Effect of Lamotrigine on the Ca2+-Sensing Cation Current in Cultured Hippocampal Neurons

2001 ◽  
Vol 86 (5) ◽  
pp. 2520-2526 ◽  
Author(s):  
Zhi-Gang Xiong ◽  
Xiang-Ping Chu ◽  
J. F. MacDonald
Keyword(s):  
Action Potentials ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Membrane Depolarization ◽  
Slow Inward Current ◽  
Calcium Sensing ◽  
Cation Current ◽  
Imaging Experiment ◽  
Intracellular Ca ◽  
Cultured Hippocampal Neurons

Concentrations of extracellular calcium ([Ca2+]e) in the CNS decrease substantially during seizure activity. We have demonstrated previously that decreases in [Ca2+]e activate a novel calcium-sensing nonselective cation (csNSC) channel in hippocampal neurons. Activation of csNSC channels is responsible for a sustained membrane depolarization and increased neuronal excitability. Our study has suggested that the csNSC channel is likely involved in generating and maintaining seizure activities. In the present study, the effects of anti-epileptic agent lamotrigine (LTG) on csNSC channels were studied in cultured mouse hippocampal neurons using patch-clamp techniques. At a holding potential of −60 mV, a slow inward current through csNSC channels was activated by a step reduction of [Ca2+]e from 1.5 to 0.2 mM. LTG decreased the amplitude of csNSC currents dose dependently with an IC50 of 171 ± 25.8 (SE) μM. The effect of LTG was independent of membrane potential. In the presence of 300 μM LTG, the amplitude of csNSC current was decreased by 31 ± 3% at −60 mV and 29 ± 2.9% at +40 mV ( P > 0.05). LTG depressed csNSC current without affecting the potency of Ca2+ block of the current (IC50 for Ca2+block of csNSC currents in the absence of LTG: 145 ± 18 μM; in the presence of 300 μM LTG: 136 ± 10 μM. n = 5, P > 0.05). In current-clamp recordings, activation of csNSC channel by reducing the [Ca2+]e caused a sustained membrane depolarization and an increase in the frequency of spontaneous firing of action potentials. LTG (300 μM) significantly inhibited csNSC channel-mediated membrane depolarization and the excitation of neurons. Fura-2 ratiometric Ca2+imaging experiment showed that LTG also inhibited the increase in intracellular Ca2+ concentration induced by csNSC channel activation. The effect of LTG on csNSC channels may partially contribute to its broad spectrum of anti-epileptic actions.

scholarly journals Zinc Enhances the Inhibitory Effects of Strychnine-Sensitive Glycine Receptors in Mouse Hippocampal Neurons

2007 ◽  
Vol 98 (6) ◽  
pp. 3666-3676 ◽  
Author(s):  
Hai Xia Zhang ◽  
Liu Lin Thio
Keyword(s):  
Action Potential ◽  
Action Potentials ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Hippocampal Slices ◽  
Glycine Receptors ◽  
Inhibitory Effects ◽  
Action Potential Firing ◽  
Embryonic Mouse ◽  
Potential Firing

Although extracellular Zn2+ is an endogenous biphasic modulator of strychnine-sensitive glycine receptors (GlyRs), the physiological significance of this modulation remains poorly understood. Zn2+ modulation of GlyR may be especially important in the hippocampus where presynaptic Zn2+ is abundant. Using cultured embryonic mouse hippocampal neurons, we examined whether 1 μM Zn2+, a potentiating concentration, enhances the inhibitory effects of GlyRs activated by sustained glycine applications. Sustained 20 μM glycine (EC25) applications alone did not decrease the number of action potentials evoked by depolarizing steps, but they did in 1 μM Zn2+. At least part of this effect resulted from Zn2+ enhancing the GlyR-induced decrease in input resistance. Sustained 20 μM glycine applications alone did not alter neuronal bursting, a form of hyperexcitability induced by omitting extracellular Mg2+. However, sustained 20 μM glycine applications depressed neuronal bursting in 1 μM Zn2+. Zn2+ did not enhance the inhibitory effects of sustained 60 μM glycine (EC70) applications in these paradigms. These results suggest that tonic GlyR activation could decrease neuronal excitability. To test this possibility, we examined the effect of the GlyR antagonist strychnine and the Zn2+ chelator tricine on action potential firing by CA1 pyramidal neurons in mouse hippocampal slices. Co-applying strychnine and tricine slightly but significantly increased the number of action potentials fired during a depolarizing current step and decreased the rheobase for action potential firing. Thus Zn2+ may modulate neuronal excitability normally and in pathological conditions such as seizures by potentiating GlyRs tonically activated by low agonist concentrations.

Astrocyte-induced modulation of synaptic transmission

1999 ◽  
Vol 77 (9) ◽  
pp. 699-706 ◽  
Author(s):  
Alfonso Araque ◽  
Rita P Sanzgiri ◽  
Vladimir Parpura ◽  
Philip G Haydon
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Receptors ◽  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Calcium Waves ◽  
Metabotropic Glutamate ◽  
Intracellular Ca ◽  
Inward Currents ◽  
Neuronal Electrical Activity ◽  
Cultured Hippocampal Neurons

The idea that astrocytes simply provide structural and trophic support to neurons has been challenged by recent evidence demonstrating that astrocytes exhibit a form of excitability and communication based on intracellular Ca2+ variations and intercellular Ca2+ waves, which can be initiated by neuronal activity. These astrocyte Ca2+ variations have now been shown to induce glutamate-dependent Ca2+ elevations and slow inward currents in neurons. More recently, it has been demonstrated that synaptic transmission between cultured hippocampal neurons can be directly modulated by astrocytes. We have reported that astrocyte stimulation can increase the frequency of miniature synaptic currents. Furthermore, we also have demonstrated that an elevation in the intracellular Ca2+ in astrocytes induces a reduction in both excitatory and inhibitory evoked synaptic transmission through the activation of selective presynaptic metabotropic glutamate receptors.Key words: astrocyte-neuron signaling, glutamate receptors, calcium waves, neuronal electrical activity, synaptic transmission.

scholarly journals Cdk-mediated phosphorylation of the Kvβ2 auxiliary subunit regulates Kv1 channel axonal targeting

2011 ◽  
Vol 192 (5) ◽  
pp. 813-824 ◽  
Author(s):  
Hélène Vacher ◽  
Jae-Won Yang ◽  
Oscar Cerda ◽  
Amapola Autillo-Touati ◽  
Bénédicte Dargent ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Regulatory Mechanism ◽  
Cyclin Dependent Kinase ◽  
Intracellular Accumulation ◽  
Axonal Membrane ◽  
Auxiliary Subunit ◽  
Cdk Phosphorylation ◽  
Axonal Targeting ◽  
Cultured Hippocampal Neurons

Kv1 channels are concentrated at specific sites in the axonal membrane, where they regulate neuronal excitability. Establishing these distributions requires regulated dissociation of Kv1 channels from the neuronal trafficking machinery and their subsequent insertion into the axonal membrane. We find that the auxiliary Kvβ2 subunit of Kv1 channels purified from brain is phosphorylated on serine residues 9 and 31, and that cyclin-dependent kinase (Cdk)–mediated phosphorylation at these sites negatively regulates the interaction of Kvβ2 with the microtubule plus end–tracking protein EB1. Endogenous Cdks, EB1, and Kvβ2 phosphorylated at serine 31 are colocalized in the axons of cultured hippocampal neurons, with enrichment at the axon initial segment (AIS). Acute inhibition of Cdk activity leads to intracellular accumulation of EB1, Kvβ2, and Kv1 channel subunits within the AIS. These studies reveal a new regulatory mechanism for the targeting of Kv1 complexes to the axonal membrane through the reversible Cdk phosphorylation-dependent binding of Kvβ2 to EB1.

Excitatory Actions of Dopamine Via D1-Like Receptors in the Rat Lateral Geniculate Nucleus

2005 ◽  
Vol 94 (6) ◽  
pp. 3708-3718 ◽  
Author(s):  
G. Govindaiah ◽  
Charles L. Cox
Keyword(s):  
Visual Information ◽  
Information Transfer ◽  
Neuronal Excitability ◽  
Slow Wave Sleep ◽  
Membrane Depolarization ◽  
Dopamine Receptor Agonist ◽  
Cation Current ◽  
Cell Recording ◽  
Specific Antagonist ◽  
Relay Neurons

The excitability of relay neurons in the dorsal geniculate nucleus (dLGN) can be altered by a variety of neuromodulators. The dLGN receives substantial dopaminergic input from the brain stem, and this innervation may play a crucial role in the gating of visual information from the retina to visual neocortex. In this study, we investigated the action of dopamine on identified dLGN neurons using whole cell recording techniques. Dopamine (2–200 μM) produced a membrane depolarization in >95% of relay neurons tested but did not alter excitability of dLGN interneurons. The D1-like dopamine receptor agonist SKF38393 (2–50 μM) produced a similar depolarization in dLGN relay neurons. However, the D2-like receptor agonists, bromocriptine (25–50 μM) and PPHT (1–50 μM), did not alter the membrane potential of relay neurons. SCH23390 (5–10 μM), a D1-like receptor antagonist, attenuated the depolarizing actions of both dopamine and SKF38393 . Furthermore, the excitatory actions of dopamine and SKF38393 were attenuated by ZD7288, a specific antagonist for the hyperpolarization activated mixed cation current, Ih. Our data suggest that dopamine, acting via D1-like receptors, activates Ih leading to a membrane depolarization. Through the modulation of dLGN neuronal excitability, ascending and descending activating systems may not only control the state of the thalamus such as the transition from slow-wave sleep to waking but also regulate the efficacy of information transfer during waking states.

scholarly journals Ps in the (Channel) Pod Are Not Alike …

2007 ◽  
Vol 7 (5) ◽  
pp. 136-137
Author(s):  
Yoav Noam ◽  
Tallie Z. Baram
Keyword(s):  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Phosphorylation Sites ◽  
Voltage Dependent ◽  
Activity Dependent ◽  
Stimulation Of ◽  
Cultured Hippocampal Neurons

Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation. Misonou H, Menegola M, Mohapatra DP, Guy LK, Park KS, Trimmer JS. J Neurosci 2006;26(52):13505–13514. Activity-dependent dephosphorylation of neuronal Kv2.1 channels yields hyperpolarizing shifts in their voltage-dependent activation and homoeostatic suppression of neuronal excitability. We recently identified 16 phosphorylation sites that modulate Kv2.1 function. Here, we show that in mammalian neurons, compared with other regulated sites, such as serine (S)563, phosphorylation at S603 is supersensitive to calcineurin-mediated dephosphorylation in response to kainate-induced seizures in vivo, and brief glutamate stimulation of cultured hippocampal neurons. In vitro calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic in vivo causes hyperphosphorylation at S603 but not S563. Distinct regulation of individual phosphorylation sites allows for graded and bidirectional homeostatic regulation of Kv2.1 function. S603 phosphorylation represents a sensitive bidirectional biosensor of neuronal activity.

scholarly journals Clustering of Extrasynaptic GABAAReceptors Modulates Tonic Inhibition in Cultured Hippocampal Neurons

2004 ◽  
Vol 279 (44) ◽  
pp. 45833-45843 ◽  
Author(s):  
Enrica Maria Petrini ◽  
Ivan Marchionni ◽  
Paola Zacchi ◽  
Werner Sieghart ◽  
Enrico Cherubini
Keyword(s):  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Prolonged Exposure ◽  
Tonic Inhibition ◽  
Aminobutyric Acid ◽  
Action Potential Generation ◽  
Potential Generation ◽  
Acid Type ◽  
Ambient Gaba ◽  
Cultured Hippocampal Neurons

Tonic inhibition plays a crucial role in regulating neuronal excitability because it sets the threshold for action potential generation and integrates excitatory signals. Tonic currents are known to be largely mediated by extrasynaptic γ-aminobutyric acid type A (GABAA) receptors that are persistently activated by submicromo-lar concentrations of ambient GABA. We recently reported that, in cultured hippocampal neurons, the clustering of synaptic GABAAreceptors significantly affects synaptic transmission (Petrini, E. M., Zacchi, P., Barberis, A., Mozrzymas, J. W., and Cherubini, E. (2003)J. Biol. Chem.278, 16271–16279). In this work, we demonstrated that the clustering of extrasynaptic GABAAreceptors modulated tonic inhibition. Depolymerization of the cytoskeleton with nocodazole promoted the disassembly of extrasynaptic clusters of δ and γ2subunit-containing GABAAreceptors. This effect was associated with a reduction in the amplitude of tonic currents and diminished shunting inhibition. Moreover, diffuse GABAAreceptors were less sensitive to the GAT-1 inhibitor NO-711 and to flurazepam. Quantitative analysis of GABA-evoked currents after prolonged exposure to submicromolar concentrations of GABA and model simulations suggest that clustering affects the gating properties of extrasynaptic GABAAreceptors. In particular, a larger occupancy of the singly and doubly bound desensitized states can account for the modulation of tonic inhibition recorded after nocodazole treatment. Moreover, comparison of tonic currents recorded during spontaneous activity and those elicited by exogenously applied low agonist concentrations allows estimation of the concentration of ambient GABA. In conclusion, receptor clustering appears to be an additional regulating factor for tonic inhibition.

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