Neurotensin Enhances GABAergic Activity in Rat Hippocampus CA1 Region by Modulating L-Type Calcium Channels

2008 ◽  
Vol 99 (5) ◽  
pp. 2134-2143 ◽  
Author(s):  
Shanshan Li ◽  
Jonathan D. Geiger ◽  
Saobo Lei
Keyword(s):  
Action Potential ◽  
Firing Rate ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Immunofluorescent Staining ◽  
Channel Blockers ◽  
Action Potential Firing ◽  
Ca1 Region ◽  
Potential Firing ◽  
Gabaergic Activity

Neurotensin (NT) is a tridecapeptide that interacts with three NT receptors; NTS1, NTS2, and NTS3. Although NT has been reported to modulate GABAergic activity in the brain, the underlying cellular and molecular mechanisms of NT are elusive. Here, we examined the effects of NT on GABAergic transmission and the involved cellular and signaling mechanisms of NT in the hippocampus. Application of NT dose-dependently increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from CA1 pyramidal neurons with no effects on the amplitude of sIPSCs. NT did not change either the frequency or the amplitude of miniature (m)IPSCs recorded in the presence of tetrodotoxin. Triple immunofluorescent staining of recorded interneurons demonstrated the expression of NTS1 on GABAergic interneurons. NT increased the action potential firing rate but decreased the afterhyperpolarization (AHP) amplitude in identified CA1 interneurons. Application of L-type calcium channel blockers (nimodipine and nifedipine) abolished NT-induced increases in action potential firing rate and sIPSC frequency and reduction in AHP amplitude, suggesting that the effects of NT are mediated by interaction with L-type Ca2+ channels. NT-induced increase in sIPSC frequency was blocked by application of the specific NTS1 antagonist SR48692, the phospholipase C (PLC) inhibitor U73122, the IP3 receptor antagonist 2-APB, and the protein kinase C inhibitor GF109203X, suggesting that NT increases γ-aminobutyric acid release via a PLC pathway. Our results provide a cellular mechanism by which NT controls GABAergic neuronal activity in hippocampus.

scholarly journals Interneuron dysfunction in a new knock-in mouse model of SCN1A GEFS+

2019 ◽  
Author(s):  
Antara Das ◽  
Bingyao Zhu ◽  
Yunyao Xie ◽  
Lisha Zeng ◽  
An T. Pham ◽  
...  
Keyword(s):  
Action Potential ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Inhibitory Interneurons ◽  
Wild Type ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Acute Hippocampal Slices ◽  
Firing Properties ◽  
Genetic Epilepsies

AbstractAdvances in genome sequencing have identified over 1300 mutations in the SCN1A sodium channel gene that result in genetic epilepsies. However, how individual mutations within SCN1A produce seizures remains elusive for most mutations. Previous work from our lab has shown that the K1270T (KT) mutation, which is linked to GEFS+ (Genetic Epilepsy with Febrile Seizure plus) in humans, causes reduced firing of GABAergic neurons in a Drosophila knock-in model. To examine the effect of this mutation in mammals, we introduced the equivalent KT mutation into the mouse Scn1a (Scn1aKT) gene using CRISPR/Cas9. Mouse lines carrying this mutation were examined in two widely used genetic backgrounds, C57BL/6NJ and 129×1/SvJ. In both backgrounds, homozygous mutants had spontaneous seizures and died by postnatal day 23. There was no difference in the lifespan of mice heterozygous for the mutation in either background when compared to wild-type littermates up to 6 months. Heterozygous mutants had heat-induced seizures at ~42 deg. Celsius, a temperature that did not induce seizures in wild-type littermates. In acute hippocampal slices, current-clamp recordings revealed a significant depolarized shift in action potential threshold and reduced action potential amplitude in parvalbumin-expressing inhibitory interneurons in Scn1aKT/+ mice. There was no change in the firing properties of excitatory CA1 pyramidal neurons. Our results indicate that Scn1aKT/+ mice develop seizures, and impaired action potential firing of inhibitory interneurons in Scn1aKT/+ mice may produce hyperexcitability in the hippocampus.

scholarly journals Kv1 potassium channels control action potential firing of putative GABAergic deep cerebellar nuclear neurons

2019 ◽  
Author(s):  
Jessica Abigail Feria Pliego ◽  
Christine M. Pedroarena
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Cerebellar Cortex ◽  
Neuronal Excitability ◽  
Inhibitory Synapses ◽  
Channel Blockers ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Low Threshold ◽  
Evoked Activity

ABSTRACTThe Kv1 voltage-gated potassium channels (kv1.1-1.8) display characteristic low-threshold activation ranges what enables their role in regulating diverse aspects of neuronal function, such as the action potential (AP) threshold and waveform, and thereby influence neuronal excitability or synaptic transmission. Kv1 channels are highly expressed in the cerebellar cortex and nuclei and mutations of human Kv1 genes are associated to episodic forms of ataxia (EAT-1). Besides the well-established role of Kv1 channels in regulating the basket-Purkinje cells inhibitory synapses of cerebellar cortex, cerebellar Kv1 channels regulate the principal deep cerebellar nuclear neurons activity (DCNs). DCNs however, include as well different groups of GABAergic cells that project locally to target principal DCNs, or to the inferior-olive or recurrently to the cerebellar cortex, but whether their function is controlled by Kv1 channels remains unclear. Here, using cerebellar slices from the GAD67-GFP line mice to identify putative GABAergic-DCNs and specific Kv1 channel blockers (dendrotoxins-alpha/I/K (DTXs)) we provide evidence that putative GABAergic-DCNs spontaneous and evoked activity is controlled by Kv1 currents. DTXs shifted in the hyperpolarizing direction the voltage threshold of spontaneous APs in GABAergic-DCNs, increased GABAergic-DCNs spontaneous firing rate and decreased these neurons ability to fire repetitively action potentials at high frequency. Moreover, in spontaneously silent putative nucleo-cortical DCNs, DTXs application induced depolarization and tonic firing. These results strongly suggest that Kv1 channels regulate GABAergic-DCNs activity and thereby can control previously unrecognized aspects of cerebellar function.

scholarly journals β3-Adrenergic receptor-dependent modulation of the medium afterhyperpolarization in rat hippocampal CA1 pyramidal neurons

2019 ◽  
Vol 121 (3) ◽  
pp. 773-784 ◽  
Author(s):  
Timothy W. Church ◽  
Jon T. Brown ◽  
Neil V. Marrion
Keyword(s):  
Action Potential ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Intracellular Camp ◽  
Action Potential Firing ◽  
Hippocampal Pyramidal Neurons ◽  
Potential Firing ◽  
H Channels

Action potential firing in hippocampal pyramidal neurons is regulated by generation of an afterhyperpolarization (AHP). Three phases of AHP are recognized, with the fast AHP regulating action potential firing at the onset of a burst and the medium and slow AHPs supressing action potential firing over hundreds of milliseconds and seconds, respectively. Activation of β-adrenergic receptors suppresses the slow AHP by a protein kinase A-dependent pathway. However, little is known regarding modulation of the medium AHP. Application of the selective β-adrenergic receptor agonist isoproterenol suppressed both the medium and slow AHPs evoked in rat CA1 hippocampal pyramidal neurons recorded from slices maintained in organotypic culture. Suppression of the slow AHP was mimicked by intracellular application of cAMP, with the suppression of the medium AHP by isoproterenol still being evident in cAMP-dialyzed cells. Suppression of both the medium and slow AHPs was antagonized by the β-adrenergic receptor antagonist propranolol. The effect of isoproterenol to suppress the medium AHP was mimicked by two β3-adrenergic receptor agonists, BRL37344 and SR58611A. The medium AHP was mediated by activation of small-conductance calcium-activated K+ channels and deactivation of H channels at the resting membrane potential. Suppression of the medium AHP by isoproterenol was reduced by pretreating cells with the H-channel blocker ZD7288. These data suggest that activation of β3-adrenergic receptors inhibits H channels, which suppresses the medium AHP in CA1 hippocampal neurons by utilizing a pathway that is independent of a rise in intracellular cAMP. This finding highlights a potential new target in modulating H-channel activity and thereby neuronal excitability. NEW & NOTEWORTHY The noradrenergic input into the hippocampus is involved in modulating long-term synaptic plasticity and is implicated in learning and memory. We demonstrate that activation of functional β3-adrenergic receptors suppresses the medium afterhyperpolarization in hippocampal pyramidal neurons. This finding provides an additional mechanism to increase action potential firing frequency, where neuronal excitability is likely to be crucial in cognition and memory.

BK channel activation by L-type Ca2+ channels CaV1.2 and CaV1.3 during the subthreshold phase of an action potential

2021 ◽  
Author(s):  
Amber E Plante ◽  
Joshua P Whitt ◽  
Andrea L. Meredith
Keyword(s):  
Membrane Potential ◽  
Action Potential ◽  
Firing Rate ◽  
Low Voltage ◽  
Bk Channels ◽  
Bk Channel ◽  
Action Potential Firing ◽  
Channel Activation ◽  
Potential Firing ◽  
Current Activation

Mammalian circadian (24-hour) rhythms are timed by the pattern of spontaneous action potential firing in the suprachiasmatic nucleus (SCN). This oscillation in firing is produced through circadian regulation of several membrane currents, including large-conductance Ca2+- and voltage-activated K+ (BK) and L-type Ca2+ channel (LTCC) currents. During the day, steady-state BK currents depend mostly on LTCCs for activation, while at night, they depend predominantly on RyRs. However, the contribution of these Ca2+ channels to BK channel activation during action potential firing has not been thoroughly investigated. In this study, we used a pharmacological approach to determine that both LTCCs and RyRs contribute to the baseline membrane potential of SCN action potential waveforms, as well as action potential-evoked BK current, during the day and night, respectively. Since the baseline membrane potential is a major determinant of circadian firing rate, we focused on the LTCCs contributing to low voltage activation of BK channels during the subthreshold phase. For these experiments, two LTCC subtypes found in SCN (CaV1.2 and CaV1.3) were co-expressed with BK channels in heterologous cells, where their differential contributions could be separately measured. CaV1.3 channels produced currents that were shifted to more hyperpolarized potentials compared to CaV1.2, resulting in increased subthreshold Ca2+ and BK currents during an action potential command. These results show that while multiple Ca2+ sources in SCN can contribute to the activation of BK current during an action potential, specific BK-CaV1.3 partnerships may optimize the subthreshold BK current activation that is critical for firing rate regulation.

scholarly journals Action potential counting at giant mossy fiber terminals gates information transfer in the hippocampus

2018 ◽  
Vol 115 (28) ◽  
pp. 7434-7439 ◽  
Author(s):  
Simon Chamberland ◽  
Yulia Timofeeva ◽  
Alesya Evstratova ◽  
Kirill Volynski ◽  
Katalin Tóth
Keyword(s):  
Action Potential ◽  
Granule Cell ◽  
Pyramidal Neurons ◽  
Mossy Fiber ◽  
Glutamate Release ◽  
Mossy Fibers ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Ca3 Pyramidal Neurons ◽  
Calbindin D

Neuronal communication relies on action potential discharge, with the frequency and the temporal precision of action potentials encoding information. Hippocampal mossy fibers have long been recognized as conditional detonators owing to prominent short-term facilitation of glutamate release displayed during granule cell burst firing. However, the spiking patterns required to trigger action potential firing in CA3 pyramidal neurons remain poorly understood. Here, we show that glutamate release from mossy fiber terminals triggers action potential firing of the target CA3 pyramidal neurons independently of the average granule cell burst frequency, a phenomenon we term action potential counting. We find that action potential counting in mossy fibers gates glutamate release over a broad physiological range of frequencies and action potential numbers. Using rapid Ca2+ imaging we also show that the magnitude of evoked Ca2+ influx stays constant during action potential trains and that accumulated residual Ca2+ is gradually extruded on a time scale of several hundred milliseconds. Using experimentally constrained 3D model of presynaptic Ca2+ influx, buffering, and diffusion, and a Monte Carlo model of Ca2+-activated vesicle fusion, we argue that action potential counting at mossy fiber boutons can be explained by a unique interplay between Ca2+ dynamics and buffering at release sites. This is largely determined by the differential contribution of major endogenous Ca2+ buffers calbindin-D28K and calmodulin and by the loose coupling between presynaptic voltage-gated Ca2+ channels and release sensors and the relatively slow Ca2+ extrusion rate. Taken together, our results identify a previously unexplored information-coding mechanism in the brain.

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