Slow Afterhyperpolarization Research Articles

Long-Term Depression of Synaptic Kainate Receptors Reduces Excitability by Relieving Inhibition of the Slow Afterhyperpolarization

Kainate receptors (KARs) are ionotropic glutamate receptors that also activate noncanonical G-protein-coupled signaling pathways to depress the slow afterhyperpolarization (sAHP). Here we show that long-term depression of KAR-mediated synaptic transmission (KAR LTD) at rat hippocampal mossy fiber synapses relieves inhibition of the sAHP by synaptic transmission. KAR LTD is induced by high-frequency mossy fiber stimulation and natural spike patterns and requires activation of adenosine A2A receptors. Natural spike patterns also cause long-term potentiation of NMDA receptor-mediated synaptic transmission that overrides the effects of KAR LTD on the cellular response to low-frequency synaptic input. However, KAR LTD is dominant at higher frequency synaptic stimulation where it decreases the cellular response by relieving inhibition of the sAHP. Thus we describe a form of glutamate receptor plasticity induced by natural spike patterns whose primary physiological function is to regulate cellular excitability.

Modulation of calcium currents and membrane properties by substance P in the lamprey spinal cord

Substance P is endogenously released within the locomotor network of the adult lamprey, accelerates the burst frequency of fictive locomotion, and reduces the reciprocal inhibition. Previous studies have shown that dopamine, serotonin, and GABA regulate calcium channels, which control neurotransmitter release, action potential duration, and slow afterhyperpolarization (sAHP). Here we examine the effect of substance P on calcium channels in motoneurons and commissural interneurons using whole cell patch clamp in the lamprey spinal cord. This study analyzed the effects of substance P on calcium currents activated in voltage clamp. We examined the calcium-dependent sAHP in current clamp, to determine the involvement of three calcium channel subtypes modulated by substance P. The effects of substance P on membrane potential and during N-methyl-d-aspartic acid (NMDA) induced oscillations were also analyzed. Depolarizing voltage steps induced inward calcium currents. Substance P reduced the currents carried by calcium by 61% in commissural interneurons and by 31% in motoneurons. Using specific calcium channel antagonists, we show that substance P reduces the sAHP primarily by inhibiting N-type (Ca(V)2.2) channels. Substance P depolarized both motoneurons and commissural interneurons, and we present evidence that this occurs due to an increased input resistance. We also explored the effects of substance P on NMDA-induced oscillations in tetrodotoxin and found it caused a frequency increase. Thus the reduction of calcium entry by substance P and the accompanying decrease of the sAHP amplitude, combined with substance P potentiation of currents activated by NMDA, may both contribute to the increase in fictive locomotion frequency.

Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike frequency adaptation in GnRH neurons

Kisspeptin signaling via its cognate receptor G protein-coupled receptor 54 (GPR54) in gonadotropin-releasing hormone (GnRH) neurons plays a critical role in regulating pituitary secretion of luteinizing hormone and thus reproductive function. GPR54 is G(q)-coupled to activation of phospholipase C and multiple second messenger signaling pathways. Previous studies have shown that kisspeptin potently depolarizes GnRH neurons through the activation of canonical transient receptor potential channels and inhibition of inwardly rectifying K(+) channels to generate sustained firing. Since the initial studies showing that kisspeptin has prolonged effects, the question has been why is there very little spike frequency adaption during sustained firing? Presently, we have discovered that kisspeptin reduces spike frequency adaptation and prolongs firing via the inhibition of a calcium-activated slow afterhyperpolarization current (I(sAHP)). GnRH neurons expressed two distinct I(sAHP), a kisspeptin-sensitive and an apamin-sensitive I(sAHP). Essentially, kisspeptin inhibited 50% of the I(sAHP) and apamin inhibited the other 50% of the current. Furthermore, the kisspeptin-mediated inhibition of I(sAHP) was abrogated by the protein kinase C (PKC) inhibitor calphostin C, and the PKC activator phorbol 12,13-dibutyrate mimicked and occluded any further effects of kisspeptin on I(sAHP). The protein kinase A (PKA) inhibitors H-89 and the Rp diastereomer of adenosine 3',5'-cyclic monophosphorothioate had no effect on the kisspeptin-mediated inhibition but were able to abrogate the inhibitory effects of forskolin on the I(sAHP), suggesting that PKA is not involved. Therefore, in addition to increasing the firing rate through an overt depolarization, kisspeptin can also facilitate sustained firing through inhibiting an apamin-insensitive I(sAHP) in GnRH neurons via a PKC.

The Slow Afterhyperpolarization: A Target of β1-Adrenergic Signaling in Hippocampus-Dependent Memory Retrieval

In rodents, adrenergic signaling by norepinephrine (NE) in the hippocampus is required for the retrieval of intermediate-term memory. NE promotes retrieval via the stimulation of β1-adrenergic receptors, the production of cAMP, and the activation of both protein kinase A (PKA) and the exchange protein activated by cAMP. However, a final effector for this signaling pathway has not been identified. Among the many targets of adrenergic signaling in the hippocampus, the slow afterhyperpolarization (sAHP) is an appealing candidate because its reduction by β1 signaling enhances excitatory neurotransmission. Here we report that reducing the sAHP is critical for the facilitation of retrieval by NE. Direct blockers of the sAHP, as well as blockers of the L-type voltage-dependent calcium influx that activates the sAHP, rescue retrieval in mutant mice lacking either NE or the β1 receptor. Complementary to this, a facilitator of L-type calcium influx impairs retrieval in wild-type mice. In addition, we examined the role of NE in the learning-related reduction of the sAHP observed ex vivo in hippocampal slices. We find that this reduction in the sAHP depends on the induction of persistent PKA activity specifically in conditioned slices. Interestingly, this persistent PKA activity is induced by NE/β1 signaling during slice preparation rather than during learning. These observations suggest that the reduction in the sAHP may not be present autonomously in vivo, but is likely induced by neuromodulatory input, which is consistent with the idea that NE is required in vivo for reduction of the sAHP during memory retrieval.

Noise Normalizes Firing Output of Mouse Lateral Geniculate Nucleus Neurons

The output of individual neurons is dependent on both synaptic and intrinsic membrane properties. While it is clear that the response of an individual neuron can be facilitated or inhibited based on the summation of its constituent synaptic inputs, it is not clear whether subthreshold activity, (e.g. synaptic “noise”- fluctuations that do not change the mean membrane potential) also serve a function in the control of neuronal output. Here we studied this by making whole-cell patch-clamp recordings from 29 mouse thalamocortical relay (TC) neurons. For each neuron we measured neuronal gain in response to either injection of current noise, or activation of the metabotropic glutamate receptor-mediated cortical feedback network (synaptic noise). As expected, injection of current noise via the recording pipette induces shifts in neuronal gain that are dependent on the amplitude of current noise, such that larger shifts in gain are observed in response to larger amplitude noise injections. Importantly we show that shifts in neuronal gain are also dependent on the intrinsic sensitivity of the neuron tested, such that the gain of intrinsically sensitive neurons is attenuated divisively in response to current noise, while the gain of insensitive neurons is facilitated multiplicatively by injection of current noise- effectively normalizing the output of the dLGN as a whole. In contrast, when the cortical feedback network was activated, only multiplicative gain changes were observed. These network activation-dependent changes were associated with reductions in the slow afterhyperpolarization (sAHP), and were mediated at least in part, by T-type calcium channels. Together, this suggests that TC neurons have the machinery necessary to compute multiple output solutions to a given set of stimuli depending on the current level of network stimulation.

A role for TREK1 in generating the slow afterhyperpolarization in developing starburst amacrine cells

Slow afterhyperpolarizations (sAHPs) play an important role in establishing the firing pattern of neurons that in turn influence network activity. sAHPs are mediated by calcium-activated potassium channels. However, the molecular identity of these channels and the mechanism linking calcium entry to their activation are still unknown. Here we present several lines of evidence suggesting that the sAHPs in developing starburst amacrine cells (SACs) are mediated by two-pore potassium channels. First, we use whole cell and perforated patch voltage clamp recordings to characterize the sAHP conductance under different pharmacological conditions. We find that this conductance was calcium dependent, reversed at EK, blocked by barium, insensitive to apamin and TEA, and activated by arachidonic acid. In addition, pharmacological inhibition of calcium-activated phosphodiesterase reduced the sAHP. Second, we performed gene profiling on isolated SACs and found that they showed strong preferential expression of the two-pore channel gene kcnk2 that encodes TREK1. Third, we demonstrated that TREK1 knockout animals exhibited an altered frequency of retinal waves, a frequency that is set by the sAHPs in SACs. With these results, we propose a model in which depolarization-induced decreases in cAMP lead to disinhibition of the two-pore potassium channels and in which the kinetics of this biochemical pathway dictate the slow activation and deactivation of the sAHP conductance. Our model offers a novel pathway for the activation of a conductance that is physiologically important.

Inositol 1,4,5-Triphosphate Drives Glutamatergic and Cholinergic Inhibition Selectively in Spiny Projection Neurons in the Striatum

The striatum is critically involved in the selection of appropriate actions in a constantly changing environment. The spiking activity of striatal spiny projection neurons (SPNs), driven by extrinsic glutamatergic inputs, is shaped by local GABAergic and cholinergic networks. For example, it is well established that different types of GABAergic interneurons, activated by extrinsic glutamatergic and local cholinergic inputs, mediate powerful feedforward inhibition of SPN activity. In this study, using mouse striatal slices, we show that glutamatergic and cholinergic inputs exert direct inhibitory regulation of SPN activity via activation of metabotropic glutamate receptors (mGluRs) and muscarinic acetylcholine receptors. While pressure ejection of the group I mGluR (mGluR1/5) agonist DHPG [(S)-3,5-dihydroxyphenylglycine] equally engages both mGluR1 and mGluR5 subtypes, the mGluR-dependent component of IPSCs elicited by intrastriatal electrical stimulation is almost exclusively mediated by the mGluR1 subtype. Ca(2+) release from intracellular stores specifically through inositol 1,4,5-triphospahte receptors (IP(3)Rs) and not ryanodine receptors (RyRs) mediates this form of inhibition by gating two types of Ca(2+)-activated K(+) channels (i.e., small-conductance SK channels and large-conductance BK channels). Conversely, spike-evoked Ca(2+) influx triggers Ca(2+) release solely through RyRs to generate SK-dependent slow afterhyperpolarizations, demonstrating functional segregation of IP(3)Rs and RyRs. Finally, IP(3)-induced Ca(2+) release is uniquely observed in SPNs and not in different types of interneurons in the striatum. These results demonstrate that IP(3)-mediated activation of SK and BK channels provides a robust mechanism for glutamatergic and cholinergic inputs to selectively suppress striatal output neuron activity.

B-Adrenergic Receptor-Mediated Suppression of the Medium After hyperpolarization in Rat Hippocampal Neurons Maintained in Culture

The firing of a train of action potentials in hippocampal pyramidal CA1 neurons is regulated by both medium (mAHP) and slow (sAHP) afterhyperpolarizations. The mAHP is generated by activation SK and M-channels, and the deactivation of hyperpolarisation-activated H-current. In contrast, the sAHP is mediated by activation of an unknown calcium-dependent potassium channel. Organotypic hippocampal slices are a useful tool for studying the effects of altered protein expression, but it is not known whether neurons maintain the channel subtypes that underlie the mAHP or sAHP. The mAHP (generated by 25 action potentials initiated from a −80 mV) was inhibited 52% by apamin (100 nM) and 49% by XE991 (10 µM), indicating that it is generated by activation of both SK and M channels. The amplitude of the mAHP was found to increase with action potential number, an effect that was blunted by apamin. These data indicate that activation of SK channels, and not M-channels, are primarily responsible for the recruitment of the mAHP in response to increasing trains of action potentials. As previously described, application of isoprenaline significantly suppressed the sAHP. Interestingly, application of isoprenaline (1 μM) also suppressed the mAHP in organotypic slices by 52 ± 0.05 % (n=5). The prior block of SK channels by apamin did not prevent suppression of the mAHP by isoprenaline, indicating that suppression of the mAHP by β-adrenergic receptor activation does not result from inhibition of SK channel activity. These data indicate that organotypic slices retain the channel subtypes that underlie the medium and slow AHPs. The novel effect of isoprenaline suggests that the increased excitability of hippocampal neurons observed in the presence of the β-receptor agonist is a combined effect of suppressing both the medium and slow AHPs.

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?

What Determines the Kinetics of the Slow Afterhyperpolarization (sAHP) in Neurons?

¹H, ¹³C, and ¹⁵N chemical shift assignments of neuronal calcium sensor protein, hippocalcin.

Hippocalcin, a member of the neuronal calcium sensor (NCS) subclass of the calmodulin superfamily, serves as an important calcium sensor for the slow afterhyperpolarizing (sAHP) current in the hippocampus, which underlies some forms of learning and memory. Hippocalcin is also a calcium sensor for hippocampal long-term depression (LTD) and genetically linked to neurodegenerative diseases. We report NMR chemical shift assignments of Ca(2+)-free hippocalcin (BMRB no. 18627).

Hippocalcin and KCNQ Channels Contribute to the Kinetics of the Slow Afterhyperpolarization

The calcium-activated slow afterhyperpolarization (sAHP) is a potassium conductance implicated in many physiological functions of the brain including memory, aging, and epilepsy. In large part, the sAHP’s importance stems from its exceedingly long-lasting time-course, which integrates action potential-induced calcium signals and allows the sAHP to control neuronal excitability and prevent runaway firing. Despite its role in neuronal physiology, the molecular mechanisms that give rise to its unique kinetics are, to our knowledge, still unknown. Recently, we identified KCNQ channels as a candidate potassium channel family that can contribute to the sAHP. Here, we test whether KCNQ channels shape the sAHP rise and decay kinetics in wild-type mice and mice lacking Hippocalcin, the putative sAHP calcium sensor. Application of retigabine to speed KCNQ channel activation accelerated the rise of the CA3 pyramidal neuron sAHP current in both wild-type and Hippocalcin knockout mice, indicating that the gating of KCNQ channels limits the sAHP activation. Interestingly, we found that the decay of the sAHP was prolonged in Hippocalcin knockout mice, and that the decay was sensitive to retigabine modulation, unlike in wild-type mice. Together, our results demonstrate that sAHP activation in CA3 pyramidal neurons is critically dependent on KCNQ channel kinetics whereas the identity of the sAHP calcium sensor determines whether KCNQ channel kinetics also limit the sAHP decay.

The microbiome is essential for normal gut intrinsic primary afferent neuron excitability in the mouse

The role of intestinal microbiota in the development and function of host physiology is of high interest, especially with respect to the nervous system. While strong evidence has accrued that intestinal bacteria alter host nervous system function, mechanisms by which this occurs have remained elusive. For this reason, we have carried out experiments examining the electrophysiological properties of neurons in the myenteric plexus of the enteric nervous system (ENS) in germ-free (GF) mice compared with specific pathogen-free (SPF) control mice and adult germ-free mice that have been conventionalized (CONV-GF) with intestinal bacteria. Segments of jejunum from 8 to 12 week old GF, SPF, and CONV-GF mice were dissected to expose the myenteric plexus. Intracellular recordings in current-clamp mode were made by impaling cells with sharp microelectrodes. Action potential (AP) shapes, firing thresholds, the number of APs fired at 2× threshold, and passive membrane characteristics were measured. In GF mice, excitability was decreased in myenteric afterhyperpolarization (AH) neurons as measured by a lower resting membrane potential and by the number of APs generated at 2× threshold. The post AP slow afterhyperpolarization (sAHP) was prolonged for GF compared with SPF and CONV-GF animals. Passive membrane characteristics were also altered in GF mice by a decrease in input resistance. Here, we report the novel finding that commensal intestinal microbiota are necessary for normal excitability of gut sensory neurons and thus provide a potential mechanism for the transfer of information between the microbiota and nervous system.

Cortical Dendritic Spine Heads Are Not Electrically Isolated by the Spine Neck from Membrane Potential Signals in Parent Dendrites

The evidence for an important hypothesis that cortical spine morphology might participate in modifying synaptic efficacy that underlies plasticity and possibly learning and memory mechanisms is inconclusive. Both theory and experiments suggest that the transfer of excitatory postsynaptic potential signals from spines to parent dendrites depends on the spine neck morphology and resistance. Furthermore, modeling of signal transfer in the opposite direction predicts that synapses on spine heads are not electrically isolated from voltages in the parent dendrite. In sharp contrast to this theoretical prediction, one of a very few measurements of electrical signals from spines reported that slow hyperpolarizing membrane potential changes are attenuated considerably by the spine neck as they spread from dendrites to synapses on spine heads. This result challenges our understanding of the electrical behavior of spines at a fundamental level. To re-examine the specific question of the transfer of dendritic signals to synapses of spines, we took advantage of a high-sensitivity Vm-imaging technique and carried out optical measurements of electrical signals from 4 groups of spines with different neck length and simultaneously from parent dendrites. The results show that spine neck does not filter membrane potential signals as they spread from the dendrites into the spine heads.

Properties of Doublecortin Expressing Neurons in the Adult Mouse Dentate Gyrus

The dentate gyrus is a neurogenic zone where neurons continue to be born throughout life, mature and integrate into the local circuitry. In adults, this generation of new neurons is thought to contribute to learning and memory formation. As newborn neurons mature, they undergo a developmental sequence in which different stages of development are marked by expression of different proteins. Doublecortin (DCX) is an early marker that is expressed in immature granule cells that are beginning migration and dendritic growth but is turned off before neurons reach maturity. In the present study, we use a mouse strain in which enhanced green fluorescent protein (EGFP) is expressed under the control of the DCX promoter. We show that these neurons have high input resistances and some cells can discharge trains of action potentials. In mature granule cells, action potentials are followed by a slow afterhyperpolarization that is absent in EGFP-positive neurons. EGFP-positive neurons had a lower spine density than mature neurons and stimulation of either the medial or lateral perforant pathway activated dual component glutamatergic synapses that had both AMPA and NMDA receptors. NMDA receptors present at these synapses had slow kinetics and were blocked by ifenprodil, indicative of high GluN2B subunit content. These results show that EGFP-positive neurons in the DCX-EGFP mice are functionally immature both in their firing properties and excitatory synapses.

Motifs in health and disease: the promise of circuit interrogation by optogenetics

Identifying the dominant dynamical motifs in cortical circuits and determining their functional relevance is of the utmost importance to understand the underlying mechanisms of psychiatric diseases and to develop effective therapies. Optogenetics can be used to interrogate cortical circuits to determine the dominant motif and thereby identify the relevant biophysical time scales that set the oscillation frequency. We review how computational models of cortical networks can help guide optogenetics experiments. We focus our attention on the pyramidal interneuron gamma motif, which is comprised of reciprocally connected excitatory and inhibitory neurons, and determine how the different biophysical time scales of the circuit components are reflected in the resonance of the power in the local field potential at the frequency of stimulation as a function of that frequency. Cardin et al. [J.A. Cardin et al. (2009)Nature, 459, 663-667] find that periodic stimulation of inhibitory cells leads to a resonance at gamma frequencies (30-80 Hz), but that stimulation of excitatory cells does not lead to a resonance. We can account for these results when the pyramidal cells are endowed with an intrinsic frequency preference due to a slow hyperpolarizing current. Furthermore, when fast α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated excitatory currents are replaced by slow N-methyl-d-aspartate (NMDA)-mediated ones in inhibitory cells, the gamma frequency resonance is reduced; however, when the same replacement is made in excitatory cells, gamma oscillations are enhanced. The results are relevant to schizophrenia, because there is evidence that NMDA receptors on parvalbumin-positive cells are primarily affected and that the regulation of gamma oscillations is impaired.

Dopaminergic Modulation of Mitral Cells and Odor Responses in the Zebrafish Olfactory Bulb

In the olfactory bulb, the modulatory neurotransmitter dopamine (DA) is coexpressed with GABA by local interneurons, but its role in odor processing remains obscure. We examined functions of DA mediated by D₂-like receptors in the olfactory bulb of adult zebrafish by pharmacology, whole-cell recordings, calcium imaging, and optogenetics. Bath application of DA had no detectable effect on odorant-evoked sensory input. DA directly hyperpolarized mitral cells (MCs) via D₂-like receptors and slightly increased their response gain. Consistent with this effect on input-output functions of MCs, small odorant responses were suppressed, whereas strong responses were enhanced in the presence of DA. These effects increased the root-mean-square contrast of population activity patterns but did not reduce their correlations. Optical stimulation of interneurons expressing channelrhodopsin-2 evoked fast GABAergic inhibitory currents in mitral cells but failed to activate D₂ receptor-mediated currents when stimuli were short. Prolonged stimulus trains, however, activated a slow hyperpolarizing current that was blocked by an antagonist of D₂-like receptors. GABA and DA are therefore both released from interneurons by electrical activity and hyperpolarize MCs, but D₂-dependent dopaminergic effects occur on slower timescales. Additional effects of DA may be mediated by D₁-like receptors. These results indicate that DA acts on D₂-like receptors via asynchronous release and/or volume transmission and implicate DA in the slow adaptation of circuit function. The shift of the membrane potential away from spike threshold could adapt mitral cells to background input without compromising their sensitivity.

Muscarinic Receptors Modulate the Intrinsic Excitability of Infralimbic Neurons and Consolidation of Fear Extinction

There is considerable interest in identifying pharmacological compounds that could be used to facilitate fear extinction. Recently, we showed that the modulation of M-type K(+) channels regulates the intrinsic excitability of infralimbic (IL) neurons and fear expression. As muscarinic acetylcholine receptors inhibit M-type K(+) channels, cholinergic inputs to IL may have an important role in controlling IL excitability and, thereby, fear expression and extinction. To test this model, we combined whole-cell patch-clamp electrophysiology and auditory fear conditioning. In prefrontal brain slices, muscarine enhanced the intrinsic excitability of IL neurons by reducing the M-current and the slow afterhyperpolarization, resulting in an increased number of spikes with shorter inter-spike intervals. Next, we examined the role of endogenous activation of muscarinic receptors in fear extinction. Systemic injected scopolamine (Scop) (muscarinic receptor antagonist) before or immediately after extinction training impaired recall of extinction 24-h later, suggesting that muscarinic receptors are critically involved in consolidation of extinction memory. Similarly, infusion of Scop into IL before extinction training also impaired recall of extinction 24-h later. Finally, we demonstrated that systemic injections of the muscarinic agonist, cevimeline (Cev), given before or immediately after extinction training facilitated recall of extinction the following day. Taken together, these findings suggest that cholinergic inputs to IL have a critical role in modulating consolidation of fear extinction and that muscarinic agonists such as Cev might be useful for facilitating extinction memory in patients suffering from anxiety disorders.

Characterization of ionic channels underlying the specific firing pattern of a novel neuronal subtype in the rat prepositus hypoglossi nucleus

In our previous study on the prepositus hypoglossi nucleus (PHN), we found a neuronal subtype exhibiting a specific firing pattern in which the first interspike interval (ISI) was longer than that of the second, designated FIL (first interspike interval long) neurons. In the present study, we explored the ionic mechanisms underlying this firing pattern using whole-cell recordings of rat brainstem slice preparations. In addition to a longer first ISI, FIL neurons showed properties such as increased slow afterhyperpolarization (AHP) of the first spike relative to the second spike. The application of 4-aminopyridine (4-AP) shortened the longer first ISI and reduced the larger AHP of the first spike, but α-dendrotoxin affected neither the ISI nor the AHP. A voltage clamp study revealed that FIL neurons express transient outward currents with slow decay kinetics. When T-type Ca2+ currents alone or T-type Ca2+ plus persistent Na+ currents were blocked, the FIL firing pattern changed to one with transient hyperpolarization and delayed spike generation characteristic of late-spiking neurons. These findings indicate that A-type K+ currents showing slow decay, T-type Ca2+ currents, and persistent Na+ currents all contribute to the specific firing pattern of FIL neurons.

Network properties of a computational model of the dorsal raphe nucleus

Serotonin (5-HT) plays an important role in regulating mood, cognition and behaviour. The midbrain dorsal raphe nucleus (DRN) is one of the primary sources of 5-HT. Recent studies show that DRN neuronal activities can encode rewarding (e.g., appetitive) and unrewarding (e.g., aversive) behaviours. Experiments have also shown that DRN neurons can exhibit heterogeneous spiking behaviours. In this work, we build and study a basic spiking neuronal network model of the DRN constrained by neuronal properties observed in experiments. We use an efficient adaptive quadratic integrate-and-fire neuronal model to capture slow afterhyperpolarization current, occasional bursting behaviours in 5-HT neurons, and fast spiking activities in the non-5-HT inhibitory neurons. Provided that our noisy and heterogeneous spiking neuronal network model adopts a feedforward inhibitory network architecture, it is able to replicate the main features of DRN neuronal activities recorded in monkeys performing a reward-based memory-guided saccade task. The model exhibits theta band oscillation, especially among the non-5-HT inhibitory neurons during the rewarding outcome of a simulated trial, thus forming a model prediction. By varying the inhibitory synaptic strengths and the afferent inputs, we find that the network model can oscillate over a range of relatively low frequencies, allow co-existence of multiple stable frequencies, and spike synchrony can spread from within a local neural subgroup to global. Our model suggests plausible network architecture, provides interesting model predictions that can be experimentally tested, and offers a sufficiently realistic multi-scale model for 5-HT neuromodulation simulations.

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons

As an immediate consequence of stroke onset, failure of the Na(+)-K(+)-ATPase pump evokes a propagating anoxic depolarization (AD) across gray matter. Acute neuronal swelling and dendritic beading arise within seconds in the future ischemic core, imaged as changes in light transmittance (ΔLT). AD is itself not a target for drug-based reduction of stroke injury because it is generated in the 1st min of stroke onset. Peri-infarct depolarizations (PIDs) are milder AD-like events that recur during the hours following AD and contribute to infarct expansion. Inhibiting PIDs with drugs could limit expansion. Two types of drugs, "caines" and σ(1)-receptor ligands, have been found to inhibit AD onset (and may also oppose PID initiation), yet their underlying actions have not been examined. Imaging ΔLT in the CA1 region simultaneously with whole cell current-clamp recording from CA1 pyramidal neurons reveal that the elevated LT front and onset of the AD are coincident. Either dibucaine or carbetapentane pretreatment significantly delays AD onset without affecting resting membrane potential or neuronal input resistance. Dibucaine decreases excitability by raising spike threshold and decreasing action potential (AP) frequency, whereas carbetapentane eliminates the fast afterhyperpolarization while accentuating the slow afterhyperpolarization to reduce AP frequency. Orthodromic and antidromic APs are eliminated by dibucaine within 15 min but not by carbetapentane. Thus both drugs reduce cortical excitability at the level of the single pyramidal neuron but through strikingly different mechanisms. In vivo, both drugs would likely inhibit recurring PIDs in the expanding penumbra and so potentially could reduce developing neuronal damage over many hours poststroke when PIDs occur.