Properties Of Neurons Research Articles

Kv4 channels improve the temporal processing of auditory neurons in the cochlear nucleus.

Kv4 channels generate A-type current known to regulate neuronal excitability. Its role in processing timing information is understudied, especially in the auditory system where temporal information is crucial for hearing. In the cochlear nucleus, principal bushy neurons are specialized for temporal processing with distinct biophysical properties owing to their expression of various voltage-gated ion channels. Previous studies reported conflicting information regarding the expression and potential role of Kv4 channels in these neurons. We explored these questions using electrophysiology in CBA/CaJ mice of either sex. A-type current was isolated from 88% of bushy neurons using Kv4 channel-selective blocker Jingzhaotoxin-X (JZ-X), which increased the intrinsic excitability of bushy neurons without altering their synaptic input. During high-rate activity, JZ-X treatment significantly increased the spike jitter and reduced the firing threshold of bushy neurons. In old mice, A-type current in bushy neurons reduced in magnitude but maintained current density, accompanied by decreased membrane surface area. In contrast, TEA-sensitive Kv3 current reduced in both magnitude and current density, indicative of a greater contribution to the altered biophysical properties of bushy neurons during ageing. Our findings suggest that Kv4 channels play significant roles in regulating neuronal excitability and improving the temporal processing of bushy neurons. Such function is likely retained with age and is not the primary mechanism driving compromised temporal processing under age-related hearing loss. KEY POINTS: Most bushy neurons of the cochlear nucleus exhibit Kv4-mediated A-type current. A-type current regulates neuronal excitability of bushy neurons without contributing to the synaptic transmission at the endbulb of Held. A-type current increases the firing threshold and improves the temporal precision of spikes in bushy neurons during high-rate activity. A-type current reduces peak amplitude in bushy neurons during ageing but maintains current density. Decreased Kv3 current, rather than Kv4 current, likely play more significant roles in altering the biophysical properties of bushy neurons during ageing, contributing to compromised temporal processing during age-related hearing loss.

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

Sympathetic motor neuron dysfunction is a missing link in age-associated sympathetic overactivity.

Overactivity of the sympathetic nervous system is a hallmark of aging. The cellular mechanisms behind this overactivity remain poorly understood, with most attention paid to likely central nervous system components. In this work, we hypothesized that aging also affects the function of motor neurons in the peripheral sympathetic ganglia. To test this hypothesis, we compared the electrophysiological responses and ion-channel activity of neurons isolated from the superior cervical ganglia of young (12 weeks), middle-aged (64 weeks), and old (115 weeks) mice. These approaches showed that aging does impact the intrinsic properties of sympathetic motor neurons, increasing spontaneous and evoked firing responses. A reduction of M current emerged as a major contributor to age-related hyperexcitability. Thus, it is essential to consider the effect of aging on motor components of the sympathetic reflex as a crucial part of the mechanism involved in sympathetic overactivity.

The BE (2)-M17 neuroblastoma cell line: revealing its potential as a cellular model for Parkinson’s disease

Parkinson’s disease is a pathology with a wide range of in vivo and in vitro models available. Among these, the SH-SY5Y neuroblastoma cell line is one of the most employed. This model expresses catecholaminergic markers and can differentiate and acquire various neuronal phenotypes. However, challenges persist, primarily concerning the variability of growth media, expression of dopaminergic markers, and a wide variety of differentiation protocols have been reported in the literature without direct comparison between them. This lack of standardized differentiation conditions impacts result reproducibility and it makes it very difficult to compare the results obtained from different research groups. An alternative cellular model is the neuroblastoma BE (2)-M17 which exhibits a high basal expression of numerous dopaminergic markers such as tyrosine hydroxylase (TH), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT). The BE (2)-M17 cells show neuronal properties, grows rapidly in conventional media, and can easily be differentiated to increase their dopaminergic phenotype. In this review, we will thoroughly explore the properties of the BE (2)-M17 cell line and discuss its potential as an excellent model for studying Parkinson’s disease.

Fasting regulates expression of voltage-gated Na+ channel Nav1.3 in subfornical organ

The subfornical organ (SFO) is a sensory circumventricular organ of the central nervous system and plays a key role in regulation of a number of homeostatic processes because of its ability to detect and respond to circulating signals and communication to homeostatic control centres. A previous study reported a change in expression of 687 transcripts in rat SFO following a 48h fast; of particular interest was the observed downregulation of the transcript encoding the Nav1.3 voltage-gated Na+ channel. Therefore, we carried out a study to examine the effects of a 48h fast on electrical properties of SFO neurons. First, we carried out an immunohistochemical analysis of rat SFO to confirm expression of Nav1.3 protein. Next, we carried out qPCR analysis of mRNA from SFO of sated rats and 48h fasted rats and confirm that a 48hr fast caused a downregulation of Nav1.3. Using patch clamp analysis of SFO neurons acutely isolated from rats following a 48h fast, a statistically significant decrease in peak Na+ current density, as well as shifts in voltage dependence of activation and inactivation, and a slowing to time dependent recovery from inactivation were observed. These changes were accompanied by a depolarization of the threshold to fire action potentials and a decrease in frequency of spontaneous action potentials. Together, these data show that the electrical properties of SFO neurons are altered by a 48hr fast, indicating SFO is a dynamic sensor of circulating signals.

Sox6 and ALDH1A1 Truncation by Asparagine Endopeptidase Defines Selective Neuronal Vulnerability in Parkinson's Disease.

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) demonstrate regionally selective susceptibility in Parkinson's disease (PD) compared to those in the ventral tegmental area (VTA). However, the molecular mechanism for this distinct vulnerability remains unclear. Here, it is shown that Legumain, also known as asparagine endopeptidase (AEP), is activated in a subgroup of SRY-box transcription factor 6 /Aldehyde dehydrogenase 1 family member A1, (Sox6+/ALDH1A1+) neurons in the ventral tier of the SNpc and cleaves Sox6 and ALDH1A1, leading to repression of Special AT-rich sequence binding protein 1 (Satb1) that is a dimeric/tetrameric transcription factor specifically binding to AT-rich DNA sequences, and toxic dopamine metabolite accumulation. AEP cuts Sox6 and ALDH1A1 in dopaminergic neurons that project to the locus coeruleus (LC), abolishing Sox6's transcriptive and ALDH1A1's enzymatic activities. Co-expressing AEP-truncated Sox6 and ALDH1A1 fragments in 3-month-old A53T SNCA transgenic mice accelerates dopamine degeneration, whereas expressing AEP-resistant Sox6 N336A/N446A and ALDH1A1 N220A mutants alleviates rotenone-induced PD pathologies. Hence, different circuitries and intrinsic properties of dopaminergic neurons in the SNpc and VTA render differential predispositions in PD.

Model of the HVC neural network as a song motor in zebra finch.

The nucleus HVC within the avian song system produces crystalized instructions which lead to precise, learned vocalization in zebra finches (Taeniopygia guttata). This paper proposes a model of the HVC neural network based on the physiological properties of individual HVC neurons, their synaptic interactions calibrated by experimental measurements, as well as the synaptic signal into this region which triggers song production. This neural network model comprises of two major neural populations in this area: neurons projecting to the nucleus RA and interneurons. Each single neuron model of HVCRA is constructed with conductance-based ion currents of fast Na+ and K+ and a leak channel, while the interneuron model includes extra transient Ca2+ current and hyperpolarization-activated inward current. The synaptic dynamics is formed with simulated delivered neurotransmitter pulses from presynaptic cells and neurotransmitter receptor opening rates of postsynaptic neurons. We show that this network model qualitatively exhibits observed electrophysiological behaviors of neurons independent or in the network, as well as the importance of bidirectional interactions between the HVCRA neuron and the HVCI neuron. We also simulate the pulse input from A11 neuron group to HVC. This signal successfully suppresses the interneuron, which leads to sequential firing of projection neurons that matches measured burst onset, duration, and spike quantities during the zebra finch motif. The result provides a biophysically based model characterizing the dynamics and functions of the HVC neural network as a song motor, and offers a reference for synaptic coupling strength in the avian brain.

Velocity coding in the central brain of bumblebees.

Moving animals experience wide-field optic flow due to the displacement of the retinal image during motion. These cues provide information about self-motion and are important for flight control and stabilization, and for more complex tasks like path integration. While in honeybees and bumblebees the use of wide-field optic flow in behavioral tasks is well investigated, little is known about the underlying neuronal processing of these cues. Furthermore, there is a discrepancy between the temporal frequency tuning observed in most motion-sensitive neurons described so far from the optic lobe of insects and the velocity tuning that has been shown for many behaviors. Here we investigated response properties of motion-sensitive neurons in the central brain of bumblebees. Extracellular recordings allowed us to present a large number of stimuli to probe the spatiotemporal tuning of these neurons. We presented moving gratings that simulated either front-to-back or back-to-front optic flow and found three response types. Direction-selective responses of one of the groups matched those of TN-neurons, which provide optic flow information to the central complex, while the other groups contained neurons with purely excitatory responses that were either selective or non-selective for stimulus direction. Most recorded units showed velocity-coding properties at lower angular velocities, but showed spatial frequency dependent responses at higher velocities. Based on behavioral data, neuronal modelling work has previously predicted the existence of non direction-selective neurons with such properties. Our data now provides physiological evidence for these neurons and shows that neurons with TN-like properties exhibit a similar velocity-dependent coding.

Transplantation of human neural stem cells repairs neural circuits and restores neurological function in the stroke-injured brain

Exogenous neural stem cell (NSC) transplantation has become one of the most promising treatment methods for chronic stroke. Recent studies have shown that most ischemia-reperfusion model rats recover spontaneously after injury, which limits the ability to observe long-term behavioral recovery. Here, we used a severe stroke rat model with 150 minutes of ischemia, which produced severe behavioral deficiencies that persisted at 12 weeks, to study the therapeutic effect of neural stem cells on neural restoration in chronic stroke. Our study showed that stroke model rats treated with human neural stem cells had long-term sustained recovery of motor function, reduced infarction volume, long-term human neural stem cell survival, and improved local inflammatory environment and angiogenesis. We also demonstrated that transplanted human neural stem cells differentiated into mature neurons in vivo, formed stable functional synaptic connections with host neurons, and exhibited the electrophysiological properties of functional mature neurons, indicating that they replaced the damaged host neurons. The findings showed that human fetal-derived neural stem cells had long-term effects for neurological recovery in a model of severe stroke, which suggests that human neural stem cells-based therapy may be effective for repairing damaged neural circuits in stroke patients.

CNSC-22. GLIOBLASTOMA CELLS EXHIBIT NEURON-LIKE EXCITABILITY IN BOTH ACUTE AND ORGANOTYPIC HUMAN BRAIN SLICES

Abstract Glioblastomas (GBM) are known for their significant intratumor heterogeneity, featuring a variety of plastic cell types that make effective treatment challenging. Recent studies have shown that neuronal-progenitor-like transcriptomic cell states at the leading edge of the tumor receive synaptic input from nearby neurons, which drives disease proliferation. However, the excitability of GBM cells remains controversial, with observations ranging from non-excitable to neuron-like excitability, complicating our understanding of their pathophysiology. In this study, we developed a novel experimental approach to study glioblastoma cells in both acute and cultured brain slices infiltrated with cancer from GBM patients. Using an adeno-associated virus for gene delivery, we selectively expressed fluorescent proteins in specific cell types. Fluorescence-guided whole-cell patch-clamp recordings were then used to analyze the electrophysiological properties of GBM cells and neurons within the tumor microenvironment. Our findings show that GBM cells have distinct electrophysiological properties, including a depolarized resting membrane potential (-31.95 ± 2.18 mV, n = 55 cells) and high membrane resistance (1.27 ± 0.19 GΩ, n = 62 cells). Approximately 56% of GBM cells at the tumor’s leading edge exhibited neuron-like excitability, generating aberrant action potentials (aAPs) upon depolarization. Collectively, our study provides direct evidence of the intrinsic excitability of GBM cells and a detailed characterization of their electrophysiological properties in the cancer-infiltrated human cortex. These insights shed new light on tumor heterogeneity and cell-cell interactions in glioblastoma, potentially guiding the development of targeted therapies.

Antioxidant, neuroprotective, and neuroblastoma cells (SH-SY5Y) differentiation effects of melanins and arginine-modified melanins from Daedaleopsis tricolor and Fomes fomentarius

BackgroundMicrobial melanins possess a broad spectrum of biological activities. However, there is little understanding of their neuroprotective and neuronal cell differentiation properties. This study aimed to extract, purify, and modify melanins from two medicinal fungi (Daedaleopsis tricolor and Fomes fomentarius), and to evaluate their antioxidant activity, as well as their cell protective ability against neurotoxins. In addition, the study also investigated the feasibility of combining melanins or modified melanins with retinoic acid (RA) to induce neuronal differentiation.MethodsMelanin was extracted and purified using alkaline acid-based methods. Antioxidant activities and neuroprotective effects were evaluated using the DPPH (1,1-diphenyl-2-picrylhydrazyl) and MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assays, respectively. In addition, morphological changes of SH-SY5Y cells were recorded by using a Pannoramic MIDI scanner.ResultsAll melanins and arginine-modified melanins displayed mild DPPH scavenging activities, which were statistically lower than that of ascorbic acid (p < 0.05). In terms of neuroprotection, both melanins and arginine-modified melanins exhibited significant cell protection against H2O2 after 24 h exposure (p < 0.05). Notably, there is no significant difference between F. fomentarius melanin and its modified form as they both increased cell viability by about 20%. Contrarily, while D. tricolor melanin enhanced the cell viability with 16%, its modified form increased the cell viability with 21%. These activities, however, are significantly lower than the positive control (N-acetylcysteine, p < 0.05). Regarding MPTP, only the arginine-modified melanins of the two fungi significantly protected the cells after 24 h exposure to the toxin (p < 0.05). Specifically, F. fomentarius and D. tricolor modified melanins enhanced the cell viability with 10.2% and 11.1%, respectively, whereas that of the positive control was 13.2%. Interestingly, combining RA (10 µM) with 20 µg/mL of either F. fomentarius, or especially D. tricolor arginine-modified melanin, significantly promoted neuroblastoma cell differentiation into mature neuronal cells compared to using RA alone (p < 0.05).ConclusionsThe arginine-modified melanins of D. tricolor and F. fomentarius have potential for neuroprotection against Parkinsonian neurotoxins. In addition, the arginine-modified melanin of D. tricolor may serve as an excellent material for research in neuroblastoma treatment.

Projections between the globus pallidus externa and cortex span motor and non-motor regions.

The globus pallidus externa (GPe) is a heterogenous nucleus of the basal ganglia, with intricate connections to other basal ganglia nuclei, as well as direct connections to the cortex. The anatomic, molecular and electrophysiologic properties of cortex-projecting pallidocortical neurons are not well characterized. Here we show that pallidocortical neurons project to diverse motor and non-motor cortical regions, are organized topographically in the GPe, and segregate into two distinct electrophysiological and molecular phenotypes. In addition, we find that the GPe receives direct synaptic input back from deep layers of diverse motor and non-motor cortical regions, some of which form reciprocal connections onto pallidocortical neurons. These results demonstrate the existence of a fast, closed-loop circuit between the GPe and the cortex which is ideally positioned to integrate information about behavioral goals, internal states, and environmental cues to rapidly modulate behavior.

Adverse Effects of Aβ1-42 Oligomers: Impaired Contextual Memory and Altered Intrinsic Properties of CA1 Pyramidal Neurons.

Aβ1-42 (amyloid beta) oligomers, the major neurotoxic culprits in Alzheimer's disease, initiate early pathophysiological events, including neuronal hyperactivity, that underlie aberrant network activity and cognitive impairment. Although several synaptotoxic effects have been extensively studied, neuronal hyperexcitability, which may also contribute to cognitive deficits, is not fully understood. Here, we found several adverse effects of in vivo injection of Aβ1-42 oligomers on contextual memory and intrinsic properties of CA1 pyramidal neurons. Male rats underwent behavioral and electrophysiological studies 1 week after microinjections into the dorsal CA1 region, followed by histological analysis. After 1 week, Aβ1-42 oligomers impaired contextual learning without affecting basic physiological functions and triggered training-induced neuronal excitability. Furthermore, riluzole, a persistent sodium current (INaP) blocker, dose-dependently reduced Aβ1-42 oligomer-induced hyperexcitability. Congo red staining, which detects insoluble amyloid deposits, further identified labeling of CA1 pyramidal neurons while immunohistochemistry with lecanemab, which detects soluble Aβ oligomers, revealed immunoreactivity of both pyramidal and non-pyramidal cells in the target area. Therefore, our study suggests that a single injection of Aβ1-42 oligomers resulted in contextual memory deficits along with concomitant neuronal hyperexcitability and amyloid deposition in the CA1 region after 1 week.

Astrocytic modulation of population encoding in mouse visual cortex via GABA transporter 3 revealed by multiplexed CRISPR/Cas9 gene editing.

Astrocytes, which are increasingly recognized as pivotal constituents of brain circuits governing a wide range of functions, express GABA transporter 3 (Gat3), an astrocyte-specific GABA transporter responsible for maintenance of extra-synaptic GABA levels. Here, we examined the functional role of Gat3 in astrocyte-mediated modulation of neuronal activity and information encoding. First, we developed a multiplexed CRISPR construct applicable for effective genetic ablation of Gat3 in the visual cortex of adult mice. Using in vivo two-photon calcium imaging of visual cortex neurons in Gat3 knockout mice, we observed changes in spontaneous and visually driven single neuronal response properties such as response magnitudes and trial-to-trial variability. Gat3 knockout exerted a pronounced influence on population-level neuronal activity, altering the response dynamics of neuronal populations and impairing their ability to accurately represent stimulus information. These findings demonstrate that Gat3 in astrocytes profoundly shapes the sensory information encoding capacity of neurons and networks within the visual cortex.

Obesogenic Cafeteria Diet Induces Dynamic Changes in Gut Microbiota, Reduces Myenteric Neuron Excitability, and Impairs Gut Contraction in Mice.

The cafeteria diet (CAF) is a superior diet model in animal experiments compared to the conventional high-fat diet (HFD), effectively inducing obesity, metabolic disturbances and multi-organ damage. Nevertheless, its impact on gut microbiota composition during the progression of obesity, along with its repercussions on the enteric nervous system (ENS) and gastrointestinal motility has not been completely elucidated. To gain more insight into the effects of CAF diet in the gut, C57BL/6 mice were fed with CAF or standard diet for 2 or 8 weeks. CAF-fed mice experienced weight gain, disturbed glucose metabolism, dysregulated expression of colonic IL-6, IL-22, TNFα and TPH1, and altered colon morphology, starting at week 2. Fecal DNA was isolated and gut microbiota composition was monitored by sequencing the V3-V4 16S rRNA region. Sequence analysis revealed that Clostridia and Proteobacteria were specific biomarkers associated with CAF-feeding at week 2, while Bacteroides, Actinobacteria were prominent at week 8. Additionally, the impact of CAF diet on ENS was investigated (week 8), where HuC/D+ neurons were measured and counted, and their biophysical properties were evaluated by patch-clamp. Gut contractility was tested in whole-mount preparations. Myenteric neurons in CAF-fed mice exhibited reduced body size, incremented cell density and decreased excitability. The amplitude and frequency of the rhythmic spontaneous contractions in colon and ileum were affected by the CAF diet. Our findings demonstrate, for the first time, that CAF diet gradually changes the gut microbiota and promotes low-grade inflammation, impacting the functional properties of myenteric neurons and gut contractility in mice.

Human iPSC-derived MSCs induce neurotrophic effects and improve metabolic activity in acute neuronal injury models.

Mesenchymal stromal cell (MSC) therapy has regenerative potentials to treat various pathological conditions including neurological diseases. MSCs isolated from various organs can differentiate into specific cell types to repair organ damages. However, their paracrine mechanisms are predicted to predominantly mediate their immunomodulatory, pro-angiogenic, and regenerative properties. While preclinical studies highlight the significant potential of MSC therapy in mitigating neurological damage from stroke and traumatic brain injury, the variability in clinical trial outcomes may stem from the inherent heterogeneity of somatic MSCs. Accumulating evidence has demonstrated that induced pluripotent stem cells (iPSCs) are an ideal alternative resource for the unlimited expansion and biomanufacturing of MSCs. Thus, we investigated how iPSC-derived MSCs (iMSCs) influence properties of iPSC-derived neurons. Our findings demonstrate that the secretome from iMSCs possesses neurotrophic effects, improving neuronal survival and promoting neuronal outgrowth and synaptic activity in vitro Additionally, the iMSCs enhance metabolic activity via mitochondrial respiration in neurons, both in vitro and in mouse models. Glycolytic pathways also increased following the administration of iMSC secretome to iPSC-derived neurons. Consistently, in vivo experiments showed that intravenous administration of iMSCs compensated for the elevated energetic demand in male mice with irradiation-induced brain injury by restoring synaptic metabolic activity during acute brain damage. 18F-FDG PET imaging also detected an increase in brain glucose uptake following iMSC administration. Together, our results highlight the potential of iMSC-based therapy in treating neuronal damage in various neurological disorders, while paving the way for future research and potential clinical applications of iMSCs in regenerative medicine.Significance Statement Regenerative biotherapeutics using MSCs have emerged as a promising intervention for treating various neurological diseases. Our study explored the potential beneficial effects of human iPSC-derived MSCs (iMSCs) on neurons. We demonstrated that molecules secreted into the culture medium by iMSCs enhance regenerative capabilities by improving neuronal survival, growth, and metabolic activity, as well as synaptic functions, in human iPSC-derived neurons. Mouse experiments also suggested the potential of iMSC therapy to mitigate synaptic mitochondrial dysfunction and enhance brain glucose uptake during acute radiation-induced brain injury, steps that contribute to restoring normal neuronal function. Our results highlight that iMSCs may be a promising alternative cell product for treating neuronal damage, overcoming the inconsistent efficacy of somatic MSCs due to cell variability.

Gap Junctions in Different Neuronal Groups Exert Different Effects on Sharp Wave-ripples of a Neuronal Network in CA1

Abstract Gap junctions are indispensable for achieving brain functions. The direct coupling between neurons connected by gap junctions may contribute to synchronization of neuronal firing and emergence of sharp wave-ripples(SWR), which affect brain functions such as memory consolidation. However, considering the heterogeneity of excitatory and inhibitory neurons, it is not quite clear whether gap junctions have the same effect on the emergence of SWR in network activity in different neuron types. In order to explore the above problems, we constructed a neuronal network located in CA1 region of hippocampus, which contains excitatory pyramidal cells, PV+BCs and axo-axonic cells. Taking into account diverse connections between neurons and properties of neurons, we investigated effects of gap junctions on SWR in different kinds of neuronal populations in the constructed network with chemical synaptic connections by neurodynamical modeling. Numerical results show that gap junctions within pyramidal neurons and PV+BCs promote the emergence of SWR, whereas gap junctions within axo-axonic cells suppress it. At the same time, it is revealed that gap junctions in axo-axonic cells play a dominant role in modulating SWR. We hope that these findings provide some inspiration for studies on neuronal heterogeneity and the enhancement of synchronicity of oscillations by gap junctions.

Firing dynamics and coupling synchronization of memristive EMR-based Chaivlo neuron utilizing equivalent energy approach.

Firing dynamics and its energy property of neuron are crucial for exploring the mechanism of intricate information processing within the nervous system. However, the energy analysis of discrete neuron is significantly lacking in comparison to the vast literature and mature theory available on continuous neuron, thereby necessitating a focused effort in this underexplored realm. In this paper, we introduce a Chaivlo neuron map by employing a flux-controlled memristor to simulate electromagnetic radiation (EMR), and a detailed analysis of its firing dynamics is conducted based on an equivalent Hamiltonian energy approach. Our observations reveal that a range of energy-based firing behaviors, such as spike firing, coexistence firing, mixed-mode firing, and chaotic bursting firing, can be induced by EMR and injected current. To delve deeper into the synchronous firing dynamics, we establish a Chaivlo network by electrically coupling two memristive EMR-based Chaivlo neurons. Subsequently, we experimentally evaluate the synchronization behavior of this network by quantifying both the synchronization factor and the average difference of equivalent Hamiltonian energy. Our findings conclusively demonstrate that both EMR and coupling strength positively contribute to the network's synchronization ability.

BDNF Differentially Affects Low- and High-Frequency Neurons in a Primary Nucleus of the Chicken Auditory Brainstem.

Neurotrophins are proteins that mediate neuronal development using spatiotemporal signaling gradients. The chicken nucleus magnocellularis (NM), an analogous structure to the mammalian anteroventral cochlear nucleus, provides a model system in which signaling between the brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB) is temporally regulated. In the NM, TrkB expression is high early in development (embryonic [E] day 9) and is downregulated until maturity (E18-21). It is currently unknown how BDNF-TrkB signaling affects neuronal properties throughout development and across a spatial (i.e., frequency) axis. To investigate this, we exogenously applied BDNF onto NM neurons ex vivo and studied intrinsic properties using whole-cell patch clamp electrophysiology. Early in development (E13), when TrkB expression is detectable with immunohistochemistry, BDNF application slowed the firing of high-frequency NM neurons, resembling an immature phenotype. Current measurements and biophysical modeling revealed that this was mediated by a decreased conductance of the voltage-dependent potassium channels. Interestingly, this effect was seen only in high-frequency neurons and not in low-frequency neurons. BDNF-TrkB signaling induced minimal changes in late-developing NM neurons (E20-21) of high and low frequencies. Our results indicate that normal developmental downregulation of BDNF-TrkB signaling promotes neuronal maturation tonotopically in the auditory brainstem, encouraging the appropriate development of neuronal properties.

In Vivo Expression of an SCA27A-linked FGF14 Mutation Results in Haploinsufficiency and Impaired Firing of Cerebellar Purkinje Neurons.

Autosomal dominant mutations in FGF14 , which encodes intracellular fibroblast growth factor 14 (iFGF14), underlie spinocerebellar ataxia type 27A (SCA27A), a devastating multisystem disorder resulting in progressive deficits in motor coordination and cognitive function. Mice lacking iFGF14 ( Fgf14 -/- ) exhibit similar phenotypes, which have been linked to iFGF14-mediated modulation of the voltage-gated sodium (Nav) channels that control the high frequency repetitive firing of Purkinje neurons, the main output neurons of the cerebellar cortex. To investigate the pathophysiological mechanisms underlying SCA27A, we developed a targeted knock-in strategy to introduce the first point mutation identified in FGF14 into the mouse Fgf14 locus ( Fgf14 F145S ), we determined the impact of in vivo expression of the mutant Fgf14 F145S allele on the motor performance of adult animals and on the firing properties of mature Purkinje neurons in acute cerebellar slices. Electrophysiological experiments revealed that repetitive firing rates are attenuated in adult Fgf14 F145S/+ cerebellar Purkinje neurons, attributed to a hyperpolarizing shift in the voltage-dependence of steady-state inactivation of Nav channels. More severe effects on firing properties and Nav channel inactivation were observed in homozygous Fgf14 F145S/F145S Purkinje neurons. Interestingly, the electrophysiological phenotypes identified in adult Fgf14 F145S/+ and Fgf14 F145S/F145S cerebellar Purkinje neurons mirror those observed in heterozygous Fgf14 +/- and homozygous Fgf14 -/- Purkinje neurons, respectively, suggesting that the mutation results in the loss of the iFGF14 protein. Western blot analysis of lysates from adult heterozygous Fgf14 F145S/+ and homozygous Fgf14 F145S/F145S animals revealed reduced or undetectable, respectively, iFGF14 expression, supporting the hypothesis that the mutant allele results in loss of the iFGF14 protein and that haploinsufficiency underlies SCA27A neurological phenotypes.