alterations are more complicated than the presynaptic effects, as cannabis can affect the glutamate receptor expression and the downstream signaling of glutamate. All these effects ultimately influence cognitive functions, particularly memory. This review will cover the current research on glutamate-cannabis interactions, as well as the future directions of research needed to understand cannabis-related health effects and neurological and psychological aspects of cannabis use.