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1.  The Global Spike: Conserved Dendritic Properties Enable Unique Ca2+ Spike Generation in Low-Threshold Spiking Neurons 
The Journal of Neuroscience  2015;35(47):15505-15522.
Low-threshold Ca2+ spikes (LTS) are an indispensible signaling mechanism for neurons in areas including the cortex, cerebellum, basal ganglia, and thalamus. They have critical physiological roles and have been strongly associated with disorders including epilepsy, Parkinson's disease, and schizophrenia. However, although dendritic T-type Ca2+ channels have been implicated in LTS generation, because the properties of low-threshold spiking neuron dendrites are unknown, the precise mechanism has remained elusive. Here, combining data from fluorescence-targeted dendritic recordings and Ca2+ imaging from low-threshold spiking cells in rat brain slices with computational modeling, the cellular mechanism responsible for LTS generation is established. Our data demonstrate that key somatodendritic electrical conduction properties are highly conserved between glutamatergic thalamocortical neurons and GABAergic thalamic reticular nucleus neurons and that these properties are critical for LTS generation. In particular, the efficiency of soma to dendrite voltage transfer is highly asymmetric in low-threshold spiking cells, and in the somatofugal direction, these neurons are particularly electrotonically compact. Our data demonstrate that LTS have remarkably similar amplitudes and occur synchronously throughout the dendritic tree. In fact, these Ca2+ spikes cannot occur locally in any part of the cell, and hence we reveal that LTS are generated by a unique whole-cell mechanism that means they always occur as spatially global spikes. This all-or-none, global electrical and biochemical signaling mechanism clearly distinguishes LTS from other signals, including backpropagating action potentials and dendritic Ca2+/NMDA spikes, and has important consequences for dendritic function in low-threshold spiking neurons.
SIGNIFICANCE STATEMENT Low-threshold Ca2+ spikes (LTS) are critical for important physiological processes, including generation of sleep-related oscillations, and are implicated in disorders including epilepsy, Parkinson's disease, and schizophrenia. However, the mechanism underlying LTS generation in neurons, which is thought to involve dendritic T-type Ca2+ channels, has remained elusive due to a lack of knowledge of the dendritic properties of low-threshold spiking cells. Combining dendritic recordings, two-photon Ca2+ imaging, and computational modeling, this study reveals that dendritic properties are highly conserved between two prominent low-threshold spiking neurons and that these properties underpin a whole-cell somatodendritic spike generation mechanism that makes the LTS a unique global electrical and biochemical signal in neurons.
doi:10.1523/JNEUROSCI.2740-15.2015
PMCID: PMC4659821  PMID: 26609149
dendrites; low-threshold spike; T-type Ca2+ channel; thalamic reticular nucleus; thalamocortical
2.  A Distinct Class of Slow (∼0.2–2 Hz) Intrinsically Bursting Layer 5 Pyramidal Neurons Determines UP/DOWN State Dynamics in the Neocortex 
The Journal of Neuroscience  2015;35(14):5442-5458.
During sleep and anesthesia, neocortical neurons exhibit rhythmic UP/DOWN membrane potential states. Although UP states are maintained by synaptic activity, the mechanisms that underlie the initiation and robust rhythmicity of UP states are unknown. Using a physiologically validated model of UP/DOWN state generation in mouse neocortical slices whereby the cholinergic tone present in vivo is reinstated, we show that the regular initiation of UP states is driven by an electrophysiologically distinct subset of morphologically identified layer 5 neurons, which exhibit intrinsic rhythmic low-frequency burst firing at ∼0.2–2 Hz. This low-frequency bursting is resistant to block of glutamatergic and GABAergic transmission but is absent when slices are maintained in a low Ca2+ medium (an alternative, widely used model of cortical UP/DOWN states), thus explaining the lack of rhythmic UP states and abnormally prolonged DOWN states in this condition. We also characterized the activity of various other pyramidal and nonpyramidal neurons during UP/DOWN states and found that an electrophysiologically distinct subset of layer 5 regular spiking pyramidal neurons fires earlier during the onset of network oscillations compared with all other types of neurons recorded. This study, therefore, identifies an important role for cell-type-specific neuronal activity in driving neocortical UP states.
doi:10.1523/JNEUROSCI.3603-14.2015
PMCID: PMC4388913  PMID: 25855163
acetylcholine; inhibition; muscarinic; rhythmic bursting; slow waves
3.  Novel astrocyte targets 
The Neuroscientist  2015;21(1):62-83.
During the last 20 years, it has been well established that a finely tuned, continuous crosstalk between neurons and astrocytes not only critically modulates physiological brain functions but also underlies many neurological diseases. In particular, this novel way of interpreting brain activity is markedly influencing our current knowledge of epilepsy, prompting a re-evaluation of old findings and guiding novel experimentation. Here, we review recent studies that have unraveled novel and unique contributions of astrocytes to the generation and spread of convulsive and nonconvulsive seizures and epileptiform activity. The emerging scenario advocates an overall framework in which a dynamic and reciprocal interplay among astrocytic and neuronal ensembles is fundamental for a fuller understanding of epilepsy. In turn, this offers novel astrocytic targets for the development of those really novel chemical entities for the control of convulsive and nonconvulsive seizures that have been acknowledged as a key priority in the management of epilepsy.
doi:10.1177/1073858414523320
PMCID: PMC4361461  PMID: 24609207
glutamate; GABA; connexin; potassium; temporal lobe epilepsy; absence epilepsy
4.  A Critical Evaluation of the Gamma-Hydroxybutyrate (GHB) Model of Absence Seizures 
CNS Neuroscience & Therapeutics  2014;21(2):123-140.
Typical absence seizures (ASs) are nonconvulsive epileptic events which are commonly observed in pediatric and juvenile epilepsies and may be present in adults suffering from other idiopathic generalized epilepsies. Our understanding of the pathophysiological mechanisms of ASs has been greatly advanced by the availability of genetic and pharmacological models, in particular the γ-hydroxybutyrate (GHB) model which, in recent years, has been extensively used in studies in transgenic mice. GHB is an endogenous brain molecule that upon administration to various species, including humans, induces not only ASs but also a state of sedation/hypnosis. Analysis of the available data clearly indicates that only in the rat does there exist a set of GHB-elicited behavioral and EEG events that can be confidently classified as ASs. Other GHB activities, particularly in mice, appear to be mostly of a sedative/hypnotic nature: thus, their relevance to ASs requires further investigation. At the molecular level, GHB acts as a weak GABA-B agonist, while the existence of a GHB receptor remains elusive. The pre- and postsynaptic actions underlying GHB-elicited ASs have been thoroughly elucidated in thalamus, but little is known about the cellular/network effects of GHB in neocortex, the other brain region involved in the generation of ASs.
doi:10.1111/cns.12337
PMCID: PMC4335601  PMID: 25403866
Cortex; EEG; GABA-B receptors; Hypnosis; Sedation; Thalamus
5.  The Thalamus as a Low Pass Filter: Filtering at the Cellular Level does Not Equate with Filtering at the Network Level 
In the mammalian central nervous system, most sensory information passes through primary sensory thalamic nuclei, however the consequence of this remains unclear. Various propositions exist, likening the thalamus to a gate, or a high pass filter. Here, using a simple leaky integrate and fire model based on physiological parameters, we show that the thalamus behaves akin to a low pass filter. Specifically, as individual cells in the thalamus rely on consistent drive to spike, stimuli that is rapidly and continuously changing over time such that it activates sensory cells with different receptive fields are unable to drive thalamic spiking. This means that thalamic encoding is robust to sensory noise, however it induces a lag in sensory representation. Thus, the thalamus stabilizes encoding of sensory information, at the cost of response rate.
doi:10.3389/fncir.2015.00089
PMCID: PMC4712306  PMID: 26834570
thalamus; sensory neuroscience; integrate-and-fire neuron; computational neuroscience; neural noise
6.  GABAB receptor-mediated activation of astrocytes by gamma-hydroxybutyric acid 
The gamma-aminobutyric acid (GABA) metabolite gamma-hydroxybutyric acid (GHB) shows a variety of behavioural effects when administered to animals and humans, including reward/addiction properties and absence seizures. At the cellular level, these actions of GHB are mediated by activation of neuronal GABAB receptors (GABABRs) where it acts as a weak agonist. Because astrocytes respond to endogenous and exogenously applied GABA by activation of both GABAA and GABABRs, here we investigated the action of GHB on astrocytes on the ventral tegmental area (VTA) and the ventrobasal (VB) thalamic nucleus, two brain areas involved in the reward and proepileptic action of GHB, respectively, and compared it with that of the potent GABABR agonist baclofen. We found that GHB and baclofen elicited dose-dependent (ED50: 1.6 mM and 1.3 µM, respectively) transient increases in intracellular Ca2+ in VTA and VB astrocytes of young mice and rats, which were accounted for by activation of their GABABRs and mediated by Ca2+ release from intracellular store release. In contrast, prolonged GHB and baclofen exposure caused a reduction in spontaneous astrocyte activity and glutamate release from VTA astrocytes. These findings have key (patho)physiological implications for our understanding of the addictive and proepileptic actions of GHB.
doi:10.1098/rstb.2013.0607
PMCID: PMC4173292  PMID: 25225100
ventral tegmental area; thalamus; baclofen; reward; absence seizures
7.  Investigating local and long-range neuronal network dynamics by simultaneous optogenetics, reverse microdialysis and silicon probe recordings in vivo 
Highlights
•Optogenetics and microdialysis can be successfully combined.•How to manipulate circuits of spontaneous and evoked activities with drugs and lights?•Thalamic control of delta waves and sleep spindles.
Background
The advent of optogenetics has given neuroscientists the opportunity to excite or inhibit neuronal population activity with high temporal resolution and cellular selectivity. Thus, when combined with recordings of neuronal ensemble activity in freely moving animals optogenetics can provide an unprecedented snapshot of the contribution of neuronal assemblies to (patho)physiological conditions in vivo. Still, the combination of optogenetic and silicone probe (or tetrode) recordings does not allow investigation of the role played by voltage- and transmitter-gated channels of the opsin-transfected neurons and/or other adjacent neurons in controlling neuronal activity.
New method and results
We demonstrate that optogenetics and silicone probe recordings can be combined with intracerebral reverse microdialysis for the long-term delivery of neuroactive drugs around the optic fiber and silicone probe. In particular, we show the effect of antagonists of T-type Ca2+ channels, hyperpolarization-activated cyclic nucleotide-gated channels and metabotropic glutamate receptors on silicone probe-recorded activity of the local opsin-transfected neurons in the ventrobasal thalamus, and demonstrate the changes that the block of these thalamic channels/receptors brings about in the network dynamics of distant somatotopic cortical neuronal ensembles.
Comparison with existing methods
This is the first demonstration of successfully combining optogenetics and neuronal ensemble recordings with reverse microdialysis. This combination of techniques overcomes some of the disadvantages that are associated with the use of intracerebral injection of a drug-containing solution at the site of laser activation.
Conclusions
The combination of reverse microdialysis, silicone probe recordings and optogenetics can unravel the short and long-term effects of specific transmitter- and voltage-gated channels on laser-modulated firing at the site of optogenetic stimulation and the actions that these manipulations exert on distant neuronal populations.
doi:10.1016/j.jneumeth.2014.06.031
PMCID: PMC4164909  PMID: 25004203
T-type Ca2+ channels; HCN channels; Metabotropic glutamate receptors; EEG; Slow waves; Sleep spindles; Delta waves; Thalamus; Cortex
8.  Essential Thalamic Contribution to Slow Waves of Natural Sleep 
The Journal of Neuroscience  2013;33(50):19599-19610.
Slow waves represent one of the prominent EEG signatures of non-rapid eye movement (non-REM) sleep and are thought to play an important role in the cellular and network plasticity that occurs during this behavioral state. These slow waves of natural sleep are currently considered to be exclusively generated by intrinsic and synaptic mechanisms within neocortical territories, although a role for the thalamus in this key physiological rhythm has been suggested but never demonstrated. Combining neuronal ensemble recordings, microdialysis, and optogenetics, here we show that the block of the thalamic output to the neocortex markedly (up to 50%) decreases the frequency of slow waves recorded during non-REM sleep in freely moving, naturally sleeping-waking rats. A smaller volume of thalamic inactivation than during sleep is required for observing similar effects on EEG slow waves recorded during anesthesia, a condition in which both bursts and single action potentials of thalamocortical neurons are almost exclusively dependent on T-type calcium channels. Thalamic inactivation more strongly reduces spindles than slow waves during both anesthesia and natural sleep. Moreover, selective excitation of thalamocortical neurons strongly entrains EEG slow waves in a narrow frequency band (0.75–1.5 Hz) only when thalamic T-type calcium channels are functionally active. These results demonstrate that the thalamus finely tunes the frequency of slow waves during non-REM sleep and anesthesia, and thus provide the first conclusive evidence that a dynamic interplay of the neocortical and thalamic oscillators of slow waves is required for the full expression of this key physiological EEG rhythm.
doi:10.1523/JNEUROSCI.3169-13.2013
PMCID: PMC3858629  PMID: 24336724
9.  γ-Hydroxybutyric Acid (GHB) Is Not an Agonist of Extrasynaptic GABAA Receptors 
PLoS ONE  2013;8(11):e79062.
γ-Hydroxybutyric acid (GHB) is an endogenous compound and a drug used clinically to treat the symptoms of narcolepsy. GHB is known to be an agonist of GABAB receptors with millimolar affinity, but also binds with much higher affinity to another site, known as the GHB receptor. While a body of evidence has shown that GHB does not bind to GABAA receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4β1δ GABAA receptors, where GHB acts as an agonist with an EC50 of 140 nM. We investigated three neuronal cell types that express a tonic GABAA receptor current mediated by extrasynaptic receptors: ventrobasal (VB) thalamic neurons, dentate gyrus granule cells and striatal medium spiny neurons. Using whole-cell voltage clamp in brain slices, we found no evidence that GHB (10 µM) induced any GABAA receptor mediated current in these cell types, nor that it modulated inhibitory synaptic currents. Furthermore, a high concentration of GHB (3 mM) was able to produce a GABAB receptor mediated current, but did not induce any other currents. These results suggest either that GHB is not a high affinity agonist at native α4β1δ receptors, or that these receptors do not exist in classical areas associated with extrasynaptic currents.
doi:10.1371/journal.pone.0079062
PMCID: PMC3823990  PMID: 24244421
11.  Metabotropic regulation of extrasynaptic GABAA receptors 
A large body of work now shows the importance of GABAA receptor-mediated tonic inhibition in regulating CNS function. However, outside of pathological conditions, there is relatively little evidence that the magnitude of tonic inhibition is itself under regulation. Here we review the mechanisms by which tonic inhibition is known to be modulated, and outline the potential behavioral consequences of this modulation. Specifically, we address the ability of protein kinase A and C to phosphorylate the extrasynaptic receptors responsible for the tonic GABAA current, and how G-protein coupled receptors can regulate tonic inhibition through these effectors. We then speculate about the possible functional consequences of regulating the magnitude of the tonic GABAA current.
doi:10.3389/fncir.2013.00171
PMCID: PMC3829460  PMID: 24298239
extrasynaptic; GABA; kinase; tonic; plasticity
12.  Unravelling the brain targets of γ-hydroxybutyric acid 
γ-Hydroxybutyric acid (GHB) is a naturally occurring γ-aminobutyric acid (GABA) metabolite that has been proposed as a neurotransmitter/neuromodulator that acts via its own receptor (GHBR). Its exogenous administration, however, elicits central nervous system-dependent effects (e.g. memory impairment, increase in sleep stages 3 and 4, dependence, seizures and coma) that are mostly mediated by GABAB receptors. The past few years have seen important developments in our understanding of GHB neurobiology: a putative GHBR has been cloned; a transgenic model of GHB aciduria has been developed; GABAB receptor knockout mice and novel GHB analogs have helped to characterize the vast majority of exogenous GHB actions mediated by GABAB receptors; and some of the cellular mechanisms underlying the dependence/abuse properties of GHB, and its ability to elicit absence seizures and an increase in sleep stages 3 and 4, have been clarified. Nevertheless, the physiological significance of a brain GHB signaling pathway is still unknown, and there is an urgent need for a well-validated functional assay for GHBRs. Moreover, as GHB can also be metabolized to GABA, it remains to be seen whether the many GABAB receptor-mediated actions of GHB are caused by GHB itself acting directly on GABAB receptors or by a GHB-derived GABA pool (or both).
doi:10.1016/j.coph.2005.10.001
PMCID: PMC2174623  PMID: 16368267
13.  Activity of cortical and thalamic neurons during the slow (<1 Hz) rhythm in the mouse in vivo 
During NREM sleep and under certain types of anaesthesia the mammalian brain exhibits a distinctive slow (<1 Hz) rhythm. At the cellular level this rhythm correlates with so-called UP and DOWN membrane potential states. In the neocortex these UP and DOWN states correspond to periods of intense network activity and widespread neuronal silence, respectively, whereas in thalamocortical (TC) neurons, UP/DOWN states take on a more stereotypical oscillatory form with UP states commencing with a low-threshold Ca2+ potential (LTCP). Whilst these properties are now well recognized for neurons in cats and rats, whether or not they are also shared by neurons in the mouse is not fully known. To address this issue we obtained intracellular recordings from neocortical and TC neurons during the slow (<1 Hz) rhythm in anaesthetized mice. We show that UP/DOWN states in this species are broadly similar to those observed in cats and rats, with UP states in neocortical neurons being characterized by a combination of action potential output and intense synaptic activity whereas UP states in TC neurons always commence with an LTCP. In some neocortical and TC neurons we observed ‘spikelets’ during UP states, supporting the possible presence of electrical coupling. Lastly, we show that upon tonic depolarization, UP/DOWN states in TC neurons are replaced by rhythmic high-threshold (HT) bursting at ~5 Hz, as predicted by in vitro studies. Thus, UP/DOWN state generation appears to be an elemental and conserved process in mammals that underlies the slow (<1 Hz) rhythm in several species, including humans.
doi:10.1007/s00424-011-1011-9
PMCID: PMC3256325  PMID: 21892727
EEG; oscillations; sleep; neocortex; thalamocortical
15.  Self-repair in a bidirectionally coupled astrocyte-neuron (AN) system based on retrograde signaling 
In this paper we demonstrate that retrograde signaling via astrocytes may underpin self-repair in the brain. Faults manifest themselves in silent or near silent neurons caused by low transmission probability (PR) synapses; the enhancement of the transmission PR of a healthy neighboring synapse by retrograde signaling can enhance the transmission PR of the “faulty” synapse (repair). Our model of self-repair is based on recent research showing that retrograde signaling via astrocytes can increase the PR of neurotransmitter release at damaged or low transmission PR synapses. The model demonstrates that astrocytes are capable of bidirectional communication with neurons which leads to modulation of synaptic activity, and that indirect signaling through retrograde messengers such as endocannabinoids leads to modulation of synaptic transmission PR. Although our model operates at the level of cells, it provides a new research direction on brain-like self-repair which can be extended to networks of astrocytes and neurons. It also provides a biologically inspired basis for developing highly adaptive, distributed computing systems that can, at fine levels of granularity, fault detect, diagnose and self-repair autonomously, without the traditional constraint of a central fault detect/repair unit.
doi:10.3389/fncom.2012.00076
PMCID: PMC3458420  PMID: 23055965
astrocyte; calcium wave; endocannabinoid; IP3; neuron; self-repair; synapse
16.  Bidirectional Coupling between Astrocytes and Neurons Mediates Learning and Dynamic Coordination in the Brain: A Multiple Modeling Approach 
PLoS ONE  2011;6(12):e29445.
In recent years research suggests that astrocyte networks, in addition to nutrient and waste processing functions, regulate both structural and synaptic plasticity. To understand the biological mechanisms that underpin such plasticity requires the development of cell level models that capture the mutual interaction between astrocytes and neurons. This paper presents a detailed model of bidirectional signaling between astrocytes and neurons (the astrocyte-neuron model or AN model) which yields new insights into the computational role of astrocyte-neuronal coupling. From a set of modeling studies we demonstrate two significant findings. Firstly, that spatial signaling via astrocytes can relay a “learning signal” to remote synaptic sites. Results show that slow inward currents cause synchronized postsynaptic activity in remote neurons and subsequently allow Spike-Timing-Dependent Plasticity based learning to occur at the associated synapses. Secondly, that bidirectional communication between neurons and astrocytes underpins dynamic coordination between neuron clusters. Although our composite AN model is presently applied to simplified neural structures and limited to coordination between localized neurons, the principle (which embodies structural, functional and dynamic complexity), and the modeling strategy may be extended to coordination among remote neuron clusters.
doi:10.1371/journal.pone.0029445
PMCID: PMC3248449  PMID: 22242121
17.  mGluR control of interneuron output regulates feedforward tonic GABAA inhibition in the visual thalamus 
Metabotropic glutamate receptors (mGluRs) play a crucial role in regulation of phasic inhibition within the visual thalamus. Here we demonstrate that mGluR-dependent modulation of interneuron GABA release results in dynamic changes in extrasynaptic GABAA (eGABAAR) receptor-dependent tonic inhibiton in thalamocortical (TC) neurons of the rat dorsal lateral geniculate nucleus (dLGN). Application of the group I selective mGluR agonist DHPG produces a concentration-dependent enhancement of both IPSC frequency and tonic GABAA current (IGABAtonic) that is due to activation of both mGluR1a and mGluR5 subtypes. In contrast, group II/III mGluR activation decreases both IPSC frequency and IGABAtonic amplitude. Using knock-out mice we show that the mGluR-dependent modulation of IGABAtonic is dependent upon expression of δ-subunit containing eGABAARs. Furthermore, unlike the dLGN, no mGluR-dependent modulation of IGABAtonic is present in TC neurons of the somatosensory ventrobasal thalamus, which lacks GABAergic interneurons. In the dLGN, enhancement of IPSC frequency and IGABAtonic by group I mGluRs is not action potential-dependent, being insensitive to TTX, but is abolished by the L-type Ca2+ channel blocker nimodipine. These results indicate selective mGluR-dependent modulation of dendro-dendritic GABA release from F2-type terminals on interneuron dendrites and demonstrate for the first time the presence of eGABAARs on TC neuron dendritic elements that participate in ‘triadic’ circuitry within the dLGN. These findings present a plausible novel mechanism for visual contrast gain at the thalamic level and shed new light upon the potential role of glial ensheathment of synaptic triads within the dLGN.
doi:10.1523/JNEUROSCI.0317-11.2011
PMCID: PMC3130900  PMID: 21653871
dorsal lateral geniculate nucleus; interneuron; metabotropic glutamate receptor; extrasynaptic GABAA receptor; thalamocortical; glomerulus
18.  TRANSITION TO ABSENCE SEIZURES AND THE ROLE OF GABAA RECEPTORS 
Epilepsy research  2011;97(3):283-289.
Absence seizures appear to be initiated in a putative cortical ‘initiation site’ by the expression of medium-amplitude 5-9Hz oscillations, that may in part be due to a decreased phasic GABAA receptor function. These oscillations rapidly spread to other cortical areas and to the thalamus, leading to fully developed generalized spike and wave discharges. In thalamocortical neurons of genetic models, phasic GABAA inhibition is either unchanged or increased, whereas tonic GABAA inhibition is increased both in genetic and pharmacological models. This enhanced tonic inhibition is required for absence seizure generation, and in genetic models it results from a malfunction in the astrocytic GABA transporter GAT-1. Contradictory results from inbred and transgenic animals still do not allow us to draw firm conclusions on changes in phasic GABAA inhibition in the GABAergic neurons of the nucleus reticularis thalami. Mathematical modelling may enhance our understanding of these competing hypotheses, by permitting investigations of their mechanistic aspects, hence enabling a greater understanding of the processes underlying seizure generation and evolution.
doi:10.1016/j.eplepsyres.2011.07.011
PMCID: PMC3227737  PMID: 21889315
phasic GABAA inhibition; tonic GABAA inhibition; GABAB receptors; GHB; GAERS; mathematical modelling
19.  Transition to absence seizures and the role of GABAA receptors 
Epilepsy Research  2011;97(3):283-289.
Summary
Absence seizures appear to be initiated in a putative cortical ‘initiation site’ by the expression of medium-amplitude 5–9 Hz oscillations, which may in part be due to a decreased phasic GABAA receptor function. These oscillations rapidly spread to other cortical areas and to the thalamus, leading to fully developed generalized spike and wave discharges. In thalamocortical neurons of genetic models, phasic GABAA inhibition is either unchanged or increased, whereas tonic GABAA inhibition is increased both in genetic and pharmacological models. This enhanced tonic inhibition is required for absence seizure generation, and in genetic models it results from a malfunction in the astrocytic GABA transporter GAT-1. Contradictory results from inbred and transgenic animals still do not allow us to draw firm conclusions on changes in phasic GABAA inhibition in the GABAergic neurons of the nucleus reticularis thalami. Mathematical modelling may enhance our understanding of these competing hypotheses, by permitting investigations of their mechanistic aspects, hence enabling a greater understanding of the processes underlying seizure generation and evolution.
doi:10.1016/j.eplepsyres.2011.07.011
PMCID: PMC3227737  PMID: 21889315
Phasic GABAA inhibition; Tonic GABAA inhibition; GABAB receptors; GHB; GAERS; Mathematical modelling
20.  The thalamic low-threshold Ca2+ potential: a key determinant of the local and global dynamics of the slow (<1 Hz) sleep oscillation in thalamocortical networks 
During non-rapid eye movement (NREM) sleep and certain types of anaesthesia, neurons in the neocortex and thalamus exhibit a distinctive slow (<1 Hz) oscillation that consists of alternating UP and DOWN membrane potential states and which correlates with a pronounced slow (<1 Hz) rhythm in the EEG. Whilst several studies have claimed that the slow oscillation is generated exclusively in neocortical networks and then transmitted to other brain areas, substantial evidence exists to suggest that the full expression of the slow oscillation in an intact thalamocortical network requires the balanced interaction of oscillator systems in both the neocortex and thalamus. Within such a scenario, we have previously argued that the powerful low-threshold Ca2+ potential (LTCP)-mediated burst of action potentials that initiates the UP states in individual thalamocortical neurons may be a vital signal for instigating UP states in related cortical areas. To investigate these issues we constructed a computational model of the thalamocortical network which encompasses the important known aspects of the slow oscillation that have been garnered from earlier in vivo and in vitro experiments. By using this model we confirm that the overall expression of the slow oscillation is intricately reliant on intact connections between thalamus and cortex. In particular, we demonstrate that UP state-related LTCP-mediated bursts in thalamocortical neurons are proficient in triggering synchronous UP states in cortical networks, thereby bringing about a synchronous slow oscillation in the whole network. The importance of LTCP-mediated action potential bursts in the slow oscillation is also underlined by the observation that their associated dendritic Ca2+ signals are the only ones that inform corticothalamic synapses of the thalamocortical neuron output, since they, but not those elicited by tonic action potential firing, reach the distal dendritic sites where these synapses are located.
doi:10.1098/rsta.2011.0126
PMCID: PMC3173871  PMID: 21893530
thalamic neurons; cortical neurons; probabilistic network model; dendrites; intrinsic calcium signalling
21.  The thalamic low-threshold Ca2+ potential: a key determinant of the local and global dynamics of the slow (<1 Hz) sleep oscillation in thalamocortical networks 
During non-rapid eye movement sleep and certain types of anaesthesia, neurons in the neocortex and thalamus exhibit a distinctive slow (<1 Hz) oscillation that consists of alternating UP and DOWN membrane potential states and which correlates with a pronounced slow (<1 Hz) rhythm in the electroencephalogram. While several studies have claimed that the slow oscillation is generated exclusively in neocortical networks and then transmitted to other brain areas, substantial evidence exists to suggest that the full expression of the slow oscillation in an intact thalamocortical (TC) network requires the balanced interaction of oscillator systems in both the neocortex and thalamus. Within such a scenario, we have previously argued that the powerful low-threshold Ca2+ potential (LTCP)-mediated burst of action potentials that initiates the UP states in individual TC neurons may be a vital signal for instigating UP states in related cortical areas. To investigate these issues we constructed a computational model of the TC network which encompasses the important known aspects of the slow oscillation that have been garnered from earlier in vivo and in vitro experiments. Using this model we confirm that the overall expression of the slow oscillation is intricately reliant on intact connections between the thalamus and the cortex. In particular, we demonstrate that UP state-related LTCP-mediated bursts in TC neurons are proficient in triggering synchronous UP states in cortical networks, thereby bringing about a synchronous slow oscillation in the whole network. The importance of LTCP-mediated action potential bursts in the slow oscillation is also underlined by the observation that their associated dendritic Ca2+ signals are the only ones that inform corticothalamic synapses of the TC neuron output, since they, but not those elicited by tonic action potential firing, reach the distal dendritic sites where these synapses are located.
doi:10.1098/rsta.2011.0126
PMCID: PMC3173871  PMID: 21893530
thalamic neurons; cortical neurons; probabilistic network model; dendrites; intrinsic calcium signalling
22.  Infra-slow (<0.1 Hz) oscillations in thalamic relay nuclei: basic mechanisms and significance to health and disease states 
Progress in brain research  2011;193:145-162.
In the absence of external stimuli the mammalian brain continues to display a rich variety of spontaneous activity. Such activity is often highly stereotypical, invariably rhythmic and can occur with periodicities ranging from a few milliseconds to several minutes. Recently there has been a particular resurgence of interest in fluctuations in brain activity occurring at <0.1 Hz, commonly referred to as very slow or infra-slow oscillations (ISOs). Whilst this is primarily due to the emergence of functional magnetic resonance imaging (fMRI) as a technique which has revolutionised the study of human brain dynamics it is also a consequence of the application of full band electroencephalography (fbEEG). Despite these technical advances the precise mechanisms which lead to ISOs in the brain remain unclear. In a host of animal studies, one brain region that consistently shows oscillations at <0.1 Hz is the thalamus. Importantly, similar oscillations can also be observed in slices of isolated thalamic relay nuclei maintained in vitro. Here, we discuss the nature and mechanisms of these oscillations, paying particular attention to a potential role for astrocytes in their genesis. We also highlight the relationship between this activity and ongoing local network oscillations in the alpha (α) (~8-13 Hz) band, drawing clear parallels with observations made in vivo. Lastly, we consider the relevance of these thalamic ISOs to the pathological activity that occurs in certain types of epilepsy.
doi:10.1016/B978-0-444-53839-0.00010-7
PMCID: PMC3173874  PMID: 21854961
acetylcholine; metabotropic glutamate receptor; EEG; gap junctions; alpha rhythm; epilepsy; adenosine; astrocytes; GIRK channels
23.  Augmentation of Tonic GABAA Inhibition in Absence Epilepsy: Therapeutic Value of Inverse Agonists at Extrasynaptic GABAA Receptors 
It is well established that impaired GABAergic inhibition within neuronal networks can lead to hypersynchronous firing patterns that are the typical cellular hallmark of convulsive epileptic seizures. However, recent findings have highlighted that a pathological enhancement of GABAergic signalling within thalamocortical circuits is a necessary and sufficient condition for nonconvulsive typical absence seizure genesis. In particular, increased activation of extrasynaptic GABAA receptors (eGABAAR) and augmented “tonic” GABAA inhibition in thalamocortical neurons have been demonstrated across a range of genetic and pharmacological models of absence epilepsy. Moreover, evidence from monogenic mouse models (stargazer/lethargic) and the polygenic Genetic Absence Epilepsy Rats from Strasbourg (GAERS) indicate that the mechanism underlying eGABAAR gain of function is nonneuronal in nature and results from a deficiency in astrocytic GABA uptake through the GAT-1 transporter. These results challenge the existing theory that typical absence seizures are underpinned by a widespread loss of GABAergic function in thalamocortical circuits and illustrate a vital role for astrocytes in the pathology of typical absence epilepsy. Moreover, they explain why pharmacological agents that enhance GABA receptor function can initiate or exacerbate absence seizures and suggest a potential therapeutic role for inverse agonists at eGABAARs in absence epilepsy.
doi:10.1155/2011/790590
PMCID: PMC3168769  PMID: 21912539
24.  Activity of cortical and thalamic neurons during the slow (<1 Hz) rhythm in the mouse in vivo 
Pflugers Archiv  2011;463(1):73-88.
During NREM sleep and under certain types of anaesthesia, the mammalian brain exhibits a distinctive slow (<1 Hz) rhythm. At the cellular level, this rhythm correlates with so-called UP and DOWN membrane potential states. In the neocortex, these UP and DOWN states correspond to periods of intense network activity and widespread neuronal silence, respectively, whereas in thalamocortical (TC) neurons, UP/DOWN states take on a more stereotypical oscillatory form, with UP states commencing with a low-threshold Ca2+ potential (LTCP). Whilst these properties are now well recognised for neurons in cats and rats, whether or not they are also shared by neurons in the mouse is not fully known. To address this issue, we obtained intracellular recordings from neocortical and TC neurons during the slow (<1 Hz) rhythm in anaesthetised mice. We show that UP/DOWN states in this species are broadly similar to those observed in cats and rats, with UP states in neocortical neurons being characterised by a combination of action potential output and intense synaptic activity, whereas UP states in TC neurons always commence with an LTCP. In some neocortical and TC neurons, we observed ‘spikelets’ during UP states, supporting the possible presence of electrical coupling. Lastly, we show that, upon tonic depolarisation, UP/DOWN states in TC neurons are replaced by rhythmic high-threshold bursting at ~5 Hz, as predicted by in vitro studies. Thus, UP/DOWN state generation appears to be an elemental and conserved process in mammals that underlies the slow (<1 Hz) rhythm in several species, including humans.
doi:10.1007/s00424-011-1011-9
PMCID: PMC3256325  PMID: 21892727
EEG; Oscillations; Sleep; Neocortex; Thalamocortical; Electroencephalogram; T-type calcium channel; Thalamus; Neocortical neurons
25.  From sleep spindles of natural sleep to spike and wave discharges of typical absence seizures: is the hypothesis still valid? 
Pflugers Archiv  2011;463(1):201-212.
The temporal coincidence of sleep spindles and spike-and-wave discharges (SWDs) in patients with idiopathic generalized epilepsies, together with the transformation of spindles into SWDs following intramuscular injection of the weak GABAA receptor (GABAAR) antagonist, penicillin, in an experimental model, brought about the view that SWDs may represent ‘perverted’ sleep spindles. Over the last 20 years, this hypothesis has received considerable support, in particular by in vitro studies of thalamic oscillations following pharmacological/genetic manipulations of GABAARs. However, from a critical appraisal of the evidence in absence epilepsy patients and well-established models of absence epilepsy it emerges that SWDs can occur as frequently during wakefulness as during sleep, with their preferential occurrence in either one of these behavioural states often being patient dependent. Moreover, whereas the EEG expression of both SWDs and sleep spindles requires the integrity of the entire cortico-thalamo-cortical network, SWDs initiates in cortex while sleep spindles in thalamus. Furthermore, the hypothesis of a reduction in GABAAR function across the entire cortico-thalamo-cortical network as the basis for the transformation of sleep spindles into SWDs is no longer tenable. In fact, while a decreased GABAAR function may be present in some cortical layers and in the reticular thalamic nucleus, both phasic and tonic GABAAR inhibitions of thalamo-cortical neurons are either unchanged or increased in this epileptic phenotype. In summary, these differences between SWDs and sleep spindles question the view that the EEG hallmark of absence seizures results from a transformation of this EEG oscillation of natural sleep.
doi:10.1007/s00424-011-1009-3
PMCID: PMC3256322  PMID: 21861061
Epilepsy; Cortex; Thalamus; Nucleus reticularis thalami; GABA receptors

Results 1-25 (45)