Vervaeke, K., Hu, H., Graham, L. J. & Storm, J. F. Contrasting effects of the persistent Na+ current on neuronal excitability and spike timing. Neuron 49, 257-270

University of Oslo, Kristiania (historical), Oslo, Norway
Neuron (Impact Factor: 15.05). 02/2006; 49(2):257-70. DOI: 10.1016/j.neuron.2005.12.022
Source: PubMed


The persistent Na+ current, INaP, is known to amplify subthreshold oscillations and synaptic potentials, but its impact on action potential generation remains enigmatic. Using computational modeling, whole-cell recording, and dynamic clamp of CA1 hippocampal pyramidal cells in brain slices, we examined how INaP changes the transduction of excitatory current into action potentials. Model simulations predicted that INaP increases afterhyperpolarizations, and, although it increases excitability by reducing rheobase, INaP also reduces the gain in discharge frequency in response to depolarizing current (f/I gain). These predictions were experimentally confirmed by using dynamic clamp, thus circumventing the longstanding problem that INaP cannot be selectively blocked. Furthermore, we found that INaP increased firing regularity in response to sustained depolarization, although it decreased spike time precision in response to single evoked EPSPs. Finally, model simulations demonstrated that I(NaP) increased the relative refractory period and decreased interspike-interval variability under conditions resembling an active network in vivo.

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    • "M-type potassium currents are considered to play a significant role in adaptation (Storm, 1990; Benda and Herz, 2003). M-type potassium currents have been included in several computational models of neurons, especially hippocampal and cortical pyramidal cells (Lytton and Sejnowski, 1991; Poirazi et al., 2003; Vervaeke et al., 2006; Xu and Clancy, 2008). However, such currents are associated with extremely small conductance densities, being of the order 1000 to 4000 times less than that of the usual delayed rectifier. "
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    ABSTRACT: Serotonergic neurons of the dorsal raphe nucleus, with their extensive innervation of limbic and higher brain regions and interactions with the endocrine system have important modulatory or regulatory effects on many cognitive, emotional and physiological processes. They have been strongly implicated in responses to stress and in the occurrence of major depressive disorder and other pyschiatric disorders. In order to quantify some of these effects, detailed mathematical models of the activity of such cells are required which describe their complex neurochemistry and neurophysiology. We consider here a single-compartment model of these neurons which is capable of describing many of the known features of spike generation, particularly the slow rhythmic pacemaking activity often observed in these cells in a variety of species. Included in the model are 11 kinds of ion channels: a fast sodium current INa, a delayed rectifier potassium current IKDR, a transient potassium current IA, a slow non-inactivating potassium current IM, a low-threshold calcium current IT, two high threshold calcium currents IL and IN, small and large conductance potassium currents ISK and IBK, a hyperpolarization-activated cation current IH and a leak current ILeak. In Sections 3-8, each current type is considered in detail and parameters estimated from voltage clamp data where possible. Three kinds of model are considered for the BK current and two for the leak current. Intracellular calcium ion concentration Cai is an additional component and calcium dynamics along with buffering and pumping is discussed in Section 9. The remainder of the article contains descriptions of computed solutions which reveal both spontaneous and driven spiking with several parameter sets. Attention is focused on the properties usually associated with these neurons, particularly long duration of action potential, steep upslope on the leading edge of spikes, pacemaker-like spiking, long-lasting afterhyperpolarization and the ramp-like return to threshold after a spike. In some cases the membrane potential trajectories display doublets or have humps or notches as have been reported in some experimental studies. The computed time courses of IA and IT during the interspike interval support the generally held view of a competition between them in influencing the frequency of spiking. Spontaneous activity was facilitated by the presence of IH which has been found in these neurons by some investigators. For reasonable sets of parameters spike frequencies between about 0.6 Hz and 1.2 Hz are obtained, but frequencies as high as 6 Hz could be obtained with special parameter choices. Topics investigated and compared with experiment include shoulders, notches, anodal break phenomena, the effects of noradrenergic input, frequency versus current curves, depolarization block, effects of cell size and the effects of IM. The inhibitory effects of activating 5-HT1A autoreceptors are also investigated. There is a considerable discussion of in vitro versus in vivo firing behavior, with focus on the roles of noradrenergic input, corticotropin-releasing factor and orexinergic inputs. Location of cells within the nucleus is probably a major factor, along with the state of the animal.
    Full-text · Article · Apr 2014 · Progress in Neurobiology
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    • "Neuronal excitability is not only critically determined by the properties of I NaT . A noninactivating, low-voltage activated Na + current component, termed persistent Na + current (I NaP ), strongly contributes to neuronal excitability in the subthreshold range (Vervaeke et al., 2006; Yue et al., 2005). I NaP is a target for numerous AEDs with activity on I NaT (Sun et al., 2007; Taverna et al., 1998). "
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    ABSTRACT: Purpose: In chronic epilepsy, a substantial proportion of up to 30% of patients remain refractory to antiepileptic drugs (AEDs). An understanding of the mechanisms of pharmacoresistance requires precise knowledge of how AEDs interact with their targets. Many commonly used AEDs act on the transient and/or the persistent components of the voltage-gated Na(+) current (I(NaT) and I(NaP) , respectively). Lacosamide (LCM) is a novel AED with a unique mode of action in that it selectively enhances slow inactivation of fast transient Na(+) channels. Given that functional loss of accessory Na(+) channel subunits is a feature of a number of neurologic disorders, including epilepsy, we examined the effects of LCM versus carbamazepine (CBZ) on the persistent Na(+) current (I(NaP) ), in the presence and absence of accessory subunits within the channel complex. Methods: Using patch-clamp recordings in intact hippocampal CA1 neurons of Scn1b null mice, I(NaP) was recorded using slow voltage ramps. Application of 100 μm CBZ or 300 μm LCM reduced the maximal I(NaP) conductance in both wild-type and control mice. Key findings: As shown previously by our group in Scn1b null mice, CBZ induced a paradoxical increase of I(NaP) conductance in the subthreshold voltage range, resulting in an ineffective block of repetitive firing in Scn1b null neurons. In contrast, LCM did not exhibit such a paradoxical increase, and accordingly maintained efficacy in blocking repetitive firing in Scn1b null mice. Significance: These results suggest that the novel anticonvulsant LCM maintains activity in the presence of impaired Na(+) channel β(1) subunit expression and thus may offer an improved efficacy profile compared with CBZ in diseases associated with an impaired expression of β sub-units as observed in epilepsy.
    Full-text · Article · Sep 2012 · Epilepsia
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    • "For instance, downregulation of a depolarizing current that activates near spike threshold or upregulation of a hyperpolarizing current in the same range would both decrease the net input resistance (i.e. the resistance that reflects a combination of the passive membrane resistance and the contribution of voltage-dependent conductances). The perisomatic Na+ persistent current (INaP) is broadly expressed in neurons [45], including in the BNST [38]. Downregulation of this current by protracted alcohol withdrawal might cause adaptations that are consistent with our finding regarding the reduced dynamic excitability of jcBNST neurons. "
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    ABSTRACT: Alcohol dependence and withdrawal has been shown to cause neuroadaptive changes at multiple levels of the nervous system. At the neuron level, adaptations of synaptic connections have been extensively studied in a number of brain areas and accumulating evidence also shows the importance of alcohol dependence-related changes in the intrinsic cellular properties of neurons. At the same time, it is still largely unknown how such neural adaptations impact the firing and integrative properties of neurons. To address these problems, here, we analyze physiological properties of neurons in the bed nucleus of stria terminalis (jcBNST) in animals with a history of alcohol dependence. As a comprehensive approach, first we measure passive and active membrane properties of neurons using conventional current clamp protocols and then analyze their firing responses under the action of simulated synaptic bombardment via dynamic clamp. We find that most physiological properties as measured by DC current injection are barely affected during protracted withdrawal. However, neuronal excitability as measured from firing responses under simulated synaptic inputs with the dynamic clamp is markedly reduced in all 3 types of jcBNST neurons. These results support the importance of studying the effects of alcohol and drugs of abuse on the firing properties of neurons with dynamic clamp protocols designed to bring the neurons into a high conductance state. Since the jcBNST integrates excitatory inputs from the basolateral amygdala (BLA) and cortical inputs from the infralimbic and the insular cortices and in turn is believed to contribute to the inhibitory input to the central nucleus of the amygdala (CeA) the reduced excitability of the jcBNST during protracted withdrawal in alcohol-dependent animals will likely affect ability of the jcBNST to shape the activity and output of the CeA.
    Full-text · Article · Aug 2012 · PLoS ONE
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