Intense brain activity elevates extracellular potassium, potentially leading to overexcitation and seizures. Astrocytes are crucial for restoring healthy potassium levels, and an emerging focus on their Kir4.1 channels has reopened the quest into the underlying mechanisms.
View Article and Find Full Text PDFNanoengineered encapsulation presents a promising strategy for targeted drug delivery to specific regions in the body. While polyelectrolyte-based biodegradable microcapsules can achieve highly localised drug release in tissues and cell cultures, delivering drugs to intracellular sites in the brain remains a significant challenge. In this study, we utilized advanced imaging techniques, both and , to investigate whether brain neurons can internalise polyelectrolyte-based microcapsules designed for drug delivery.
View Article and Find Full Text PDFBrain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply. Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism, but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood. Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors.
View Article and Find Full Text PDFMeasuring signal propagation through nerves is a classical electrophysiological technique established decades ago to evaluate sensory and motor functions in the nervous system. The whole-nerve preparation provides a valuable model to investigate nerve function ex vivo; however, it requires specific knowledge to ensure successful and stable measurements. Although the methodology for sciatic nerve recordings has long existed, a method for reliable and long-lasting recordings from myelinated and non-myelinated (nociceptive) fibers still needs to be adapted for pharmacological testing.
View Article and Find Full Text PDFXerostomia (dry-mouth syndrome) is a painful and debilitating condition that frequently occurs in individuals with diabetes and is associated with impaired saliva production and salivary gland hypofunction. Saliva fluid production relies on Ca-coupled secretion driven by neurotransmitter stimulation of submandibular acinar cells. Although impairments in intracellular Ca signalling have been reported in various xerostomia models, the specific Ca-dependent mechanisms underlying saliva fluid hypofunction in diabetes remain unclear.
View Article and Find Full Text PDFNeutrophils are white blood cells that are critical to acute inflammatory and adaptive immune responses. Their swarming-pattern behavior is controlled by multiple cellular cascades involving calcium-dependent release of various signaling molecules. Previous studies have reported that neutrophils express glutamate receptors and can release glutamate but evidence of direct neutrophil-neutrophil communication has been elusive.
View Article and Find Full Text PDFMechanisms that entrain and pace rhythmic epileptiform discharges remain debated. Traditionally, the quest to understand them has focused on interneuronal networks driven by synaptic GABAergic connections. However, synchronized interneuronal discharges could also trigger the transient elevations of extracellular GABA across the tissue volume, thus raising tonic conductance (G) of synaptic and extrasynaptic GABA receptors in multiple cells.
View Article and Find Full Text PDFThe dorsal horn (DH) neurons of the spinal cord play a critical role in nociceptive input integration and processing in the central nervous system. Engaged neuronal classes and cell-specific excitability shape nociceptive computation within the DH. The DH hyperexcitability (central sensitisation) has been considered a fundamental mechanism in mediating nociceptive hypersensitivity, with the proven role of Ca-permeable AMPA receptors (AMPARs).
View Article and Find Full Text PDFBrain ischemic stroke is among the leading causes of death and long-term disability. New treatments that alleviate brain cell damage until blood supply is restored are urgently required. The emerging focus of anti-stroke strategies has been on blood-brain-barrier permeable drugs that exhibit multiple sites of action.
View Article and Find Full Text PDFMotor disability is a common outcome of spinal cord injury (SCI). The recovery of motor function after injury depends on the severity of neurotrauma; motor deficit can be reversible, at least partially, due to the innate tissue capability to recover, which, however, deteriorates with age. Pain is often a comorbidity of injury, although its prediction remains poor.
View Article and Find Full Text PDFHuman iPSC lines represent a powerful translational model of tauopathies. We have recently described a pathophysiological phenotype of neuronal excitability of human cells derived from the patients with familial frontotemporal dementia and parkinsonism (FTDP-17) caused by the MAPT 10+16 splice-site mutation. This mutation leads to the increased splicing of 4R tau isoforms.
View Article and Find Full Text PDFIntroduction: The second most common form of early-onset dementia-frontotemporal dementia (FTD)-is often characterized by the aggregation of the microtubule-associated protein tau. Here we studied the mechanism of tau-induced neuronal dysfunction in neurons with the FTD-related 10+16 MAPT mutation.
Methods: Live imaging, electrophysiology, and redox proteomics were used in 10+16 induced pluripotent stem cell-derived neurons and a model of tau spreading in primary cultures.
Channels (Austin)
December 2021
The activity-dependent trafficking of AMPA receptors (AMPAR) mediates synaptic strength and plasticity, while the perturbed trafficking of the receptors of different subunit compositions has been linked to memory impairment and to causing neuropathology. In the spinal cord, nociceptive-induced changes in AMPAR trafficking determine the central sensitization of the dorsal horn (DH): changes in AMPAR subunit composition compromise the balance between synaptic excitation and inhibition, rendering interneurons hyperexcitable to afferent inputs, and promoting Ca influx into the DH neurons, thereby amplifying neuronal hyperexcitability. The DH circuits become over-excitable and carry out aberrant sensory processing; this causes an increase in pain sensation in central sensory pathways, giving rise to chronic pain syndrome.
View Article and Find Full Text PDFDendritic integration of synaptic inputs involves their increased electrotonic attenuation at distal dendrites, which can be counterbalanced by the increased synaptic receptor density. However, during network activity, the influence of individual synapses depends on their release fidelity, the dendritic distribution of which remains poorly understood. Here, we employed classical optical quantal analyses and a genetically encoded optical glutamate sensor in acute hippocampal slices of rats and mice to monitor glutamate release at CA3-CA1 synapses.
View Article and Find Full Text PDFNeurological disorders and traumas often involve loss of specific neuronal connections, which would require intervention with high spatial precision. We have previously demonstrated the biocompatibility and therapeutic potential of the layer-by-layer (LbL)-fabricated microcapsules aimed at the localized delivery of specific channel blockers to peripheral nerves. Here, we explore the potential of LbL-microcapsules to enable site-specific, directional action of neurotrophins to stimulate neuronal morphogenesis and synaptic circuit formation.
View Article and Find Full Text PDFBrain cells continuously produce and release protons into the extracellular space, with the rate of acid production corresponding to the levels of neuronal activity and metabolism. Efficient buffering and removal of excess H is essential for brain function, not least because all the electrogenic and biochemical machinery of synaptic transmission is highly sensitive to changes in pH. Here, we describe an astroglial mechanism that contributes to the protection of the brain milieu from acidification.
View Article and Find Full Text PDFExtrasynaptic actions of glutamate are limited by high-affinity transporters expressed by perisynaptic astroglial processes (PAPs): this helps maintain point-to-point transmission in excitatory circuits. Memory formation in the brain is associated with synaptic remodeling, but how this affects PAPs and therefore extrasynaptic glutamate actions is poorly understood. Here, we used advanced imaging methods, in situ and in vivo, to find that a classical synaptic memory mechanism, long-term potentiation (LTP), triggers withdrawal of PAPs from potentiated synapses.
View Article and Find Full Text PDFThe patterned microchamber arrays based on biocompatible polymers are a versatile cargo delivery system for drug storage and site-/time-specific drug release on demand. However, functional evidence of their action on nerve cells, in particular their potential for enabling patterned neuronal morphogenesis, remains unclear. Recently, we have established that the polylactic acid (PLA)-based microchamber arrays are biocompatible with human cells of neuronal phenotype and provide safe loading for hydrophilic substances of low molecular weight, with successive site-specific cargo release on-demand to trigger local cell responses.
View Article and Find Full Text PDFFrontotemporal dementia and parkinsonism (FTDP-17) caused by the 10+16 splice-site mutation in the gene encoding microtubule-associated protein tau () provides an established platform to model tau-related dementia Neurons derived from human induced pluripotent stem cells (iPSCs) have been shown to recapitulate the neurodevelopmental profile of tau pathology during corticogenesis, as in the adult human brain. However, the neurophysiological phenotype of these cells has remained unknown, leaving unanswered questions regarding the functional relevance and the gnostic power of this disease model. In this study, we used electrophysiology to explore the membrane properties and intrinsic excitability of the generated neurons and found that human cells mature by ∼150 days of neurogenesis to become compatible with matured cortical neurons.
View Article and Find Full Text PDFIn the original publication of this article [1], text has been introduced erroneously to Figs. 4a and 5d due to a typesetting mistake.
View Article and Find Full Text PDFInformation processing and memory formation in the brain relies on release of the main excitatory neurotransmitter glutamate from presynaptic axonal specialisations. The classical Hebbian paradigm of synaptic memory, long-term potentiation (LTP) of transmission, has been widely associated with an increase in the postsynaptic receptor current. Whether and to what degree LTP induction also enhances presynaptic glutamate release has been the subject of debate.
View Article and Find Full Text PDFActivity-dependent remodeling of excitatory connections underpins memory formation in the brain. Serotonin receptors are known to contribute to such remodeling, yet the underlying molecular machinery remains poorly understood. Here, we employ high-resolution time-lapse FRET imaging in neuroblastoma cells and neuronal dendrites to establish that activation of serotonin receptor 5-HT (5-HTR) rapidly triggers spatially-restricted RhoA activity and G13-mediated phosphorylation of cofilin, thus locally boosting the filamentous actin fraction.
View Article and Find Full Text PDFWorld J Stem Cells
November 2019
Neural stem cells (NSC) act as a versatile tool for neuronal cell replacement strategies to treat neurodegenerative disorders in which functional neurorestorative mechanisms are limited. While the beneficial effects of such cell-based therapy have already been documented in terms of neurodegeneration of various origins, a neurophysiological basis for improvement in the recovery of neurological function is still not completely understood. This overview briefly describes the cumulative evidence from electrophysiological studies of NSC-derived neurons, aimed at establishing the maturation of differentiated neurons within a host microenvironment, and their integration into the host circuits, with a particular focus on the neurogenesis of NSC grafts within the post-ischemic milieu.
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