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BioRxiv : the Preprint Server For... Jun 2024The stability of functional brain network is maintained by homeostatic plasticity, which restores equilibrium following perturbation. As the initiation site of action...
UNLABELLED
The stability of functional brain network is maintained by homeostatic plasticity, which restores equilibrium following perturbation. As the initiation site of action potentials, the axon initial segment (AIS) of glutamatergic projection neurons (PyNs) undergoes dynamic adjustment that exerts powerful control over neuronal firing properties in response to changes in network states. Although AIS plasticity has been reported to be coupled with the changes of network activity, it is poorly understood whether it involves direct synaptic input to the AIS. Here we show that changes of GABAergic synaptic input to the AIS of cortical PyNs, specifically from chandelier cells (ChCs), are sufficient to drive homeostatic tuning of the AIS within 1-2 weeks, while those from parvalbumin-positive basket cells do not. This tuning is reflected in the morphology of the AIS, the expression level of voltage-gated sodium channels, and the intrinsic neuronal excitability of PyNs. Interestingly, the timing of AIS tuning in PyNs of the prefrontal cortex corresponds to the recovery of changes in social behavior caused by alterations of ChC synaptic transmission. Thus, homeostatic plasticity of the AIS at postsynaptic PyNs may counteract deficits elicited by imbalanced ChC presynaptic input.
TEASER
Axon initial segment dynamically responds to changes in local input from chandelier cells to prevent abnormal neuronal functions.
PubMed: 38659885
DOI: 10.1101/2024.04.11.589005 -
ENeuro May 2024Canonically, action potentials of most mammalian neurons initiate at the axon initial segment (AIS) and propagate bidirectionally: orthodromically along the distal axon...
Canonically, action potentials of most mammalian neurons initiate at the axon initial segment (AIS) and propagate bidirectionally: orthodromically along the distal axon and retrogradely into the soma and dendrites. Under some circumstances, action potentials may initiate ectopically, at sites distal to the AIS, and propagate antidromically along the axon. These "ectopic action potentials" (EAPs) have been observed in experimental models of seizures and chronic pain, and more rarely in nonpathological forebrain neurons. Here we report that a large majority of parvalbumin-expressing (PV+) interneurons in the upper layers of mouse neocortex, from both orbitofrontal and primary somatosensory areas, fire EAPs after sufficient activation of their somata. Somatostatin-expressing interneurons also fire EAPs, though less robustly. Ectopic firing in PV+ cells occurs in varying temporal patterns and can persist for several seconds. PV+ cells evoke strong synaptic inhibition in pyramidal neurons and interneurons and play critical roles in cortical function. Our results suggest that ectopic spiking of PV+ interneurons is common and may contribute to both normal and pathological network functions of the neocortex.
Topics: Animals; Parvalbumins; Interneurons; Neocortex; Action Potentials; Mice, Transgenic; Male; Mice; Female; Mice, Inbred C57BL; Pyramidal Cells; Somatostatin
PubMed: 38637152
DOI: 10.1523/ENEURO.0314-23.2024 -
Journal of Neuropathology and... May 2024Golgi methods were used to study human neuropathology in the 1970s, 1980s, and 1990s of the last century. Although a relatively small number of laboratories applied... (Review)
Review
Golgi methods were used to study human neuropathology in the 1970s, 1980s, and 1990s of the last century. Although a relatively small number of laboratories applied these methods, their impact was crucial by increasing knowledge about: (1) the morphology, orientation, and localization of neurons in human cerebral and cerebellar malformations and ganglionic tumors, and (2) the presence of abnormal structures including large and thin spines (spine dysgenesis) in several disorders linked to mental retardation, focal enlargements of the axon hillock and dendrites (meganeurites) in neuronal storage diseases, growth cone-like appendages in Alzheimer disease, as well as abnormal structures in other dementias. Although there were initial concerns about their reliability, reduced dendritic branches and dendritic spines were identified as common alterations in mental retardation, dementia, and other pathological conditions. Similar observations in appropriate experimental models have supported many abnormalities that were first identified using Golgi methods in human material. Moreover, electron microscopy, immunohistochemistry, fluorescent tracers, and combined methods have proven the accuracy of pioneering observations uniquely visualized as 3D images of fully stained individual neurons. Although Golgi methods had their golden age many years ago, these methods may still be useful complementary tools in human neuropathology.
Topics: Animals; Humans; History, 20th Century; History, 21st Century; Neurons; Neuropathology; Silver Staining
PubMed: 38622902
DOI: 10.1093/jnen/nlae031 -
Current Research in Neurobiology 2024Parvalbumin-expressing (PV+) inhibitory interneurons drive gamma oscillations (30-80 Hz), which underlie higher cognitive functions. In this review, we discuss two... (Review)
Review
Parvalbumin-expressing (PV+) inhibitory interneurons drive gamma oscillations (30-80 Hz), which underlie higher cognitive functions. In this review, we discuss two groups/aspects of fundamental properties of PV+ interneurons. In the first group (dubbed ), we list properties representing optimal synaptic integration in PV+ interneurons designed to support fast oscillations. For example: [i] Information can neither enter nor leave the neocortex without the engagement of fast PV+ -mediated inhibition; [ii] Voltage responses in PV+ interneuron dendrites integrate linearly to reduce impact of the fluctuations in the afferent drive; and [iii] Reversed somatodendritic Rm gradient accelerates the time courses of synaptic potentials arriving at the soma. In the second group (dubbed ), we list morphological and biophysical properties responsible for (a) short synaptic delays, and (b) efficient postsynaptic outcomes. For example: [i] Fast-spiking ability that allows PV+ interneurons to outpace other cortical neurons (pyramidal neurons). [ii] Myelinated axon (which is only found in the PV+ subclass of interneurons) to secure fast-spiking at the initial axon segment; and [iii] Inhibitory autapses - autoinhibition, which assures brief biphasic voltage transients and supports postinhibitory rebounds. Recent advent of scientific tools, such as viral strategies to target PV cells and the ability to monitor PV cells via in vivo imaging during behavior, will aid in defining the role of PV cells in the CNS. Given the link between PV+ interneurons and cognition, in the future, it would be useful to carry out physiological recordings in the PV+ cell type selectively and characterize if and how psychiatric and neurological diseases affect initiation and propagation of electrical signals in this cortical sub-circuit. Voltage imaging may allow fast recordings of electrical signals from many PV+ interneurons simultaneously.
PubMed: 38616956
DOI: 10.1016/j.crneur.2023.100121 -
The Journal of Physiology May 2024We are studying the mechanisms of H-reflex operant conditioning, a simple form of learning. Modelling studies in the literature and our previous data suggested that...
We are studying the mechanisms of H-reflex operant conditioning, a simple form of learning. Modelling studies in the literature and our previous data suggested that changes in the axon initial segment (AIS) might contribute. To explore this, we used blinded quantitative histological and immunohistochemical methods to study in adult rats the impact of H-reflex conditioning on the AIS of the spinal motoneuron that produces the reflex. Successful, but not unsuccessful, H-reflex up-conditioning was associated with greater AIS length and distance from soma; greater length correlated with greater H-reflex increase. Modelling studies in the literature suggest that these increases may increase motoneuron excitability, supporting the hypothesis that they may contribute to H-reflex increase. Up-conditioning did not affect AIS ankyrin G (AnkG) immunoreactivity (IR), p-p38 protein kinase IR, or GABAergic terminals. Successful, but not unsuccessful, H-reflex down-conditioning was associated with more GABAergic terminals on the AIS, weaker AnkG-IR, and stronger p-p38-IR. More GABAergic terminals and weaker AnkG-IR correlated with greater H-reflex decrease. These changes might potentially contribute to the positive shift in motoneuron firing threshold underlying H-reflex decrease; they are consistent with modelling suggesting that sodium channel change may be responsible. H-reflex down-conditioning did not affect AIS dimensions. This evidence that AIS plasticity is associated with and might contribute to H-reflex conditioning adds to evidence that motor learning involves both spinal and brain plasticity, and both neuronal and synaptic plasticity. AIS properties of spinal motoneurons are likely to reflect the combined influence of all the motor skills that share these motoneurons. KEY POINTS: Neuronal action potentials normally begin in the axon initial segment (AIS). AIS plasticity affects neuronal excitability in development and disease. Whether it does so in learning is unknown. Operant conditioning of a spinal reflex, a simple learning model, changes the rat spinal motoneuron AIS. Successful, but not unsuccessful, H-reflex up-conditioning is associated with greater AIS length and distance from soma. Successful, but not unsuccessful, down-conditioning is associated with more AIS GABAergic terminals, less ankyrin G, and more p-p38 protein kinase. The associations between AIS plasticity and successful H-reflex conditioning are consistent with those between AIS plasticity and functional changes in development and disease, and with those predicted by modelling studies in the literature. Motor learning changes neurons and synapses in spinal cord and brain. Because spinal motoneurons are the final common pathway for behaviour, their AIS properties probably reflect the combined impact of all the behaviours that use these motoneurons.
Topics: Animals; Motor Neurons; Rats; Male; H-Reflex; Rats, Sprague-Dawley; Axon Initial Segment; Learning; Spinal Cord; Axons; Neuronal Plasticity; Conditioning, Operant; Ankyrins
PubMed: 38568869
DOI: 10.1113/JP283875 -
Journal of Cell Science Apr 2024In neurons, the microtubule (MT) cytoskeleton forms the basis for long-distance protein transport from the cell body into and out of dendrites and axons. To maintain...
In neurons, the microtubule (MT) cytoskeleton forms the basis for long-distance protein transport from the cell body into and out of dendrites and axons. To maintain neuronal polarity, the axon initial segment (AIS) serves as a physical barrier, separating the axon from the somatodendritic compartment and acting as a filter for axonal cargo. Selective trafficking is further instructed by axonal enrichment of MT post-translational modifications, which affect MT dynamics and the activity of motor proteins. Here, we compared two knockout mouse lines lacking the respective enzymes for MT tyrosination and detyrosination, and found that both knockouts led to a shortening of the AIS. Neurons from both lines also showed an increased immobile fraction of endolysosomes present in the axon, whereas mobile organelles displayed shortened run distances in the retrograde direction. Overall, our results highlight the importance of maintaining the balance of tyrosinated and detyrosinated MTs for proper AIS length and axonal transport processes.
Topics: Animals; Microtubules; Axonal Transport; Tyrosine; Lysosomes; Mice; Mice, Knockout; Axons; Endosomes; Neurons
PubMed: 38525600
DOI: 10.1242/jcs.261737 -
Nature Communications Mar 2024The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of...
The axon-initial-segment (AIS) of mature neurons contains microtubule (MT) fascicles (linear bundles) implicated as retrograde diffusion barriers in the retention of MT-associated protein (MAP) tau inside axons. Tau dysfunction and leakage outside of the axon is associated with neurodegeneration. We report on the structure of steady-state MT bundles in varying concentrations of Mg or Ca divalent cations in mixtures containing αβ-tubulin, full-length tau, and GTP at 37 °C in a physiological buffer. A concentration-time kinetic phase diagram generated by synchrotron SAXS reveals a wide-spacing MT bundle phase (B), a transient intermediate MT bundle phase (B), and a tubulin ring phase. SAXS with TEM of plastic-embedded samples provides evidence of a viscoelastic intervening network (IN) of complexes of tubulin oligomers and tau stabilizing MT bundles. In this model, αβ-tubulin oligomers in the IN are crosslinked by tau's MT binding repeats, which also link αβ-tubulin oligomers to αβ-tubulin within the MT lattice. The model challenges whether the cross-bridging of MTs is attributed entirely to MAPs. Tubulin-tau complexes in the IN or bound to isolated MTs are potential sites for enzymatic modification of tau, promoting nucleation and growth of tau fibrils in tauopathies.
Topics: Microtubules; Scattering, Small Angle; tau Proteins; Tubulin; X-Ray Diffraction; Humans
PubMed: 38491006
DOI: 10.1038/s41467-024-46438-x -
PLoS Computational Biology Mar 2024In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS), which has a high density of...
In a variety of neurons, action potentials (APs) initiate at the proximal axon, within a region called the axon initial segment (AIS), which has a high density of voltage-gated sodium channels (NaVs) on its membrane. In pyramidal neurons, the proximal AIS has been reported to exhibit a higher proportion of NaVs with gating properties that are "right-shifted" to more depolarized voltages, compared to the distal AIS. Further, recent experiments have revealed that as neurons develop, the spatial distribution of NaV subtypes along the AIS can change substantially, suggesting that neurons tune their excitability by modifying said distribution. When neurons are stimulated axonally, computational modelling has shown that this spatial separation of gating properties in the AIS enhances the backpropagation of APs into the dendrites. In contrast, in the more natural scenario of somatic stimulation, our simulations show that the same distribution can impede backpropagation, suggesting that the choice of orthodromic versus antidromic stimulation can bias or even invert experimental findings regarding the role of NaV subtypes in the AIS. We implemented a range of hypothetical NaV distributions in the AIS of three multicompartmental pyramidal cell models and investigated the precise kinetic mechanisms underlying such effects, as the spatial distribution of NaV subtypes is varied. With axonal stimulation, proximal NaV availability dominates, such that concentrating right-shifted NaVs in the proximal AIS promotes backpropagation. However, with somatic stimulation, the models are insensitive to availability kinetics. Instead, the higher activation threshold of right-shifted NaVs in the AIS impedes backpropagation. Therefore, recently observed developmental changes to the spatial separation and relative proportions of NaV1.2 and NaV1.6 in the AIS differentially impact activation and availability. The observed effects on backpropagation, and potentially learning via its putative role in synaptic plasticity (e.g. through spike-timing-dependent plasticity), are opposite for orthodromic versus antidromic stimulation, which should inform hypotheses about the impact of the developmentally regulated subcellular localization of these NaV subtypes.
Topics: Axon Initial Segment; NAV1.6 Voltage-Gated Sodium Channel; Axons; Neurons; Action Potentials; Voltage-Gated Sodium Channels
PubMed: 38489374
DOI: 10.1371/journal.pcbi.1011846 -
Cell Reports Mar 2024The KCNT1 gene encodes the sodium-activated potassium channel Slack (KCNT1, K1.1), a regulator of neuronal excitability. Gain-of-function mutations in humans cause...
The KCNT1 gene encodes the sodium-activated potassium channel Slack (KCNT1, K1.1), a regulator of neuronal excitability. Gain-of-function mutations in humans cause cortical network hyperexcitability, seizures, and severe intellectual disability. Using a mouse model expressing the Slack-R455H mutation, we find that Na-dependent K (K) and voltage-dependent sodium (Na) currents are increased in both excitatory and inhibitory cortical neurons. These increased currents, however, enhance the firing of excitability neurons but suppress that of inhibitory neurons. We further show that the expression of Na channel subunits, particularly that of Na1.6, is upregulated and that the length of the axon initial segment and of axonal Na immunostaining is increased in both neuron types. Our study on the coordinate regulation of K currents and the expression of Na channels may provide an avenue for understanding and treating epilepsies and other neurological disorders.
Topics: Humans; Axons; Epilepsy; Mutation; Nerve Tissue Proteins; Neurons; Potassium Channels; Potassium Channels, Sodium-Activated; Animals; Mice
PubMed: 38457342
DOI: 10.1016/j.celrep.2024.113904