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Advanced Science (Weinheim,... Oct 2023In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic...
In tauopathy conditions, such as Alzheimer's disease (AD), highly soluble and natively unfolded tau polymerizes into an insoluble filament; however, the mechanistic details of this process remain unclear. In the brains of AD patients, only a minor segment of tau forms β-helix-stacked protofilaments, while its flanking regions form disordered fuzzy coats. Here, it is demonstrated that the tau AD nucleation core (tau-AC) sufficiently induced self-aggregation and recruited full-length tau to filaments. Unexpectedly, phospho-mimetic forms of tau-AC (at Ser324 or Ser356) show markedly reduced oligomerization and seeding propensities. Biophysical analysis reveal that the N-terminus of tau-AC facilitates the fibrillization kinetics as a nucleation motif, which becomes sterically shielded through phosphorylation-induced conformational changes in tau-AC. Tau-AC oligomers are efficiently internalized into cells via endocytosis and induced endogenous tau aggregation. In primary hippocampal neurons, tau-AC impaired axon initial segment plasticity upon chronic depolarization and is mislocalized to the somatodendritic compartments. Furthermore, it is observed significantly impaired memory retrieval in mice intrahippocampally injected with tau-AC fibrils, which corresponds to the neuropathological staining and neuronal loss in the brain. These findings identify tau-AC species as a key neuropathological driver in AD, suggesting novel strategies for therapeutic intervention.
Topics: Mice; Humans; Animals; Alzheimer Disease; tau Proteins; Brain; Neurons; Phosphorylation
PubMed: 37594721
DOI: 10.1002/advs.202302035 -
BioRxiv : the Preprint Server For... Aug 2023Non-synaptic ('intrinsic') plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic...
Non-synaptic ('intrinsic') plasticity of membrane excitability contributes to aspects of memory formation, but it remains unclear whether it merely facilitates synaptic long-term potentiation (LTP), or whether it plays a permissive role in determining the impact of synaptic weight increase. We use tactile stimulation and electrical activation of parallel fibers to probe intrinsic and synaptic contributions to receptive field (RF) plasticity in awake mice during two-photon calcium imaging of cerebellar Purkinje cells. Repetitive activation of both stimuli induced response potentiation that is impaired in mice with selective deficits in either intrinsic plasticity (SK2 KO) or LTP (CaMKII TT305/6VA). Intrinsic, but not synaptic, plasticity expands the local, dendritic RF representation. Simultaneous dendrite and axon initial segment recordings confirm that these dendritic events affect axonal output. Our findings support the hypothesis that intrinsic plasticity provides an amplification mechanism that exerts a permissive control over the impact of LTP on neuronal responsiveness.
PubMed: 37502848
DOI: 10.1101/2023.07.19.549760 -
Nature Neuroscience Aug 2023Genetically defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our...
Genetically defined subgroups of inhibitory interneurons are thought to play distinct roles in learning, but heterogeneity within these subgroups has limited our understanding of the scope and nature of their specific contributions. Here we reveal that the chandelier cell (ChC), an interneuron type that specializes in inhibiting the axon-initial segment (AIS) of pyramidal neurons, establishes cortical microcircuits for organizing neural coding through selective axo-axonic synaptic plasticity. We found that organized motor control is mediated by enhanced population coding of direction-tuned premotor neurons, with tuning refined through suppression of irrelevant neuronal activity. ChCs contribute to learning-dependent refinements by providing selective inhibitory control over individual pyramidal neurons rather than global suppression. Quantitative analysis of structural plasticity across axo-axonic synapses revealed that ChCs redistributed inhibitory weights to individual pyramidal neurons during learning. These results demonstrate an adaptive logic of the inhibitory circuit motif responsible for organizing distributed neural representations. Thus, ChCs permit efficient cortical computation in a targeted cell-specific manner.
Topics: Behavior Control; Axons; Neurons; Pyramidal Cells; Synapses; Interneurons
PubMed: 37474640
DOI: 10.1038/s41593-023-01380-x -
Science Advances Jul 2023The gold-standard fixative for immunohistochemistry is 4% formaldehyde; however, it limits antibody access to target molecules that are buried within specialized...
The gold-standard fixative for immunohistochemistry is 4% formaldehyde; however, it limits antibody access to target molecules that are buried within specialized neuronal components, such as ionotropic receptors at the postsynapse and voltage-gated ion channels at the axon initial segment, often requiring additional antigen-exposing techniques to detect their authentic signals. To solve this problem, we used glyoxal, a two-carbon atom di-aldehyde. We found that glyoxal fixation greatly improved antibody penetration and immunoreactivity, uncovering signals for buried molecules by conventional immunohistochemical procedures at light and electron microscopic levels. It also enhanced immunosignals of most other molecules, which are known to be detectable in formaldehyde-fixed sections. Furthermore, we unearthed several specific primary antibodies that were once judged to be unusable in formaldehyde-fixed tissues, allowing us to successfully localize so far controversial synaptic adhesion molecule Neuroligin 1. Thus, glyoxal is a highly effective fixative for immunostaining, and a side-by-side comparison of glyoxal and formaldehyde fixation is recommended for routine immunostaining in neuroscience research.
Topics: Fixatives; Tissue Fixation; Glyoxal; Formaldehyde; Antigens; Antibodies
PubMed: 37450597
DOI: 10.1126/sciadv.adf7084 -
Frontiers in Cellular Neuroscience 2023Imbalance between excitation and inhibition in the cerebral cortex is one of the main theories in neuropsychiatric disorder pathophysiology. Cortical inhibition is...
Imbalance between excitation and inhibition in the cerebral cortex is one of the main theories in neuropsychiatric disorder pathophysiology. Cortical inhibition is finely regulated by a variety of highly specialized GABAergic interneuron types, which are thought to organize neural network activities. Among interneurons, axo-axonic cells are unique in making synapses with the axon initial segment of pyramidal neurons. Alterations of axo-axonic cells have been proposed to be implicated in disorders including epilepsy, schizophrenia and autism spectrum disorder. However, evidence for the alteration of axo-axonic cells in disease has only been examined in narrative reviews. By performing a systematic review of studies investigating axo-axonic cells and axo-axonic communication in epilepsy, schizophrenia and autism spectrum disorder, we outline convergent findings and discrepancies in the literature. Overall, the implication of axo-axonic cells in neuropsychiatric disorders might have been overstated. Additional work is needed to assess initial, mostly indirect findings, and to unravel how defects in axo-axonic cells translates to cortical dysregulation and, in turn, to pathological states.
PubMed: 37435048
DOI: 10.3389/fncel.2023.1212202 -
Advances in Physiology Education Sep 2023Active learning and practices are strongly encouraged or made mandatory by local, national, and European organizations. Therefore, we set up an interactive practical...
Active learning and practices are strongly encouraged or made mandatory by local, national, and European organizations. Therefore, we set up an interactive practical classroom, engaging all of the attending students of the year ( = 47). Each student was assigned a physiological role (marked on a cardboard sign) in the following events: stimulation on motoneuron dendrites, sodium ions (Na) influx and potassium ions (K) efflux, action potentials onset and saltatory conduction along the axon, acetylcholine (ACh) neurotransmitter exocytosis following Ca influx, ACh binding to postsynaptic membrane receptors, ACh-esterase action, excitatory postsynaptic potential, release of Ca from the sarcoplasmic reticulum, mechanism of muscular contraction and relaxation, and rigor mortis. A sketch was drawn with colored chalks on the ground outside the room: the motoneuron with its dendrites, cell body, initial segment, myelinated axon, and synaptic bouton; the postsynaptic plasma membrane of the muscle fiber; and the sarcoplasmic reticulum. Students each had their own role and were asked to position themselves and move, accordingly. This resulted in a complete, dynamic, and fluid representation being performed. The evaluation of the effectiveness of the students' learning was limited at this pilot stage. However, positive feedback was received in the self-evaluation reports that were written by students on the physiological meaning of their own role, as well as in the satisfaction questionnaires requested by the University. The rate of students who successfully passed the written exam and the rate of correct answers that included the specific topics addressed in this practice were reported. We set up an interactive practical classroom, engaging all the attending students of the year ( = 47). Each student was assigned a physiological role marked on a cardboard sign, starting from motoneuron stimulation up to skeletal muscle contraction and relaxation. Students were asked to actively reproduce physiological events, positioning themselves and moving around and onto drawings on the ground (motoneuron, synapsis, sarcoplasmic reticulum, etc.). Finally, a complete, dynamic, and fluid representation was performed.
Topics: Humans; Motor Neurons; Muscle Contraction; Action Potentials; Synapses; Axons; Muscle, Skeletal
PubMed: 37411014
DOI: 10.1152/advan.00047.2023 -
Cells May 2023Dominantly inherited missense mutations of the gene, which encodes the K1.1 potassium channel subunit, cause Episodic Ataxia type 1 (EA1). Although the cerebellar...
Dominantly inherited missense mutations of the gene, which encodes the K1.1 potassium channel subunit, cause Episodic Ataxia type 1 (EA1). Although the cerebellar incoordination is thought to arise from abnormal Purkinje cell output, the underlying functional deficit remains unclear. Here we examine synaptic and non-synaptic inhibition of Purkinje cells by cerebellar basket cells in an adult mouse model of EA1. The synaptic function of basket cell terminals was unaffected, despite their intense enrichment for K1.1-containing channels. In turn, the phase response curve quantifying the influence of basket cell input on Purkine cell output was maintained. However, ultra-fast non-synaptic ephaptic coupling, which occurs in the cerebellar 'pinceau' formation surrounding the axon initial segment of Purkinje cells, was profoundly reduced in EA1 mice in comparison with their wild type littermates. The altered temporal profile of basket cell inhibition of Purkinje cells underlines the importance of Kv1.1 channels for this form of signalling, and may contribute to the clinical phenotype of EA1.
Topics: Purkinje Cells; Neural Inhibition; Animals; Mice; Disease Models, Animal; Kv1.1 Potassium Channel; Synapses; Cell Communication; Synaptic Transmission; Ataxia; Myokymia; Evoked Potentials; Mice, Inbred C57BL; Male; Female
PubMed: 37408217
DOI: 10.3390/cells12101382 -
ENeuro Jun 2023The fruit fly has provided important insights into how sensory information is transduced by transient receptor potential (TRP) channels in the peripheral nervous system...
The fruit fly has provided important insights into how sensory information is transduced by transient receptor potential (TRP) channels in the peripheral nervous system (PNS). However, TRP channels alone have not been able to completely model mechanosensitive transduction in mechanoreceptive chordotonal neurons (CNs). Here, we show that, in addition to TRP channels, the sole voltage-gated sodium channel (Na) in , Para, is localized to the dendrites of CNs. Para is localized to the distal tip of the dendrites in all CNs, from embryos to adults, and is colocalized with the mechanosensitive TRP channels No mechanoreceptor potential C (NompC) and Inactive/Nanchung (Iav/Nan). Para localization also demarcates spike initiation zones (SIZs) in axons and the dendritic localization of Para is indicative of a likely dendritic SIZ in fly CNs. Para is not present in the dendrites of other peripheral sensory neurons. In both multipolar and bipolar neurons in the PNS, Para is present in a proximal region of the axon, comparable to the axonal initial segment (AIS) in vertebrates, 40-60 μm from the soma in multipolar neurons and 20-40 μm in bipolar neurons. Whole-cell reduction of expression using RNAi in CNs of the adult Johnston's organ (JO) severely affects sound-evoked potentials (SEPs). However, the duality of Para localization in the CN dendrites and axons identifies a need to develop resources to study compartment-specific roles of proteins that will enable us to better understand Para's role in mechanosensitive transduction.
Topics: Animals; Action Potentials; Axons; Dendrites; Drosophila; Drosophila melanogaster; Sensory Receptor Cells; Transient Receptor Potential Channels; Voltage-Gated Sodium Channels
PubMed: 37328295
DOI: 10.1523/ENEURO.0105-23.2023 -
Nature Communications Jun 2023Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including...
Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.
Topics: Animals; Mice; Epilepsy; KCNQ Potassium Channels; KCNQ2 Potassium Channel; KCNQ3 Potassium Channel; Neurons; Seizures
PubMed: 37321992
DOI: 10.1038/s41467-023-39203-z -
ELife Jun 2023Globular bushy cells (GBCs) of the cochlear nucleus play central roles in the temporal processing of sound. Despite investigation over many decades, fundamental...
Globular bushy cells (GBCs) of the cochlear nucleus play central roles in the temporal processing of sound. Despite investigation over many decades, fundamental questions remain about their dendrite structure, afferent innervation, and integration of synaptic inputs. Here, we use volume electron microscopy (EM) of the mouse cochlear nucleus to construct synaptic maps that precisely specify convergence ratios and synaptic weights for auditory nerve innervation and accurate surface areas of all postsynaptic compartments. Detailed biophysically based compartmental models can help develop hypotheses regarding how GBCs integrate inputs to yield their recorded responses to sound. We established a pipeline to export a precise reconstruction of auditory nerve axons and their endbulb terminals together with high-resolution dendrite, soma, and axon reconstructions into biophysically detailed compartmental models that could be activated by a standard cochlear transduction model. With these constraints, the models predict auditory nerve input profiles whereby all endbulbs onto a GBC are subthreshold (coincidence detection mode), or one or two inputs are suprathreshold (mixed mode). The models also predict the relative importance of dendrite geometry, soma size, and axon initial segment length in setting action potential threshold and generating heterogeneity in sound-evoked responses, and thereby propose mechanisms by which GBCs may homeostatically adjust their excitability. Volume EM also reveals new dendritic structures and dendrites that lack innervation. This framework defines a pathway from subcellular morphology to synaptic connectivity, and facilitates investigation into the roles of specific cellular features in sound encoding. We also clarify the need for new experimental measurements to provide missing cellular parameters, and predict responses to sound for further in vivo studies, thereby serving as a template for investigation of other neuron classes.
Topics: Animals; Mice; Cochlear Nucleus; Time Perception; Epidemiological Models; Neurons; Cochlear Nerve; Synapses; Synaptic Transmission
PubMed: 37288824
DOI: 10.7554/eLife.83393