The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na(+) channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na(+) channel density. We found that low-threshold Na(v)1.6 and high-threshold Na(v)1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na(+) current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Na(v)1.6 promotes action potential initiation, whereas proximal Na(v)1.2 promotes its backpropagation to the soma.
Sodium channels add variety to inhibitory interneurons Different populations of inhibitory interneurons in the cerebral cortex express distinct subtypes of sodium channels, resulting in diverse action potential thresholds and network excitability.
Studies in rodents revealed that selective accumulation of Na+ channel subtypes at the axon initial segment (AIS) determines action potential (AP) initiation and backpropagation in cortical pyramidal cells (PCs); however, in human cortex, the molecular identity of Na+ channels distributed at PC axons, including the AIS and the nodes of Ranvier, remains unclear. We performed immunostaining experiments in human cortical tissues removed surgically to cure brain diseases. We found strong immunosignals of Na+ channels and two channel subtypes, NaV1.2 and NaV1.6, at the AIS of human cortical PCs. Although both channel subtypes were expressed along the entire AIS, the peak immunosignals of NaV1.2 and NaV1.6 were found at proximal and distal AIS regions, respectively. Surprisingly, in addition to the presence of NaV1.6 at the nodes of Ranvier, NaV1.2 was also found in a subpopulation of nodes in the adult human cortex, different from the absence of NaV1.2 in myelinated axons in rodents. NaV1.1 immunosignals were not detected at either the AIS or the nodes of Ranvier of PCs; however, they were expressed at interneuron axons with different distribution patterns. Further experiments revealed that parvalbumin-positive GABAergic axon cartridges selectively innervated distal AIS regions with relatively high immunosignals of NaV1.6 but not the proximal NaV1.2-enriched compartments, suggesting an important role of axo-axonic cells in regulating AP initiation in human PCs. Together, our results show that both NaV1.2 and NaV1.6 (but not NaV1.1) channel subtypes are expressed at the AIS and the nodes of Ranvier in adult human cortical PCs, suggesting that these channel subtypes control neuronal excitability and signal conduction in PC axons.
Asynchronous GABA release occurs at output synapses of fast-spiking interneurons in human and rat neocortex and is elevated in epileptic tissues from both species.
Dysregulation of voltage-gated sodium channels (VGSCs) is associated with multiple clinical disorders, including febrile seizures (FS). The contribution of different sodium channel subtypes to environmentally triggered seizures is not well understood. Here we demonstrate that somatic and axonal sodium channels primarily mediated through NaV1.2 and NaV1.6 subtypes, respectively, behave differentially at FT, and might play distinct roles in FS generation. In contrast to sodium channels on the main axonal trunk, somatic ones are more resistant to inactivation and display significantly augmented currents, faster gating rates and kinetics of recovery from inactivation at FT, features that promote neuronal excitabilities. Pharmacological inhibition of NaV1.2 by Phrixotoxin-3 (PTx3) suppressed FT-induced neuronal hyperexcitability in brain slice, while up-regulation of NaV1.2 as in NaV1.6 knockout mice showed an opposite effect. Consistently, NaV1.6 knockout mice were more susceptible to FS, exhibiting much lower temperature threshold and shorter onset latency than wildtype mice. Neuron modeling further suggests that NaV1.2 is the major subtype mediating FT-induced neuronal hyperexcitability, and predicts potential outcomes of alterations in sodium channel subtype composition. Together, these data reveal a role of native NaV1.2 on neuronal excitability at FT and its important contribution to FS pathogenesis.
Key points• Dopamine and its receptors in prefrontal cortex (PFC) play an important role in regulating synaptic transmission and PFC-mediated cognitive functions.• Considering that presynaptic action potential waveform can modulate postsynaptic responses, we investigated whether axonal K + channels and action potential waveform are subjected to modulation by dopamine.• Patch-clamp recording from the axon of PFC pyramidal neurons showed that the activation of D1 and D2 dopamine receptors decreased and enhanced axonal K + currents, respectively. Further experiments revealed that intracellular cAMP-PKA pathway was involved in this dopaminergic modulation of axonal K + currents.• Recording from axons disconnected from the soma revealed that the dopaminergic modulation still occurred, indicating the presence of functional dopamine receptors along the axon.• We further demonstrate that axonal action potentials were substantially prolonged by D1 receptor activation. Taken together, our results reveal a new mechanism for dopaminergic modulation of neuronal signalling in PFC.Abstract Voltage-gated K + (K V ) channels play critical roles in shaping neuronal signals. K V channels distributed in the perisomatic regions and thick dendrites of cortical pyramidal neurons have been extensively studied. However, the properties and regulation of K V channels distributed in the thin axons remain unknown. In this study, by performing somatic and axonal patch-clamp recordings from layer 5 pyramidal neurons of prefrontal cortical slices, we showed that the rapidly inactivating A-currents mediated the transient K + currents evoked by action potential (AP) waveform command (K AP ) at the soma, whereas the rapidly activating but slowly inactivating K V 1-mediated D-currents dominated the K AP at the axon. In addition, activation of D1-like receptors for dopamine decreased the axonal K + currents, as a result of an increase in the activity of cAMP-PKA pathway. In contrast, activation of D2-like receptors showed an opposite effect on the axonal K + currents. Further experiments demonstrated that functional D1-like receptors were expressed at the main axon trunk and their activation could broaden the waveforms of axonal APs. Together, these results show that axonal K V channels were subjected to dopamine modulation, and this modulation could regulate the waveforms of propagating APs at the axon, suggesting an important role of dopaminergic modulation of axonal K V channels in regulating neuronal signalling.
Early comparative embryogenesis can reflect the organization and evolutionary origins of brain areas. Neurogenesis in the auditory areas of sauropsids displays a clear core-to-shell distinction, but it remains unclear in mammals. To address this issue, [3H]-thymidine was injected into pregnant mice on consecutive embryonic (E) days (E10-E19) to date neuronal birthdays. Immunohistochemistry for substance P, calbindin, and parvalbumin was conducted to distinguish the core and shell auditory regions. The results showed that: 1) cell generation began at E13 in the external or dorsal nucleus of the inferior colliculus (IC), but it did not start in the caudomedial portion of the central nucleus of IC, and significantly fewer cells were produced in the medial and rostromedial portions of the central nucleus of IC; 2) cells were generated at E11 in the dorsal and medial divisions of the medial geniculate complex (MGd and MGm, respectively), whereas cell generation was absent in the medial and rostromedial portions of the ventral medial geniculate complex (MGv), and fewer cells were produced in the caudomedial portion of MGv; 3) in the telencephalic auditory cortex, cells were produced at E11 or E12 in layer I and the subplate, which receive projections from the MGd and MGm. However, cell generation occurred at E13-E18 in layers II-VI, including the area receiving projections from the MGv. The core-to-shell distinction of neurogenesis is thus present in the mesencephalic to telencephalic auditory areas in the mouse. This distinction of neurogenesis is discussed from an evolutionary perspective.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.