Neurotransmitter Research Articles

Ameliorative effect and underlying mechanism of the Xiaxue Kaiqiao formula on age-related dementia in Samp8 mice

Dementia, a major symptom of several neurodegenerative diseases, can be improved by acetylcholinesterase inhibitors (AChE); however, due to the complex etiology and long course of dementia, the efficacy of these drugs remains limited. Significant empirical evidence shows that traditional Chinese medicine (TCM) markedly ameliorates intractable disease; nevertheless, a suitable regimen has yet to be widely accepted, which is likely the result of gaps in the understanding of its causality. We propose that taking advantage of the TCM theory of collateral activation and prevention of accumulation by purgation may improve dementia treatment; thus, we designed the Xiaxue Kaiqiao formula (XKF) accordingly. To explore the ameliorative effect and underlying mechanism of XKF on dementia in a Samp8 mouse model. Samp8 mice were treated with XKF for eight weeks, and the amelioration of dementia was subsequently assessed using the novel object recognition, Barnes maze, and open-field behavioral tests. Neuropathological alterations were observed by immunofluorescence (IF) and Golgi staining of brain tissue. Drug safety was evaluated by blood biochemical tests, organ coefficients, and hematoxylin-eosin (H&E) staining. Proteomics analysis was performed on frozen brain tissue using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Behavioral testing revealed that the administration of XKF had significant ameliorative effects on memory discrimination, spatial learning memory, and anxiety in Samp8 mice. IF staining showed that XKF reduced the loss of postsynaptic density protein 95 (PSD95), myelin, neurons, and axons, as well as decreased the proliferation of astrocytes and microglia in the hippocampal and temporal lobe regions. Evaluation of drug safety demonstrated no abnormal organ morphology following XKF treatment. XKF treatment improved the symptoms of dementia in Samp8 mice, indicating the potential for clinical application. The mechanism underlying the ameliorative effect of XKF on dementia is likely increased synaptic transmission between neurons. Our data provide reliable evidence for the TCM theory of collateral activation and prevention of accumulation by purgation.

Gain of bipolar disorder-related lncRNA AP1AR-DT in mice induces depressive and anxiety-like behaviors by reducing Negr1-mediated excitatory synaptic transmission

Abstract Background Bipolar disorder is a complex polygenic disorder that is characterized by recurrent episodes of depression and mania, the heterogeneity of which is likely complicated by epigenetic modifications that remain to be elucidated. Methods We performed transcriptomic analysis of peripheral blood RNA from monozygotic (MZ) twins discordant for bipolar disorder to identify disease-associated differentially expressed long noncoding RNAs (DE-lncRNAs), which were further validated in the PsychENCODE brain RNA-seq dataset. We then performed behavioral tests, electrophysiological assays, chromatin immunoprecipitation, and PCR to investigate the function of DE-lncRNAs in the mouse and cell models. Statistical analyses were performed using GraphPad Prism 9.0 or SPSS. Results We identified a bipolar disorder-associated upregulated long non-coding RNA (lncRNA), AP1AR-DT. We observed that overexpression of AP1AR-DT in the mouse medial prefrontal cortex (mPFC) resulted in a reduction of both the total spine density and the spontaneous excitatory postsynaptic current (sEPSC) frequency of mPFC neurons as well as depressive and anxiety-like behaviors. A combination of the results of brain transcriptome analysis of AP1AR-DT overexpressing mice brains with the known genes associated with bipolar disorder revealed that NEGR1, which encodes neuronal growth regulator 1, is one of the AP1AR-DT targets and is reduced in vivo upon gain of AP1AR-DT in mice. We further demonstrated that overexpression of recombinant Negr1 in the mPFC neurons of AP1AR-DTOE mice ameliorates depressive and anxiety-like behaviors and normalizes the reduced excitatory synaptic transmission induced by the gain of AP1AR-DT. We finally identified that AP1AR-DT reduces NEGR1 expression by competing for the transcriptional activator NRF1 in the overlapping binding site of the NEGR1 promoter region. Conclusions The epigenetic and pathophysiological mechanism linking AP1AR-DT to the modulation of depressive and anxiety-like behaviors and excitatory synaptic function provides etiological implications for bipolar disorder.

Diversity of Neurotransmitter-Producing Human Skin Commensals

Recent findings indicate that human microbiota can excrete trace amines, dopamine, and serotonin. These neurotransmitters (NTs) can either affect classical neurotransmitter signaling or directly trigger trace amine-associated receptors (TAARs), with still unclear consequences for host physiology. Compared to gut microbiota, less information is available on the role of skin microbiota in NT production. To explore this, 1909 skin isolates, mainly from the genera Staphylococcus, Bacillus, and Corynebacterium, were tested for NT production. Only 6.7% of the isolates were capable of producing NTs, all of which belonged to the Staphylococcus genus. Based on substrate specificity, we identified two distinct profiles among the NT producers. One group primarily produced tryptamine (TRY) and phenylethylamine (PEA), while the other mainly produced tyramine (TYM) and dopamine (Dopa). These differing production profiles could be attributed to the activity of two distinct aromatic amino acid decarboxylase enzymes, SadA and TDC, responsible for generating the TRY/PEA and TYM/Dopa product spectra, respectively. SadA and TDC orthologues differ in structure and size; SadA has approximately 475 amino acids, whereas the TDC type consists of about 620 amino acids. The genomic localization of the respective genes also varies: tdc genes are typically found in small, conserved gene clusters, while sadA genes are not. The heterologous expression of sadA and tdc in Escherichia coli yielded the same product spectrum as the parent strains. The possible effects of skin microbiota-derived NTs on neuroreceptor signaling in the human host remain to be investigated.

Anterior piriform cortex dysfunction underlies autism spectrum disorders-related olfactory deficits in Fmr1 conditional deletion mice.

Previous studies indicated that ASD-related olfactory dysfunctions are rooted in the piriform cortex. However, the direct evidence supporting a causal link between the dysfunction of the piriform cortex and olfactory disorders in ASD is limited. In the present study, we explored the role of anterior piriform cortex (aPC) in ASD-related olfactory disorders by specifically ablating Fmr1, a leading known monogenic cause for ASD, in the pyramidal neurons. Our data demonstrated that the targeted deletion of Fmr1 in aPC pyramidal neurons was sufficient to induce deficits in olfactory detection. In vivo and in vitro electrophysiological recordings showed that the deletion of Fmr1 increased the activity of pyramidal neurons, exhibiting an enhanced excitatory response and a reduced inhibitory response upon odor stimulation. Furthermore, specific deletion of Fmr1 enhanced the power of beta oscillations during odor stimuli, meanwhile, disturbed excitatory and inhibitory synaptic transmission. The abnormal morphology of pyramidal neurons induced by the deletion of Fmr1 may be responsible for the impaired aPC neuronal function. These findings suggest that dysfunction of the aPC may play a role in olfactory impairments observed in ASD models related to Fmr1 deficiency.

Time-dependent phenotypical changes of microglia drive alterations in hippocampal synaptic transmission in acute slices

It is widely acknowledged that microglia actively regulate synaptic function in the brain. Remarkably, much of our understanding regarding the role of microglia in synaptic regulation is derived from studies in acute brain slices. However, it is still uncertain to what extent the preparation and maintenance of acute slices can influence microglial function and whether microglial changes may affect synaptic transmission. In this study, we examined the impact of acute slice resting time on hippocampal CA1 microglia, by assessing morphological and functional parameters at two distinct time intervals. We report that after 4 h from slicing microglia undergo morphological, functional, and transcriptional changes, including a decrease in the number of branches and in their movement speed. Furthermore, microglia acquire a reactive phenotype, characterized by increased amplitude of outward rectifying K+ currents, increased expression of the pro-inflammatory cytokine Tnfα and altered expression of the microglial receptors Cx3cr1 and P2y12r. We also examined time-dependent changes of excitatory synaptic transmission in CA1 pyramidal neurons from acute hippocampal slices, reporting time-dependent decrease in both amplitude and frequency of postsynaptic currents (sEPSCs), along with a decrease in spine density. Noticeably, sEPSCs amplitude decrease was absent in slices prepared from PLX5622 microglia-depleted mice, suggesting that this time-dependent effect on synaptic transmission is microglia-dependent. Our findings highlight possible causal relation between microglia phenotypic changes in the hours following slice preparation and concomitant synaptic changes, pointing to the mechanisms of acute synaptic modulation, whose understanding is crucial for unraveling microglia-neurons interplay in nature. Furthermore, they emphasize the potential issues associated with experimental time windows in ex vivo samples.

New Pharmacological Insight into Etanercept and Pregabalin in Allodynia and Nociception: Behavioral Studies in a Murine Neuropathic Pain Model

Background/Objectives: Neuropathic pain is challenging to treat, often resistant to current therapies, and associated with significant side effects. Pregabalin, an anticonvulsant that modulates calcium channels, is effective but can impair mental and motor functions, especially in older patients. To improve patient outcomes, reducing the doses of pregabalin and combining it with other drugs targeting different neuropathic pain mechanisms may be beneficial. TNF-α blockers such as etanercept have shown potential in addressing neuropathic pain by affecting sodium channels, synaptic transmission, and neuroinflammation. This study evaluates the efficacy and safety of combining low doses of etanercept and pregabalin in allodynia and nociceptive tests. Materials and Methods: Male C57/BL6 mice underwent chronic constriction injury (CCI) of the sciatic nerve to induce neuropathic pain. They were divided into seven groups: sham control, CCI control, low and high doses of pregabalin, low and high doses of etanercept, and a combination of low doses of both drugs. Behavioral tests, including von Frey, hot-plate, and rotarod tests, were used to assess pain responses and motor activity. Results: The results indicated that a high dose of pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia but impaired motor function. Conversely, low doses of etanercept alone had no significant effect. However, the combination of low doses of etanercept (20 mg/kg) and pregabalin (5 mg/kg) effectively alleviated pain without compromising locomotor activity. Conclusions: These results suggest a novel therapeutic strategy for neuropathic pain, enhancing analgesic efficacy while minimizing adverse effects.

Targeting Glucose Metabolism: A Novel Therapeutic Approach for Parkinson’s Disease

Glucose metabolism is essential for the maintenance and function of the central nervous system. Although the brain constitutes only 2% of the body weight, it consumes approximately 20% of the body’s total energy, predominantly derived from glucose. This high energy demand of the brain underscores its reliance on glucose to fuel various functions, including neuronal activity, synaptic transmission, and the maintenance of ion gradients necessary for nerve impulse transmission. Increasing evidence shows that many neurodegenerative diseases, including Parkinson’s disease (PD), are associated with abnormalities in glucose metabolism. PD is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by the accumulation of α-synuclein protein aggregates. These pathological features are exacerbated by mitochondrial dysfunction, oxidative stress, and neuroinflammation, all of which are influenced by glucose metabolism disruptions. Emerging evidence suggests that targeting glucose metabolism could offer therapeutic benefits for PD. Several antidiabetic drugs have shown promise in animal models and clinical trials for mitigating the symptoms and progression of PD. This review explores the current understanding of the association between PD and glucose metabolism, emphasizing the potential of antidiabetic medications as a novel therapeutic approach. By improving glucose uptake and utilization, enhancing mitochondrial function, and reducing neuroinflammation, these drugs could address key pathophysiological mechanisms in PD, offering hope for more effective management of this debilitating disease.

Possible Mechanism for Perception of Auditory-Verbal Hallucinations in Schizophrenia and Approaches to Their Weakening

We put forward a hypothesis that the processing and perception of auditory-verbal hallucinations in schizophrenia — internally generated speech, occurs in the same neural circuits as speech from external sources. These topographically organized cortico—basal ganglia—thalamocortical neural circuits include auditory, language, and frontal neocortical areas. It follows from our proposed mechanism for sound processing, that the increased action on dopamine D2 receptors on striatal neurons, which is considered the cause of hallucinations, should lead to a determined reorganization of activity in these neural circuits. As a result of this reorganization, the inhibition of neurons in the thalamic nuclei, including the internal geniculate body, should decrease synergistically through the direct and indirect pathways in the basal ganglia, and the excitation of connected with them cortical neurons, in the activity of which speech is represented, should increase. From this mechanism it follows that in order to weaken the perception of auditory-verbal hallucinations, it is necessary to increase the inhibition of thalamic neurons. Taking into account the known data on the distribution of receptors of different types on neurons in the striatum, thalamus and neocortex, as well as the previously formulated unified modification rules for the effectiveness of synaptic transmission in different structures, we proposed that agonists of adenosine A1 and muscarinic M4 receptors located on striatonigral spiny cells, giving rise to a direct disinhibitory pathway through the basal ganglia as well as antagonists of delta-opioid and cannabinoid CB1 receptors, located on striatopallidal spiny cells, giving rise to an indirect inhibitory pathway through the basal ganglia may be useful to weaken the perception of hallucinations. In addition, activation of A1 receptors can directly weaken the activity of neurons in the thalamus and neocortex due to the induction of long-term depression in the efficiency of their excitation. Inactivation of cannabinoid CB1 receptors on the projection GABAergic cells of the reticular thalamic nucleus may enhance their inhibitory effect on neurons of different thalamic nuclei. Since the proposed substances only indirectly affect the dopaminergic system, their use should not cause such pronounced side effects as D2 receptor antagonists, antipsychotics that are widely used to suppress auditory-verbal hallucinations.

Wnt-5a Signaling Mediates Metaplasticity at Hippocampal CA3-CA1 Synapses in Mice.

Wnt signaling plays a role in synaptic plasticity, but the specific cellular events and molecular components involved in Wnt signaling-mediated synaptic plasticity are not well defined. Here, we report a change in the threshold required to induce synaptic plasticity that facilitates the induction of long-term potentiation (LTP) and inhibits the induction of long-term depression (LTD) during brief exposure to the noncanonical ligand Wnt-5a. Both effects are related to the metaplastic switch of hippocampal CA3-CA1 synaptic transmission, a complex mechanism underlying the regulation of the threshold required to induce synaptic plasticity and of synaptic efficacy. We observed an early increase in the amplitude of field excitatory postsynaptic potentials (fEPSPs) that persisted over time, including after washout. The first phase involves an increase in the fEPSP amplitude that is required to trigger a spontaneous second phase that depends on Jun N-terminal kinase (JNK) and N-methyl D-aspartate receptor (NMDAR) activity. These changes are prevented by treatment with secreted frizzled-related protein 2 (sFRP-2), an endogenous antagonist of Wnt ligands. Here, we demonstrate the contribution of Wnt-5a signaling to a process associated with metaplasticity at CA3-CA1 synapses that favors LTP over LTD.

A vagus nerve dominant tetra-synaptic ascending pathway for gastric pain processing.

Gastric pain has limited treatment options and the mechanisms within the central circuitry remain largely unclear. This study investigates the central circuitry in gastric pain induced by noxious gastric distension (GD) in mice. Here, we identified that the nucleus tractus solitarius (NTS) serves as the first-level center of gastric pain, primarily via the vagus nerve. The prelimbic cortex (PL) is engaged in the perception of gastric pain. The lateral parabrachial nucleus (LPB) and the paraventricular thalamic nucleus (PVT) are crucial regions for synaptic transmission from the NTS to the PL. The glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry is necessary and sufficient for the processing of gastric pain. Overall, our finding reveals a glutamatergic tetra-synaptic NTS-LPB-PVT-PL circuitry that transmits gastric nociceptive signaling by the vagus nerve in mice. It provides an insight into the gastric pain ascending pathway and offers potential therapeutic targets for relieving visceral pain.

Dopamine builds and reveals reward-associated latent behavioral attractors.

Phasic variations in dopamine levels are interpreted as a teaching signal reinforcing rewarded behaviors. However, behavior also depends on the motivational, neuromodulatory effect of phasic dopamine. In this study, we reveal a neurodynamical principle that unifies these roles in a recurrent network-based decision architecture embodied through an action-perception loop with the task space, the MAGNet model. Dopamine optogenetic conditioning in mice was accounted for by an embodied network model in which attractors encode internal goals. Dopamine-dependent synaptic plasticity created "latent" attractors, to which dynamics converged, but only locally. Attractor basins were widened by dopamine-modulated synaptic excitability, rendering goals accessible globally, i.e. from distal positions. We validated these predictions optogenetically in mice: dopamine neuromodulation suddenly and specifically attracted animals toward rewarded locations, without off-target motor effects. We thus propose that motivational dopamine reveals dopamine-built attractors representing potential goals in a behavioral landscape.

Neuro-Actuating Photonic Skin Enabled by Ion-Gel Transistor with Thermo-Adaptive Block Copolymer.

Despite significant progress in developing artificial synapses to emulate the human nervous system for bio-signal transmission, synapses with thermo-adaptive coloration and soft actuators driven by temperature change have seldom been reported. Herein, a photonic neuro-actuating synaptic skin is presented enabling thermoresponsive synaptic signal transmission, color variation, and actuation. First, a thermoresponsive display synapse is developed based on a 3-terminal ion-gel transistor with a poly (3,4-ethylene dioxythiophene):poly (styrene sulfonate) (PEDOT:PSS) semiconducting channel mixed with 2D titanium carbide (Ti3C2Tx) MXene and a thermo-adaptive 1D block copolymer (BCP) photonic crystal (PC) gate insulator. Temperature-dependent synaptic behavior is successfully observed in the ion-gel transistor with the corresponding structural colors, leading to a thermo-adaptive display synapse. The 3 × 3 arrays of thermo-adaptive display synapses with Joule heaters show that each pixel is controlled by the thermoresponsive structural color and synaptic output. The synaptic output current from the MXene ion-gel transistor can be converted and amplified to a voltage signal, which powers a soft actuator connected to the ion-gel display synapse and triggers temperature-dependent actuation related to the thermoresponsive synaptic performance. This study showcases a thermo-adaptive photonic neuro-actuating artificial skin that emulates muscle-combined neuronal human skin with visualization capability.

Unraveling the role and mechanism of mitochondria in postoperative cognitive dysfunction: a narrative review.

Postoperative cognitive dysfunction (POCD) is a frequent neurological complication encountered during the perioperative period with unclear mechanisms and no effective treatments. Recent research into the pathogenesis of POCD has primarily focused on neuroinflammation, oxidative stress, changes in neural synaptic plasticity and neurotransmitter imbalances. Given the high-energy metabolism of neurons and their critical dependency on mitochondria, mitochondrial dysfunction directly affects neuronal function. Additionally, as the primary organelles generating reactive oxygen species, mitochondria are closely linked to the pathological processes of neuroinflammation. Surgery and anesthesia can induce mitochondrial dysfunction, increase mitochondrial oxidative stress, and disrupt mitochondrial quality-control mechanisms via various pathways, hence serving as key initiators of the POCD pathological process. We conducted a review on the role and potential mechanisms of mitochondria in postoperative cognitive dysfunction by consulting relevant literature from the PubMed and EMBASE databases spanning the past 25years. Our findings indicate that surgery and anesthesia can inhibit mitochondrial respiration, thereby reducing ATP production, decreasing mitochondrial membrane potential, promoting mitochondrial fission, inducing mitochondrial calcium buffering abnormalities and iron accumulation, inhibiting mitophagy, and increasing mitochondrial oxidative stress. Mitochondrial dysfunction and damage can ultimately lead to impaired neuronal function, abnormal synaptic transmission, impaired synthesis and release of neurotransmitters, and even neuronal death, resulting in cognitive dysfunction. Targeted mitochondrial therapies have shown positive outcomes, holding promise as a novel treatment for POCD.

EPCO-38. IDENTIFYING THE MOLECULAR SIGNATURE OF INFILTRATING EDGE IN GLIOBLASTOMA AS DRIVERS OF TUMOUR INVASION AND RECURRENCE

Abstract Complete tumour resection in glioblastoma patients is not possible. Residual therapy-resistant edge-derived cells drive tumour recurrence and infiltrative expansion in glioblastoma. Features that are specific to malignant edge-derived cells may serve as predictive biomarkers to allow individual tailoring of the treatment plan to slow down tumour invasion and prevent tumour recurrence in GBM patients following standard therapy. Intratumoural spatial heterogeneity facilitates therapeutic resistance and recurrence in glioblastoma. Our knowledge on glioblastoma heterogeneity is mostly restricted to the surgically resectable tumour core, while the functional characterization of tumour cells at the infiltrating edge remains largely elusive due to the presence of normal functional brain tissue in the peritumoural lesion. Edge-derived cells exhibit larger capacity for infiltrative expansion and are the main drivers of treatment failure and tumour recurrence, making them action targets for novel treatment approaches in glioblastoma. To resolve the transcriptional heterogeneity of GBM within the spatial context, we profiled gene expression of different tumour regions (“edge” and “core”) obtained at initial surgical resection from primary and recurrent IDH-WT GBM patients with Visium 10x and GeoMx. We show that infiltrative edge-derived cells are spatially segregated and are characterized by regionally shared distinct genomic and transcriptomic signatures that promote invasiveness and underly disease recurrence. Tumour edge is enriched for neuronal signatures, while tumour core displays larger transcriptional subpopulation diversity and abundance of proliferative cells with a high capacity for self-renewal, consistent with the proliferative and cancer stem cell-enriched phenotype in early GBM progressors. Upregulated DEGs of tumour edge cells are significantly associated with ion regulation of transport, chemical synaptic transmission, and nervous system development. These modules may represent tumour cell hijacking of neuronal programs specifically at the tumour periphery as described in the context of glioma-neuron synaptic communication and formation of neurite-like microtubes. Upregulation of ion regulation transport at the tumour periphery indicates enhanced neuronal activity and excitability driving infiltrating growth.

Comparative specialization of intrinsic cardiac neurons in humans, mice and pigs.

Intrinsic cardiac neurons (ICNs) play a crucial role in the proper functioning of the heart; yet a paucity of data pertaining to human ICNs exist. We took a multidisciplinary approach to complete a detailed cellular comparison of the structure and function of ICNs from mice, pigs and humans. Immunohistochemistry of whole and sectioned ganglia, transmission electron microscopy, intracellular microelectrode recording and dye filling for quantitative morphometry were used to define the neurophysiology, histochemistry and ultrastructure of these neurons across species. The densely packed, smaller ICNs of mouse lacked dendrites, formed axosomatic connections and had high synaptic efficacy constituting an obligatory synapse. At pig ICNs, a convergence of subthreshold cholinergic inputs onto extensive dendritic arbors supported greater summation and integration of synaptic input. Human ICNs were tonically firing, with synaptic stimulation evoking large suprathreshold EPSPs like mouse, and subthreshold potentials like pig. Ultrastructural examination of synaptic terminals revealed conserved architecture, yet small clear vesicles were larger in pigs and humans. The presence and localization of ganglionic neuropeptides was distinct, with abundant vasoactive intestinal polypeptide observed in human but not pig or mouse ganglia, and little substance P or calcitonin gene-related peptide in pig ganglia. Action potential waveforms were similar, but human ICNs had larger after-hyperpolarizations. Intrinsic excitability differed; 95% of human neurons were tonic, all pig neurons were phasic, and both phasic and tonic phenotypes were observed in mouse. In combination, this publicly accessible, multimodal atlas of ICNs from mice, pigs and humans identifies similarities and differences in the evolution of ICNs. KEY POINTS: Intrinsic cardiac neurons (ICNs) are essential to the regulation of cardiac function. We investigated the neurochemistry, morphology, ultrastructure, membrane physiology and synaptic transmission of ICNs from donated human hearts in parallel with identical studies of ICNs from mice and pigs to create a publicly accessible cellular atlas detailing the structure and function of these neurons across species. In addition to presenting foundational data on human ICNs, this comparative study identifies both conserved and derived attributes of these neurons within mammals. The findings have significant implications for understanding the regulation of cardiac autonomic function in humans and may greatly influence strategies for neuromodulation in conditions such as atrial fibrillation and heart failure.

Genome-wide meta-analysis conducted in three large biobanks expands the genetic landscape of lumbar disc herniations

Given that lumbar disc herniation (LDH) is a prevalent spinal condition that causes significant individual suffering and societal costs, the genetic basis of LDH has received relatively little research. Our aim is to increase understanding of the genetic factors influencing LDH. We perform a genome-wide association analysis (GWAS) of LDH in the FinnGen project and in Estonian and UK biobanks, followed by a genome-wide meta-analysis to combine the results. In the meta-analysis, we identify 41 loci that have not been associated with LDH in prior studies on top of the 23 known risk loci. We detect LDH-associated loci in the vicinity of genes related to inflammation, disc-related structures, and synaptic transmission. Overall, our research contributes to a deeper understanding of the genetic factors behind LDH, potentially paving the way for the development of new therapeutics, prevention methods, and treatments for symptomatic LDH in the future.

Fluoxetine does not influence response to continuous theta burst stimulation in human motor cortex.

Selective serotonin reuptake inhibitors are thought to exert a clinical effect through various mechanisms, including through alteration in synaptic plasticity. Repetitive transcranial magnetic stimulation can induce temporary changes in synaptic excitability in cerebral cortex that resemble long-term potentiation and long-term depression that serve as a measure of synaptic plasticity invivo. A version of repetitive transcranial magnetic stimulation called continuous theta burst stimulation can induce inhibition of cortical excitability that can be measured through a motor evoked potential. Previous work has suggested that this response can be modulated by administration of selective serotonin reuptake inhibitors. Thirty-one healthy volunteers received both fluoxetine 20 mg and placebo in randomly ordered sessions, followed by spaced continuous theta burst stimulation to motor cortex. Changes in Motor Evoked Potentials were then recorded over 60 min. The response to spaced continuous theta burst stimulation did not differ significantly between fluoxetine and placebo sessions. Spaced continuous theta burst stimulation produced a paradoxical excitatory response in an unexpected number of participants. A single dose of fluoxetine 20 mg does not influence the response to continuous theta burst stimulation. Previous results suggesting an effect of selective serotonin reuptake inhibitors on inhibitory non-invasive brain stimulation protocols may be due to insufficiently large sample sizes.

PKA regulation of neuronal function requires the dissociation of catalytic subunits from regulatory subunits

Protein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that PKA catalytic subunits dissociate from regulatory subunits in the presence of cAMP, whereas a second model proposes that catalytic subunits remain associated with regulatory subunits following physiological activation. Here, we report that different PKA subtypes, as defined by the regulatory subunit, exhibit distinct subcellular localization at rest in CA1 neurons of cultured hippocampal slices. Nevertheless, when all tested PKA subtypes are activated by norepinephrine, presumably via the β-adrenergic receptor, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. These differential spatial dynamics between the subunits indicate that at least a significant fraction of PKA dissociates. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA. These results indicate that endogenous PKA regulatory and catalytic subunits dissociate to achieve PKA function in neurons.

PKA regulation of neuronal function requires the dissociation of catalytic subunits from regulatory subunits.

Protein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that PKA catalytic subunits dissociate from regulatory subunits in the presence of cAMP, whereas a second model proposes that catalytic subunits remain associated with regulatory subunits following physiological activation. Here, we report that different PKA subtypes, as defined by the regulatory subunit, exhibit distinct subcellular localization at rest in CA1 neurons of cultured hippocampal slices. Nevertheless, when all tested PKA subtypes are activated by norepinephrine, presumably via the β-adrenergic receptor, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. These differential spatial dynamics between the subunits indicate that at least a significant fraction of PKA dissociates. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA. These results indicate that endogenous PKA regulatory and catalytic subunits dissociate to achieve PKA function in neurons.

Exploring the potential pharmacological mechanism of aripiprazole against hyperprolactinemia based on network pharmacology and molecular docking

The current primary therapeutic approach for schizophrenia is antipsychotic medication, and antipsychotic-induced hyperprolactinemia occurs in 40–80% of patients with schizophrenia. Aripiprazole, an atypical antipsychotic belonging to the quinolinone derivative class, can reduce the likelihood of developing hyperprolactinemia, but the pharmacological mechanisms of this reduction are unknown. This study aimed to explore the molecular mechanism of action of aripiprazole in treating hyperprolactinemia based on network pharmacology and molecular docking techniques. This study identified a total of 151 potential targets for aripiprazole from the DrugBank, TCMSP, BATMAN-TCM, TargetNet, and SwissTargetPrediction databases. Additionally, 71 hyperprolactinemia targets were obtained from the PharmGKB, DrugBank, TTD, GeneCards, OMIM, and DisGENET databases. Utilizing Venny 2.1.0 software, an intersection of 27 genes was identified between aripiprazole and hyperprolactinemia. To construct a common target protein–protein interaction (PPI) network, the common targets obtained from both sources were input into the STRING database. The resulting PPI network was then imported into Cytoscape 3.7.2 software, which identified eight core targets associated with aripiprazole’s treatment of hyperprolactinemia. Subsequently, a PPI network was established for these targets. Enrichment analysis of the key targets was conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes in the DAVID database. Additionally, molecular docking verification of the interaction between aripiprazole and the core targets was performed using AutoDock Vina software. Aripiprazole’s intervention in hyperprolactinemia primarily targets the following core proteins: Solute Carrier Family 6 Member 3 (SLC6A3), monoamine oxidase (MAO-B), Dopamine D2 receptor (DRD2), 5-hydroxytryptamine (serotonin) receptor 2A (HTR2A), 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C), cytochrome P450 2D6 (CYP2D6), Dopamine D1 receptor (DRD1), Dopamine D4 receptor (DRD4). These targets are predominantly involved in biological processes such as the adenylate cyclase-activating adrenergic receptor signaling pathway, G-protein coupled receptor signaling pathway coupled to cyclic nucleotide second messenger, phospholipase C-activating G-protein coupled receptor signaling pathway, chemical synaptic transmission, and response to xenobiotic stimulus. Primary enrichment occurs in signaling pathways such as the neuroactive ligand-receptor interaction and serotonergic synapse pathways. Molecular docking results demonstrate a favorable affinity between aripiprazole and the core target proteins MAO-B, DRD2, SLC6A3, HTR2C, HTR2A, CYP2D6, DRD4, and DRD1. Network pharmacology predicted potential targets and signaling pathways for aripiprazole’s intervention in hyperprolactinemia, offering theoretical support and a reference basis for optimizing clinical strategies and drug development involving aripiprazole.