The effect of Brucella abortus on glial activation and cell death in adult male rat's hippocampus.

A zoonotic disease called brucellosis can cause flu-like symptoms and heart inflammation. The bacteria responsible for this disease can also enter the brain, causing a condition called neurobrucellosis that can result in long-term neurological problems. In this study, researchers aimed to determine the changes in the hippocampal cells of rats infected with Brucella. For the study, 24 adult male albino rats were inoculated with 1 × 106 CFU Brucella abortus 544. The rats were then deeply anesthetized, and their hippocampus samples were taken for stereological, histological, and molecular studies. The results showed that the infected rats had increased microgliosis and astrogliosis. Furthermore, a high level of caspase-3 in their hippocampal tissue indicated their susceptibility to apoptosis. Additionally, there was a decrease in expression of Ki67, which further supported this. Sholl's analysis confirmed a significant failure in glial morphology. The study demonstrated that the pathogen has the ability to destroy the hippocampus and potentially affect its normal physiology. However, more research is needed to clarify various aspects of neurobrucellosis.

Genetic patterning in hippocampus of rat undergoing impaired spatial memory induced by long-term heat stress.

The organism's normal physiological function is greatly impacted in a febrile environment, leading to the manifestation of pathological conditions including elevated body temperature, dehydration, gastric bleeding, and spermatogenic dysfunction. Numerous lines of evidence indicate that heat stress significantly impacts the brain's structure and function. Previous studies have demonstrated that both animals and humans experience cognitive impairment as a result of exposure to high temperatures. However, there is a lack of research on the effects of prolonged exposure to high-temperature environments on learning and memory function, as well as the underlying molecular regulatory mechanisms. In this study, we examined the impact of long-term heat stress exposure on spatial memory function in rats and conducted transcriptome sequencing analysis of rat hippocampal tissues to identify the crucial molecular targets affected by prolonged heat stress exposure. It was found that the long-term heat stress impaired rats' spatial memory function due to the pathological damages and apoptosis of hippocampal neurons at the CA3 region, which is accompanied with the decrease of growth hormone level in peripheral blood. RNA sequencing analysis revealed the signaling pathways related to positive regulation of external stimulation response and innate immune response were dramatically affected by heat stress. Among the verified differentially expressed genes, the knockdown of Arhgap36 in neuronal cell line HT22 significantly enhances the cell apoptosis, suggesting the impaired spatial memory induced by long-term heat stress may at least partially be mediated by the dysregulation of Arhgap36 in hippocampal neurons. The uncovered relationship between molecular changes in the hippocampus and behavioral alterations induced by long-term heat stress may offer valuable insights for the development of therapeutic targets and protective drugs to enhance memory function in heat-exposed individuals.

Discussion of spinal cord neurons apoptosis and neuroprotection mechanism of NGF gene transfection mediated by recombinant adenovirus in EAE mice.

To investigate the spinal cord neuron apoptosis and neuroprotective mechanism of nerve growth factorganismsor (NGF) gene mediated by recombinant adenovirus (Ad-NGF) via peripheral transfection in mice with experimental autoimmune encephalomyelitis (EAE). Forty healthy female C57BL/6 mice were randomly divided into a control group, adenovirus (AdV) group, EAE group, and Ad-NGF transfection group; the control group received no treatment; the AdV group received adenovirus injection via the tail vein; the EAE and Ad-NGF transfection groups were induced with experimental autoimmune encephalomyelitis (EAE) using myelin oligodendrocyte glycoprotein 35-55 (MOG35-55), Ad-NGF transfection group received Ad-NGF injection via the tail vein, and daily neurological impairment scores were obtained. AQThe TUNEL method was employed to observe spinal neuron apoptosis in each group of mice; protein immunoblotting (western blot) and RT-PCR were used to measure NGF levels in the spinal cord tissues of each group, and western blotting was used to assess levels of cleaved caspase-3, Bax, and Bcl-2. ELISA and RT-PCR were employed to detect protein and mRNA levels of neuron-specific enolase (NSE) in spinal cord tissues, respectively. The control group and AdV mice did not develop symptoms. Compared to the EAE group, in the Ad-NGF transfection group, neurological function scores, TUNEL-positive cell counts, the ratio of NeuN + TUNEL to NeuN, levels of Bax and cleaved caspase-3 apoptotic proteins were significantly reduced, while Bcl-2 protein expression was increased. Expression levels of NGF, NGF-mRNA, NSE, and NSE-mRNA in spinal cord tissues were significantly elevated (P < 0.01). Immunofluorescence labeling revealed a significant punctate aggregation of apoptotic cells in spinal neurons of the EAE group, while the aggregation phenomenon was less pronounced in the Ad-NGF transfection group. Ad-NGF transfected by the periphery has a protective effect on spinal cord neurons in EAE mice by up-regulation NGF level, down-regulating apoptotic protein Caspase-3 in spinal cord neurons, inhibiting spinal cord neuron apoptosis and promoting NSE expression.

Fluoxetine antagonizes the acute response of LPS: Blocks K2P channels.

The channels responsible for maintaining resting membrane potential are known as K2P (two-P-domain K+ subunit) channels, a subset of which are known to be blocked by Fluoxetine. In this experiment, the compound's effects on the membrane potential were examined on muscles in larval Drosophila overexpressing a subtype of K2P channel (known in Drosophila as dORKA1 or ORKA1) and compared to larvae without overexpression. The compound was also observed in sequence and/or combination with a form of lipopolysaccharide (LPS) that transiently activates K2P channels. Different concentrations of Fluoxetine were tested, and it was also examined in cocktail with the LPS. At 25 µM Fluoxetine exposure, muscle in control larvae underwent depolarization, while muscles overexpressing K2P channels hyperpolarized; at 50 µM, however, much more variable responses were observed. The LPS caused hyperpolarization in both larval strains, but the effect was more transient in the Canton-S line than in the K2P overexpressors. Finally, LPS continued to cause hyperpolarization even in the presence of Fluoxetine, while Fluoxetine quickly depolarized the muscle during exposure to LPS. The cocktail showed a smaller effect on muscles overexpressing ORKA1 as compared to the controls, indicating that Fluoxetine does not block the ORKA1 subtype. This study is significant because it demonstrates how overexpression of K2P channels alters membrane response to LPS and Fluoxetine exposure.

A Case Report and Review of Literature on Hirayama Disease.

Hirayama disease (HD) is a rare, benign, self-limiting condition that typically affects individuals in their 20s. Although the disease is self-limiting, it can result in functional impairment in those affected. The most common presentation is an asymmetrical, unilateral, or bilateral upper limb weakness with wasting. With an interesting pathogenesis and lack of definitive treatment, HD is an interesting neurological conundrum. Mild symptoms in patients often lead to underreporting of the disease, as individuals may not seek medical attention or may not recognize their symptoms. Most case reports in the literature are from Asia and the Middle East. We report a case of HD in a male patient in his 20s with gradual bilateral upper limb weakness and wasting, confirmed by imaging and nerve conduction studies.

Personalised penetrance estimation for C9orf72-related amyotrophic lateral sclerosis and frontotemporal dementia.

Background: C9orf72 hexanucleotide repeat expansions are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in European populations. Variable disease penetrance between families presents a challenge for genetic counselling of at-risk relatives and reduces the predictive utility of testing asymptomatic relatives. We have developed a novel model for estimating penetrance in individual families affected by C9orf72 using available family history information, allowing the calculation of personalised risk estimates. Methods: Published aggregated age-of-onset data for C9orf72-related ALS/FTD were used to generate age-related cumulative relative risks for at-risk relatives within pedigrees. Age-related relative risks are combined with a priori chance of individuals carrying an expansion based on known pedigree information. Penetrance is calculated as a number of affected individuals divided by the sum of cumulative age-related risks of relatives being affected by 80 years. Results: This method allows family-specific penetrance to be estimated from family history and at-risk relatives' personalised age-related ALS/FTD risks to be calculated and illustrated graphically. Penetrance reduces as the number and age of at-risk unaffected relatives increases. Conclusions: Family history remains the best indicator of penetrance in C9orf72 expansion carriers. Calculating family-specific penetrance can aid genetic counselling by allowing at-risk relatives a more accurate understanding of their individual risk.

Potassium nitrate suppresses hyperactivities of Vc neurons of the model with dentin hypersensitivity.

OBJECTIVE: Potassium nitrate (KNO3) suppresses nociception induced by dental hypersensitivity (HYS). We aimed to examine the effects of KNO3 on the neural activity of the trigeminal spinal subnucleus caudalis (Vc) in HYS model rats. METHODS: KNO3 or vehicle was applied to the exposed dentin of HYS rats for 3 days. c-Fos expression and neuronal activity in the Vc after acetone treatment for cold stimulation were examined to evaluate the effects of KNO3 application on dentin. RESULTS: The number of c-Fos-immunoreactive cells in the Vc was lower in the group that received KNO3 (KNO3 group) than in the group that received vehicle (control group). Spike firing of Vc neurons in response to cold stimulation of the dentin was recorded before and after KNO3 application to the cavity, and the increased neural activity was effectively suppressed by KNO3 application. Scanning electron microscopy revealed that the dentin tubules were not occluded by deposits in any of the groups. CONCLUSIONS: KNO3-induced suppression of Vc neuronal activity does not involve physical occlusion of the dentin tubules but likely involves suppression of Aδ or C-fiber activities in the tooth pulp, resulting in the suppression of Vc neuronal activities.

YTHDF1 in periaqueductal gray inhibitory neurons contributes to morphine withdrawal responses in mice.

BACKGROUND: Physical symptoms and aversion induced by opioid withdrawal strongly affect the management of opioid addiction. YTH N6-methyladenosine (m6A) RNA binding protein 1 (YTHDF1), an m6A-binding protein, from the periaqueductal gray (PAG) reportedly contributes to morphine tolerance and hyperalgesia. However, the role of YTHDF1 in morphine withdrawal remains unclear. METHODS: A naloxone-precipitated morphine withdrawal model was established in C57/BL6 mice or transgenic mice. YTHDF1 was knocked down via adeno-associated virus transfection. Combined with the results of the single-cell RNA sequencing analysis, the changes in morphine withdrawal somatic signs and conditioned place aversion (CPA) scores were compared when YTHDF1 originating from different neurons in the ventrolateral periaqueductal gray (vlPAG) was knocked down. We further explored the role of inflammatory factors and transcription factors related to inflammatory response in morphine withdrawal. RESULTS: Our results revealed that YTHDF1 expression was upregulated in the vlPAG of mice with morphine withdrawal and that the knockdown of vlPAG YTHDF1 attenuated morphine withdrawal-related somatic signs and aversion. The levels of NF-κB and p-NF-κB were reduced after the inhibition of YTHDF1 in the vlPAG. YTHDF1 from vlPAG inhibitory neurons, rather than excitatory neurons, facilitated morphine withdrawal responses. The inhibition of YTHDF1 in vlPAG somatostatin (Sst)-expressing neurons relieved somatic signs of morphine withdrawal and aversion, whereas the knockdown of YTHDF1 in cholecystokinin (Cck)-expressing or parvalbumin (PV)-expressing neurons did not change morphine withdrawal-induced responses. The activity of c-fos + neurons, the intensity of the calcium signal, the density of dendritic spines, and the frequency of mIPSCs in the vlPAG, which were increased in mice with morphine withdrawal, were decreased with the inhibition of YTHDF1 from vlPAG inhibitory neurons or Sst-expressing neurons. Knockdown of NF-κB in Sst-expressing neurons also alleviated morphine withdrawal-induced responses. CONCLUSIONS: YTHDF1 originating from Sst-expressing neurons in the vlPAG is crucial for the modulation of morphine withdrawal responses, and the underlying mechanism might be related to the regulation of the expression and phosphorylation of NF-κB.

Comprehensive Characterization of a Subfamily of Ca2+-Binding Proteins in Mouse and Human Retinal Neurons at Single-Cell Resolution.

Ca2+-binding proteins (CaBPs; CaBP1-5) are a subfamily of neuronal Ca2+ sensors with high homology to calmodulin. Notably, CaBP4, which is exclusively expressed in rod and cone photoreceptors, is crucial for maintaining normal retinal functions. However, the functional roles of CaBP1, CaBP2, and CaBP5 in the retina remain elusive, primarily due to limited understanding of their expression patterns within inner retinal neurons. In this study, we conducted a comprehensive transcript analysis using single-cell RNA sequencing datasets to investigate the gene expression profiles of CaBPs in mouse and human retinal neurons. Our findings revealed notable similarities in the overall expression patterns of CaBPs across both species. Specifically, nearly all amacrine cell, ganglion cell, and horizontal cell types exclusively expressed CaBP1. In contrast, the majority of bipolar cell types, including rod bipolar (RB) cells, expressed distinct combinations of CaBP1, CaBP2, and CaBP5, rather than a single CaBP as previously hypothesized. Remarkably, mouse rods and human cones exclusively expressed CaBP4, whereas mouse cones and human rods coexpressed both CaBP4 and CaBP5. Our single-cell reverse transcription polymerase chain reaction analysis confirmed the coexpression CaBP1 and CaBP5 in individual RBs from mice of either sex. Additionally, all three splice variants of CaBP1, primarily L-CaBP1, were detected in mouse RBs. Taken together, our study offers a comprehensive overview of the distribution of CaBPs in mouse and human retinal neurons, providing valuable insights into their roles in visual functions.

Intratympanic injection of MSC-derived small extracellular vesicles protects spiral ganglion neurons from degeneration.

Sensorineural hearing loss is one of the most prevalent sensory deficits. Spiral ganglion neurons (SGNs) exhibit very limited regeneration capacity and their degeneration leads to profound hearing loss. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEV) have been demonstrated to repair tissue damage in various degenerative diseases. However, the effects of MSC-sEV on SGN degeneration remain unclear. In this study, we investigated the efficacy of MSC-sEV for protection against ouabain-induced SGN degeneration. MSC-sEV were derived from rat bone marrow and their components related to neuron growth were determined by proteomic analysis. In primary culture SGNs, MSC-sEV significantly promoted neurite growth and growth cone development. The RNA-Seq analysis of SGNs showed that enriched pathways include neuron development and axon regeneration, consistent with proteomics. In ouabain induced SGN degeneration rat model, MSC-sEV administration via intratympanic injection significantly enhanced SGN survival and mitigated hearing loss. Furthermore, after ouabain treatment, SGNs displayed evident signs of apoptosis, including nuclei condensation and fragmentation, with numerous cells exhibiting TUNEL-positive. However, administration of MSC-sEV effectively decreased the number of TUNEL-positive cells and reduced caspase-3 activation. In conclusion, our findings demonstrate the potential of MSC-sEV in preventing SGN degeneration and promoting neural growth, suggesting intratympanic injection of MSC-sEV is a specific and efficient strategy for neural hearing loss.

Which neurodevelopmental processes continue in humans after birth?

Once we are born, the number and location of nerve cells in most parts of the brain remain unchanged. These types of structural changes are therefore a significant form of flexibility for the neural circuits where they occur. In humans, the postnatal birth of neurons is limited; however, neurons do continue to migrate into some brain regions throughout infancy and even into adolescence. In human infants, multiple migratory pathways deliver interneurons to destinations across the frontal and temporal lobe cortex. Shorter-range migration of excitatory neurons also appears to continue during adolescence, particularly near the amygdala paralaminar nucleus, a region that follows a delayed trajectory of growth from infancy to adulthood. The significance of the timing for when different brain regions recruit new neurons through these methods is unknown; however, both processes of protracted migration and maturation are prominent in humans. Mechanisms like these that reconfigure neuronal circuits are a substrate for critical periods of plasticity and could contribute to distinctive circuit functionality in human brains.

MCT1-mediated endothelial cell lactate shuttle as a target for promoting axon regeneration after spinal cord injury.

Rationale: Spinal cord injury (SCI)-induced vascular damage causes ischemia and hypoxia at the injury site, which, in turn, leads to profound metabolic disruptions. The effects of these metabolic alterations on neural tissue remodeling and functional recovery have yet to be elucidated. The current study aimed to investigate the consequences of the SCI-induced hypoxic environment at the epicenter of the injury. Methods: This study employed metabolomics to assess changes in energy metabolism after SCI. The use of a lactate sensor identified lactate shuttle between endothelial cells (ECs) and neurons. Reanalysis of single-cell RNA sequencing data demonstrated reduced MCT1 expression in ECs after SCI. Additionally, an adeno-associated virus (AAV) overexpressing MCT1 was utilized to elucidate its role in endothelial-neuronal interactions, tissue repair, and functional recovery. Results: The findings revealed markedly decreased monocarboxylate transporter 1 (MCT1) expression that facilitates lactate delivery to neurons to support their energy metabolism in ECs post-SCI. This decreased expression of MCT1 disrupts lactate transport to neurons, resulting in a metabolic imbalance that impedes axonal regeneration. Strikingly, our results suggested that administering adeno-associated virus specifically to ECs to restore MCT1 expression enhances axonal regeneration and improves functional recovery in SCI mice. These findings indicate a novel link between lactate shuttling from endothelial cells to neurons following SCI and subsequent neural functional recovery. Conclusion: In summary, the current study highlights a novel metabolic pathway for therapeutic interventions in the treatment of SCI. Additionally, our findings indicate the potential benefits of targeting lactate transport mechanisms in recovery from SCI.

Infarct of the Middle Cerebellar Peduncle Mimicking Bell's Palsy: A Case Report.

The anterior inferior cerebellar artery (AICA) supplies the middle cerebellar peduncle, lower pons, upper medulla, and anterior inferior cerebellum. Ischemia in the AICA can cause the lateral inferior pontine syndrome. AICA syndrome is characterized by facial sensory loss and weakness, Horner syndrome, prolonged vertigo, audio-vestibular loss, and cerebellar signs. Many studies on AICA territory infarcts have demonstrated the rarity of complete AICA syndrome. In all cases of AICA territory infarcts, involvement of the middle cerebellar peduncle was observed, with the seventh cranial nerve (facial nerve) being the most frequently involved cranial nerve, vertigo was the most common presenting symptom, and atherosclerosis was the most common etiology. This case report aims to investigate the occurrence of middle cerebellar peduncle infarcts that mimic Bell's palsy, highlighting the importance of accurate diagnosis and appropriate management in such cases. Recognizing the unique characteristics and clinical presentation of middle cerebellar peduncle (MCP) infarcts is essential for distinguishing them from more common conditions like Bell's palsy, thereby ensuring timely and effective treatment.

TRPM4 inhibition slows neuritogenesis progression of cortical neurons.

TRPM4 is a non-selective cation channel activated by intracellular Ca2+ but only permeable to monovalent cations, its activation regulates membrane potential and intracellular calcium. This channel participates in the migration and adhesion of non-excitable cells and forms an integral part of the focal adhesion complex. In neurons, TRPM4 expression starts before birth and its function at this stage is not clear, but it may function in processes such as neurite development. Here we investigate the role of TRPM4 in neuritogenesis. We found that neurons at DIV 0 express TRPM4, the inhibition of TRPM4 using 9-Ph reduces neurite number and slows the progression of neurite development, keeping neurons in stage 1. The genetic suppression of TRPM4 using an shRNA at later stages (DIV2) reduces neurite length. Conversely, at DIV 0, TRPM4 inhibition augments the Cch-induced Ca2 + i increase, altering the calcium homeostasis. Together, these results show that TRPM4 participates in progression of neurite development and suggest a critical role of the calcium modulation during this stage of neuronal development.

Audio Signal-Stimulated Multilayered HfOx/TiOy Spiking Neuron Network for Neuromorphic Computing.

As the key hardware of a brain-like chip based on a spiking neuron network (SNN), memristor has attracted more attention due to its similarity with biological neurons and synapses to deal with the audio signal. However, designing stable artificial neurons and synapse devices with a controllable switching pathway to form a hardware network is a challenge. For the first time, we report that artificial neurons and synapses based on multilayered HfOx/TiOy memristor crossbar arrays can be used for the SNN training of audio signals, which display the tunable threshold switching and memory switching characteristics. It is found that tunable volatile and nonvolatile switching from the multilayered HfOx/TiOy memristor is induced by the size-controlled atomic oxygen vacancy pathway, which depends on the atomic sublayer in the multilayered structure. The successful emulation of the biological neuron's integrate-and-fire function can be achieved through the utilization of the tunable threshold switching characteristic. Based on the stable performance of the multilayered HfOx/TiOy neuron and synapse, we constructed a hardware SNN architecture for processing audio signals, which provides a base for the recognition of audio signals through the function of integration and firing. Our design of an atomic conductive pathway by using a multilayered TiOy/HfOx memristor supplies a new method for the construction of an artificial neuron and synapse in the same matrix, which can reduce the cost of integration in an AI chip. The implementation of synaptic functionalities by the hardware of SNNs paves the way for novel neuromorphic computing paradigms in the AI era.

Unveiling the Neurodegenerative Alterations through Oral Stem Cells.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the progressive and selective loss of dopaminergic (DAergic) neurons in the midbrain. The replacement of neuromelanin (NM)-containing DAergic neurons in the substantia nigra and the enhancement of NM concentration could offer a promising and safe approach to treating PD symptoms. The objective of this study was to investigate and compare the potential of human periapical-cysts mesenchymal stem cells (hPCy-MSCs) and dental pulp stem cells (DPSCs) to differentiate into DAergic NM-producing neurons and to generate functional 3-dimensional (3D) midbrain-like organoids in vitro. We assessed the changes in morphology and behavior of neuron-like cells (NLCs) as well as the expression of molecular markers characterizing the DAergic neurons. Furthermore, we observed electrically active and functionally mature DAergic neurons by means of electrophysiological assays, NM dosage assays, and the quantification of dopamine release by high-performance liquid chromatography. Our results demonstrate for the first time that both hPCy-MSCs and DPSCs are capable of differentiating into NLCs, further confirmed by the increase in lactate levels in the medium of cells exposed to neurogenic conditions. Importantly, we have induced such NLCs to further differentiate into functional DAergic NM-producing neurons. Finally, 3D midbrain-like organoids have been produced from oral stem cells: they appear as neurosphere-like structures diffusely expressing the neural marker ß-III tubulin and containing NM-like granules. Our findings open up a novel and fascinating opportunity to rethink oral stem cells, and the derived 3D disease models, as a strategic and reliable tool for unveiling the neurodegenerative alterations.

Effects of COVID-19 on motor neuron disease mortality in the United States: a population-based cross-sectional study.

BACKGROUND: In March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) to be a pandemic, stating that those with underlying health conditions are most susceptible, including motor neuron disease (MND). OBJECTIVE: To examine the effect the COVID-19 pandemic had on deaths from MND in the United States. METHODS: Death certificate data for all MND deaths aged 20 years and older were analyzed from 2017 to 2019 (pre-COVID), then expanded to include 2020 and 2021 (COVID) deaths to evaluate if COVID-19 impacted MND deaths. RESULTS: The average number of MND deaths documented during the COVID-19 years was 8009, up from 7485 MND deaths pre-COVID. The age-adjusted mortality rate among the non-Hispanic population increased during COVID to 2.78 per 100,000 persons (95% CI = 2.73-2.82) from 1.81 (95% CI = 1.78-1.84). The Hispanic population also saw an increase in mortality rate during COVID (1.61, 95% CI = 1.51-1.71) compared with pre-COVID (1.10, 95% CI = 1.03-1.17). Decedent's home as a place of death also saw a mortality rate increase during COVID (1.51, 95% CI = 1.48-1.54) compared with pre-COVID (1.30, 95% CI = 1.27-1.32). For the Hispanic population, the rate peaked at 80-84 years pre-COVID, but for the COVID years, the rate peaked earlier, at 75-79 years. CONCLUSION: The total number of MND deaths was greater during COVID than in the preceding years. The analysis suggests there might have been a consequence of circumstances surrounding the global pandemic and the associated restrictions.

Astrocyte-mediated neuronal irregularities and dynamics: the complexity of the tripartite synapse.

Despite significant advancements in recent decades, gaining a comprehensive understanding of brain computations remains a significant challenge in neuroscience. Using computational models is crucial for unraveling this complex phenomenon and is equally indispensable for studying neurological disorders. This endeavor has created many neuronal models that capture brain dynamics at various scales and complexities. However, most existing models do not account for the potential influence of glial cells, particularly astrocytes, on neuronal physiology. This gap persists even with the emerging evidence indicating their critical role in regulating neural network activity, plasticity, and even neurological pathologies. To address this gap, some works proposed models that include neuron-glia interactions. Also, while some literature focuses on sophisticated models of neuron-glia interactions that mimic the complexity of physiological phenomena, there are also existing works that propose simplified models of neural-glial ensembles. Building upon these efforts, we aimed to contribute further to the field by proposing a simplified tripartite synapse model that encompasses the presynaptic neuron, postsynaptic neuron, and astrocyte. We defined the tripartite synapse model based on the Adaptive Exponential Integrate-and-Fire neuron model and a simplified scheme of the astrocyte model previously proposed by Postnov. Through our simulations, we demonstrated how astrocytes can influence neuronal firing behavior by sequentially activating and deactivating different pathways within the tripartite synapse. This modulation by astrocytes can shape neuronal behavior and introduce irregularities in the firing patterns of both presynaptic and postsynaptic neurons through the introduction of new pathways and configurations of relevant parameters.

Distinct functional domains of Dystroglycan regulate inhibitory synapse formation and maintenance in cerebellar Purkinje cells.

Dystroglycan is a cell adhesion molecule that localizes to synapses throughout the nervous system. While Dystroglycan is required to maintain inhibitory synapses from cerebellar molecular layer interneurons (MLIs) onto Purkinje cells (PCs) whether initial synaptogenesis during development is dependent on Dystroglycan has not been examined. We show that conditional deletion of Dystroglycan from Purkinje cells prior to synaptogenesis results in impaired MLI:PC synapse formation and function due to reduced presynaptic inputs and abnormal postsynaptic GABAA receptor clustering. Using genetic manipulations that disrupt glycosylation of Dystroglycan or truncate its cytoplasmic domain, we show that Dystroglycan's role in synapse function requires both extracellular and intracellular interactions, whereas synapse formation requires only extracellular interactions. Together, these findings provide molecular insight into the mechanism of inhibitory synapse formation and maintenance in cerebellar cortex.