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William Guido - One of the best experts on this subject based on the ideXlab platform.
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Retinal input regulates the timing of corticogeniculate innervation.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013Co-Authors: Tania A. Seabrook, Rana N. El-danaf, Thomas E. Krahe, Michael A. Fox, William GuidoAbstract:Neurons in layer VI of visual cortex represent one of the largest sources of nonretinal input to the dorsal lateral geniculate nucleus (dLGN) and play a major role in modulating the gain of Thalamic signal transmission. However, little is known about how and when these descending projections arrive and make functional connections with dLGN cells. Here we used a transgenic mouse to visualize corticogeniculate projections to examine the timing of cortical innervation in dLGN. Corticogeniculate innervation occurred at postnatal ages and was delayed compared with the arrival of retinal afferents. Cortical fibers began to enter dLGN at postnatal day 3 (P3) to P4, a time when retinogeniculate innervation is complete. However, cortical projections did not fully innervate dLGN until eye opening (P12), well after the time when retinal inputs from the two eyes segregate to form nonoverlapping eye-specific domains. In vitro Thalamic Slice recordings revealed that newly arriving cortical axons form functional connections with dLGN cells. However, adult-like responses that exhibited paired pulse facilitation did not fully emerge until 2 weeks of age. Finally, surgical or genetic elimination of retinal input greatly accelerated the rate of corticogeniculate innervation, with axons invading between P2 and P3 and fully innervating dLGN by P8 to P10. However, recordings in genetically deafferented mice showed that corticogeniculate synapses continued to mature at the same rate as controls. These studies suggest that retinal and cortical innervation of dLGN is highly coordinated and that input from retina plays an important role in regulating the rate of corticogeniculate innervation.
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Requirements for synaptically evoked plateau potentials in relay cells of the dorsal lateral geniculate nucleus of the mouse
The Journal of Physiology, 2011Co-Authors: Emily Dilger, Hee-sup Shin, William GuidoAbstract:Non-technical summary In the developing visual system, spontaneous retinal activity plays an important role in the refinement of retinal ganglion cell projections to the dorsal lateral geniculate nucleus (dLGN) of thalamus. How such changes are implemented remains unknown. Recordings of post-synaptic dLGN cell activity suggest that plateau-like, L-type Ca2+ channel-mediated depolarizations figure prominently in remodelling. Plateaus are developmentally regulated and their incidence is controlled by the changing patterns of excitatory and inhibitory connections onto dLGN cells. At early ages there is a high degree of retinal convergence, and excitatory post-synaptic events summate to produce depolarizations sufficient to activate plateaus. As these excitatory inputs are pruned and inhibitory connections emerge, the net excitatory drive is reduced and plateaus wane. Additionally, L-type channels are highly expressed at young ages, and subunit disruptions resulting in decreased expression also affect the incidence of plateaus. These studies help elucidate the mechanisms underlying activity-dependent refinement of sensory connections. Abstract In developing cells of the mouse dorsal lateral geniculate nucleus (dLGN), synaptic responses evoked by optic tract (OT) stimulation give rise to long-lasting, high-amplitude depolarizations known as plateau potentials. These events are mediated by L-type Ca2+ channels and occur during early postnatal life, a time when retinogeniculate connections are remodelling. To better understand the relationship between L-type activity and dLGN development we used an in vitro Thalamic Slice preparation which preserves the retinal connections and intrinsic circuitry in dLGN and examined how synaptic responses evoked by OT stimulation lead to the activation of plateau potentials. By varying the strength and temporal frequency of OT stimulation we identified at least three factors that contribute to the developmental regulation of plateau activity: the degree of retinal convergence, the temporal pattern of retinal stimulation and the emergence of feed-forward inhibition. Before natural eye opening (postnatal day 14), the excitatory synaptic responses of relay cells receiving multiple retinal inputs summated in both the spatial and temporal domains to produce depolarizations sufficient to activate L-type activity. After eye opening, when inhibitory responses are fully developed, plateau activity was rarely evoked even with high temporal rates of OT stimulation. When the bulk of this inhibition was blocked by bath application of bicuculline, the incidence of plateau activity increased significantly. We also made use of a transgenic mouse that lacks the β3 subunit of the L-type Ca2+ channel. These mutants have far fewer membrane-bound Ca2+ channels and attenuated L-type activity. In β3 nulls, L-type plateau activity was rarely observed even at young ages when plateau activity prevails. Thus, in addition to the changing patterns of synaptic connectivity and retinal activity, the expression of L-type Ca2+ channels is a requisite component in the manifestation of plateau activity.
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Requirements for synaptically evoked plateau potentials in relay cells of the dorsal lateral geniculate nucleus of the mouse.
The Journal of physiology, 2010Co-Authors: Emily Dilger, Hee-sup Shin, William GuidoAbstract:In developing cells of the mouse dorsal lateral geniculate nucleus (dLGN), synaptic responses evoked by optic tract (OT) stimulation give rise to long-lasting, high-amplitude depolarizations known as plateau potentials. These events are mediated by L-type Ca2+ channels and occur during early postnatal life, a time when retinogeniculate connections are remodelling. To better understand the relationship between L-type activity and dLGN development we used an in vitro Thalamic Slice preparation which preserves the retinal connections and intrinsic circuitry in dLGN and examined how synaptic responses evoked by OT stimulation lead to the activation of plateau potentials. By varying the strength and temporal frequency of OT stimulation we identified at least three factors that contribute to the developmental regulation of plateau activity: the degree of retinal convergence, the temporal pattern of retinal stimulation and the emergence of feed-forward inhibition. Before natural eye opening (postnatal day 14), the excitatory synaptic responses of relay cells receiving multiple retinal inputs summated in both the spatial and temporal domains to produce depolarizations sufficient to activate L-type activity. After eye opening, when inhibitory responses are fully developed, plateau activity was rarely evoked even with high temporal rates of OT stimulation. When the bulk of this inhibition was blocked by bath application of bicuculline, the incidence of plateau activity increased significantly. We also made use of a transgenic mouse that lacks the β3 subunit of the L-type Ca2+ channel. These mutants have far fewer membrane-bound Ca2+ channels and attenuated L-type activity. In β3 nulls, L-type plateau activity was rarely observed even at young ages when plateau activity prevails. Thus, in addition to the changing patterns of synaptic connectivity and retinal activity, the expression of L-type Ca2+ channels is a requisite component in the manifestation of plateau activity.
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A shout out to immature synapses. Focus on "different roles for AMPA and NMDA receptors in transmission at the immature retinogeniculate synapse".
Journal of neurophysiology, 2007Co-Authors: William GuidoAbstract:A major topic of investigation in the field of developmental neuroscience is to understand how newly formed excitatory synapses receive and transmit information. It is now widely accepted that neural activity plays an important role in a number of developmental processes, including the refinement and establishment of orderly connections (Grubb and Thompson 2004). However, it remains unclear how many immature excitatory synapses (i.e., ones that utilize glutamate as a neurotransmitter) participate in the relay of activity. Contributing to this problem is the finding that immature glutamatergic synapses are comprised largely of N-methyl-D-aspartate (NMDA) receptors and lack AMPA receptors that mediate fast excitatory transmission. Such synapses are said to be “silent,” incapable of causing postsynaptic action potentials from resting levels because in addition to glutamate, the NMDA receptor requires membrane depolarization to relieve a voltage-dependent Mg 2 block. How then do silent synapses “speak” loudly enough to cause postsynaptic firing and thereby successfully relay information? In a recent article, Liu and Chen (2008) provide some answers to this question. They examine the synaptic responses and intrinsic properties of developing neurons by making use of an in vitro Thalamic Slice preparation that maintains the excitatory synaptic connections between retinal ganglion cells and relay cells of the dorsal lateral geniculate nucleus (LGN). In an elegant series of whole cell recording experiments, they show how a constellation of properties, including ligand-gated channel kinetics, receptor subunit composition, extended presence of neurotransmitter
John R. Huguenard - One of the best experts on this subject based on the ideXlab platform.
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Development and validation of a potent and specific inhibitor provides evidence for the CLC-2 chloride channel as a potential epilepsy target
2020Co-Authors: Anna K. Koster, Austin L. Reese, Yuri A. Kuryshev, Xianlan Wen, Keri A. Mckiernan, Erin E. Gray, Mark P. Beenhakker, John R. HuguenardAbstract:Summary CLC-2 is a voltage-gated chloride channel expressed ubiquitously in mammalian tissue. Studies to define how CLC-2 contributes to normal and pathophysiological brain function have produced controversial results, in part due to the absence of precise pharmacological tools for modulating CLC-2 function. Herein, we describe the development and optimization of a new small-molecule inhibitor of CLC-2, AK-42, that exhibits unprecedented potency and specificity. Computational docking, validated by mutagenesis and kinetic studies, indicates that AK-42 binds to an extracellular vestibule above the channel pore. AK-42 acutely and specifically inhibits CLC-2 currents in CA1 hippocampal pyramidal neurons. Use of AK-42 in an established Thalamic-Slice model for studying epilepsy suggests a role for CLC-2 in modulating electrical excitability and implicates CLC-2 as a possible anti-epileptic target. These results establish AK-42 as a powerful new tool for investigating CLC-2 physiology in the central nervous system.
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Peptidergic Modulation of IntraThalamic Circuit Activity In Vitro: Actions of Cholecystokinin
2013Co-Authors: Charles L. Cox, John R. Huguenard, David A. PrinceAbstract:Cholecystokinin (CCK)-mediated actions on intraThalamic rhythmic activities were examined in an in vitro rat Thalamic Slice preparation. Single electrical stimuli in the Thalamic reticular nucleus (nRt) evoked rhythmic activity (1–15 sec duration) in nRt and the adjacent ventrobasal nucleus (VB). Low CCK concentrations (20–50 nM) suppressed rhythmic oscillations in 43 % of experiments but prolonged such activities in the remaining Slices. Higher CCK concentrations (100–400 nM) had a predominantly antioscillatory effect. Suppression of oscillations was associated with a relatively large membrane depolarization of nRt neurons that changed their firing mode from phasic (burst) to tonic (single-spike) output. This decreased burst discharge of nRt neurons during CCK application reduced inhibitory drive onto VB neurons from multiple peaked inhibitory postsynaptic currents (IPSCs) t
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GABAB and NMDA Receptors Contribute to Spindle-Like Oscillations in Rat Thalamus In Vitro
Journal of neurophysiology, 2001Co-Authors: Richard B. Jacobsen, Daniel Ulrich, John R. HuguenardAbstract:Thalamic Slice preparations, in which intraThalamic connectivity between the reticular nucleus and relay nuclei is maintained, are capable of sustaining rhythmic burst firing activity in rodents an...
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Peptidergic Modulation of IntraThalamic Circuit Activity In Vitro: Actions of Cholecystokinin
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997Co-Authors: Charles L. Cox, John R. Huguenard, David A. PrinceAbstract:Cholecystokinin (CCK)-mediated actions on intraThalamic rhythmic activities were examined in an in vitro rat Thalamic Slice preparation. Single electrical stimuli in the Thalamic reticular nucleus (nRt) evoked rhythmic activity (1‐15 sec duration) in nRt and the adjacent ventrobasal nucleus (VB). Low CCK concentrations (20‐50 nM) suppressed rhythmic oscillations in 43% of experiments but prolonged such activities in the remaining Slices. Higher CCK concentrations (100‐400 nM) had a predominantly antioscillatory effect. Suppression of oscillations was associated with a relatively large membrane depolarization of nRt neurons that changed their firing mode from phasic (burst) to tonic (single-spike) output. This decreased burst discharge of nRt neurons during CCK application reduced inhibitory drive onto VB neurons from multiple peaked inhibitory postsynaptic currents (IPSCs) to single peaked inhibitory events. We hypothesize that suppression of inhibitory drive onto VB neurons decreases their probability of burst output, which, together with a reduction of nRt burst output, dampens the oscillatory activity. Low CCK concentrations, which produced little or no depolarization of nRt neurons, did not alter the firing mode of the nRt neurons. However, the probability of burst output from nRt neurons in response to subthreshold stimuli was increased in low CCK concentrations, presumably leading to an increase in the number of nRt neurons participating in the rhythmic activity. Ourfindings suggest that the neuropeptide CCK, by altering the firing characteristics of nRt neurons, has powerful modulatory effects on intraThalamic rhythms; the ultimate action was dependent on CCK concentration and resting state of these cells.
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Heterogeneous Axonal Arborizations of Rat Thalamic Reticular Neurons in the Ventrobasal Nucleus
The Journal of comparative neurology, 1996Co-Authors: Charles L. Cox, John R. Huguenard, David A. PrinceAbstract:The y-aminobutyric acid (GABA)-containing neurons of the Thalamic reticular nucleus (nRt) are a major source of inhibitory innervation in dorsal Thalamic nuclei. Individual nRt neurons were intracellularly recorded and labelled in an in vitro rat Thalamic Slice preparation to investigate their projection into ventrobasal Thalamic nuclei (VB). Camera lucida reconstructions of 37 neurons indicated that nRt innervation ranges from a compact, focal projection to a widespread, diffuse projection encompassing large areas of VB. The main axons of 65% of the cells gave rise to intra-nRt collaterals prior to leaving the nucleus and, once within VB, ramified into one of three branching patterns: cluster, intermediate, and diffuse. The cluster arborization encompassed a focal region averagmg approximately 25,000 pm2 and contained a high density of axonal swellings, indicative of a topographic projection. The intermediate structure extended across an area approximately fourfold greater and also contained numerous axonal swellings. The diffuse arborization of nRt neurons covered a large region of VB and contained a relatively low density of axonal swellings. Analysis of somatic size and shape revealed that diffuse arborizations arose from significantly smaller, fusiform-shaped somata. Cytochrome oxidase reactivity or parvalbumin immunoreactivity was used to delineate a discontinuous staining pattern representing Thalamic barreloids. The size of a cluster arborization closely approximated that of an individual barreloid. The heterogeneous arborizations from nRt neurons may reflect a dynamic range of inhibitory influences of nRt on dorsal Thalamic activity. IW~ Wilry-Liss, Inc.
Charles L. Cox - One of the best experts on this subject based on the ideXlab platform.
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Peptidergic Modulation of IntraThalamic Circuit Activity In Vitro: Actions of Cholecystokinin
2013Co-Authors: Charles L. Cox, John R. Huguenard, David A. PrinceAbstract:Cholecystokinin (CCK)-mediated actions on intraThalamic rhythmic activities were examined in an in vitro rat Thalamic Slice preparation. Single electrical stimuli in the Thalamic reticular nucleus (nRt) evoked rhythmic activity (1–15 sec duration) in nRt and the adjacent ventrobasal nucleus (VB). Low CCK concentrations (20–50 nM) suppressed rhythmic oscillations in 43 % of experiments but prolonged such activities in the remaining Slices. Higher CCK concentrations (100–400 nM) had a predominantly antioscillatory effect. Suppression of oscillations was associated with a relatively large membrane depolarization of nRt neurons that changed their firing mode from phasic (burst) to tonic (single-spike) output. This decreased burst discharge of nRt neurons during CCK application reduced inhibitory drive onto VB neurons from multiple peaked inhibitory postsynaptic currents (IPSCs) t
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Attenuation of inhibitory synaptic transmission by glial dysfunction in rat thalamus.
Synapse (New York N.Y.), 2011Co-Authors: Sunggu Yang, Charles L. CoxAbstract:The thalamus serves as the obligatory gateway to the neocortex for sensory processing, and also serves as a pathway for corticocortical communication. In addition, the reciprocal synaptic connectivity between the Thalamic reticular nucleus (TRN) and adjacent Thalamic relay nuclei generates rhythmic activities similar to that observed during different arousal states and certain neurological conditions such as absence epilepsy. Epileptiform activity can arise from a variety of neural mechanisms, but in addition glia are thought to have an important role in such activities as well. Glia serve a central role in glutamine synthesis, a precursor for glutamate or GABA in nerve terminals. While alterations in glutamine shuttling from glia to neurons can influence GABA and glutamate neurotransmission; the consequences of such action on synaptic transmission and subsequent network activities within Thalamic circuits is less understood. We investigated the consequences of altering glutamine transport on inhibitory transmission and intraThalamic activities using the in vitro Thalamic Slice preparation. Disruption of the glutamine shuttling by the neuronal glutamine transporter (system A transporter) antagonist, α-(methylamino)isobutyric acid (MeAIB), or the selective gliotoxic drug, fluorocitric acid (Fc) dramatically decreased intraThalamic rhythmic activities. At the single cell level, MeAIB and Fc significantly attenuated electrically evoked inhibitory postsynaptic currents (eIPSCs) in Thalamic relay neurons; however, miniature IPSCs were unaffected. These data indicate that glutamate-glutamine shuttle is critical for sustaining Thalamic synaptic transmission, and thereby alterations in this shuttle can influence intraThalamic rhythmic activities associated with absence epilepsy.
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Modulation of Thalamic neuron excitability by orexins
Neuropharmacology, 2006Co-Authors: Gubbi Govindaiah, Charles L. CoxAbstract:Orexins (hypocretins) are peptides of hypoThalamic origin that play an important role in maintaining wakefulness. Reduced orexin levels have been associated with an increased incidence of narcolepsy. Considering Thalamic nuclei are interconnected with virtually all neocortical regions and the thalamus has been found to produce distinct activities related to different levels of arousal, we have examined the actions of orexins on Thalamic neurons using an in vitro Thalamic Slice preparation. The orexins (orexin-A and orexin-B) produced distinct actions within different intralaminar nuclei. Orexin-B strongly depolarized the majority of centrolateral nucleus (CL) neurons (71%), but depolarized a significantly smaller population of parafascicular nuclei (Pf) neurons (10%). In the mediodorsal Thalamic nucleus (MD), orexin-B depolarized 21% of the neurons tested. Overall, orexin-B was found to be more potent than Orexin-A. Orexin-A depolarized a significantly smaller population of CL neurons (23%), but had no effect on Pf neurons. In addition, orexin-A produced a small depolarization in 28% of neurons in the Thalamic reticular nucleus (TRN). Both orexin-A and orexin-B had no effect on neurons in the lateral posterior (LP), lateralodorsal (LD), posterior Thalamic (Po), ventrobasal (VB) nucleus and lateral geniculate nucleus (LGN). The depolarizing actions of orexins were sufficient to alter the firing mode of these neurons from a burst- to tonic-firing mode. The excitatory actions of orexin-B result from a decrease in the apparent leak potassium current (Kleak). The orexin-B mediated excitation was also attenuated by bupivacaine suggesting the involvement of Kleak current. Further, the actions of orexin-B were occluded by the classical neurotransmitter dopamine, indicating the orexins may share similar ionic mechanisms. Thus, the depolarizing actions of orexins may play a key role in altering the firing mode of Thalamic neurons associated with different states of consciousness.
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Fourier Analysis of Sinusoidally Driven Thalamocortical Relay Neurons and a Minimal Integrate-and-Fire-or-Burst Model
Journal of neurophysiology, 2000Co-Authors: Gregory D. Smith, Charles L. Cox, S. Murray Sherman, John RinzelAbstract:We performed intracellular recordings of relay neurons from the lateral geniculate nucleus of a cat Thalamic Slice preparation. We measured responses during both tonic and burst firing modes to sin...
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Peptidergic Modulation of IntraThalamic Circuit Activity In Vitro: Actions of Cholecystokinin
The Journal of neuroscience : the official journal of the Society for Neuroscience, 1997Co-Authors: Charles L. Cox, John R. Huguenard, David A. PrinceAbstract:Cholecystokinin (CCK)-mediated actions on intraThalamic rhythmic activities were examined in an in vitro rat Thalamic Slice preparation. Single electrical stimuli in the Thalamic reticular nucleus (nRt) evoked rhythmic activity (1‐15 sec duration) in nRt and the adjacent ventrobasal nucleus (VB). Low CCK concentrations (20‐50 nM) suppressed rhythmic oscillations in 43% of experiments but prolonged such activities in the remaining Slices. Higher CCK concentrations (100‐400 nM) had a predominantly antioscillatory effect. Suppression of oscillations was associated with a relatively large membrane depolarization of nRt neurons that changed their firing mode from phasic (burst) to tonic (single-spike) output. This decreased burst discharge of nRt neurons during CCK application reduced inhibitory drive onto VB neurons from multiple peaked inhibitory postsynaptic currents (IPSCs) to single peaked inhibitory events. We hypothesize that suppression of inhibitory drive onto VB neurons decreases their probability of burst output, which, together with a reduction of nRt burst output, dampens the oscillatory activity. Low CCK concentrations, which produced little or no depolarization of nRt neurons, did not alter the firing mode of the nRt neurons. However, the probability of burst output from nRt neurons in response to subthreshold stimuli was increased in low CCK concentrations, presumably leading to an increase in the number of nRt neurons participating in the rhythmic activity. Ourfindings suggest that the neuropeptide CCK, by altering the firing characteristics of nRt neurons, has powerful modulatory effects on intraThalamic rhythms; the ultimate action was dependent on CCK concentration and resting state of these cells.
John Rinzel - One of the best experts on this subject based on the ideXlab platform.
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Fourier Analysis of Sinusoidally Driven Thalamocortical Relay Neurons and a Minimal Integrate-and-Fire-or-Burst Model
Journal of neurophysiology, 2000Co-Authors: Gregory D. Smith, Charles L. Cox, S. Murray Sherman, John RinzelAbstract:We performed intracellular recordings of relay neurons from the lateral geniculate nucleus of a cat Thalamic Slice preparation. We measured responses during both tonic and burst firing modes to sin...
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PROPAGATION OF SPINDLE WAVES IN A Thalamic Slice MODEL
Journal of neurophysiology, 1996Co-Authors: David Golomb, Xiao Jing Wang, John RinzelAbstract:1. We study the propagation and dynamics of spindle waves in Thalamic Slices by developing and analyzing a model of reciprocally coupled populations of excitatory thalamocortical (TC) neurons and inhibitory Thalamic reticular (RE) neurons. 2. Each TC neuron has three intrinsic ionic currents: a low-threshold T-type Ca+2 current (ICa-T), a hyperpolarization-activated cation ("sag") current (Ih) and a leak current. Each RE cell also has three currents: ICa-T, a leak current, and a calcium-activated potassium current (IAHP). Isolated TC cells are at rest, can burst when released or depolarized from a hyperpolarized level, and burst rhythmically under moderate constant hyperpolarizing current. Isolated RE cells are at a hyperpolarized resting membrane potential and can burst when depolarized. 3. TC cells excite RE cells with fast alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) synapses, and RE cells inhibit TC cells with fast gamma-aminobutyric acid-A (GABAA) and slow GABAB synapses and inhibit each other with GABAA synapses only. GABAB postsynaptic conductances operate far from saturation, and the slow inhibitory postsynaptic potentials (IPSPs) increase with the width of the presynaptic burst. The model network is a one-dimensional cellular array with localized coupling. The synaptic coupling strength decays with the distance between the pre- and postsynaptic cells, either exponentially or as a step function. 4. The "intact" network can oscillate with partial synchrony and a population frequency of approximately 10 Hz. RE cells emit bursts almost at every oscillation cycle, whereas TC cells do so almost at every other cycle. Block of GABAB receptors hardly changes the network behavior. Block of GABAA receptors leads the network to a slowed oscillatory state, where the population frequency is approximately 4 Hz and both RE and TC cells fire unusually long bursts at every cycle and in full synchrony. These results are consistent with the experimental observations of von Krosigk, Bal, and McCormick. We obtain such consistency only when the above assumptions regarding the synaptic dynamics, particularly nonsaturating GABAB synapses, are fulfilled. 5. The Slice model has a stable rest state with no neural activity. By initially depolarizing a few neurons at one end of the Slice while all the other cells are at rest, a recruitment process may be initiated, and a wavefront of oscillatory activity propagates across the Slice. Ahead of the wavefront, neurons are quiescent; neurons behind it oscillate. We find that the wave progresses forward in a lurching manner. TC cells that have just become inhibited must be hyperpolarized for a long enough time before they can fire rebound bursts and recruit RE cells. This step limits the wavefront velocity and may involve a substantial part of the cycle when no cells at the front are depolarized. 6. The wavefront velocity increases linearly with the characteristic spatial length of the connectivity (the footprint length). It increases only gradually with the synaptic strength, logarithmically in the case of an exponential connection function and only slightly for a step connection function. It also decreases gradually with a potassium leak conductance that hyperpolarizes RE cells. 7. To reproduce the experimentally measured wavefront velocity of approximately 1 mm/s, together with other in vitro observations, both the RE-to-TC and the TC-to-RE projections in the model should be spatially localized. The sum of the RE-to-TC and the TC-to-RE synaptic footprint lengths should be on the order of 100 microns. (ABSTRACT TRUNCATED AT 250 WORDS)
Emily Dilger - One of the best experts on this subject based on the ideXlab platform.
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Requirements for synaptically evoked plateau potentials in relay cells of the dorsal lateral geniculate nucleus of the mouse
The Journal of Physiology, 2011Co-Authors: Emily Dilger, Hee-sup Shin, William GuidoAbstract:Non-technical summary In the developing visual system, spontaneous retinal activity plays an important role in the refinement of retinal ganglion cell projections to the dorsal lateral geniculate nucleus (dLGN) of thalamus. How such changes are implemented remains unknown. Recordings of post-synaptic dLGN cell activity suggest that plateau-like, L-type Ca2+ channel-mediated depolarizations figure prominently in remodelling. Plateaus are developmentally regulated and their incidence is controlled by the changing patterns of excitatory and inhibitory connections onto dLGN cells. At early ages there is a high degree of retinal convergence, and excitatory post-synaptic events summate to produce depolarizations sufficient to activate plateaus. As these excitatory inputs are pruned and inhibitory connections emerge, the net excitatory drive is reduced and plateaus wane. Additionally, L-type channels are highly expressed at young ages, and subunit disruptions resulting in decreased expression also affect the incidence of plateaus. These studies help elucidate the mechanisms underlying activity-dependent refinement of sensory connections. Abstract In developing cells of the mouse dorsal lateral geniculate nucleus (dLGN), synaptic responses evoked by optic tract (OT) stimulation give rise to long-lasting, high-amplitude depolarizations known as plateau potentials. These events are mediated by L-type Ca2+ channels and occur during early postnatal life, a time when retinogeniculate connections are remodelling. To better understand the relationship between L-type activity and dLGN development we used an in vitro Thalamic Slice preparation which preserves the retinal connections and intrinsic circuitry in dLGN and examined how synaptic responses evoked by OT stimulation lead to the activation of plateau potentials. By varying the strength and temporal frequency of OT stimulation we identified at least three factors that contribute to the developmental regulation of plateau activity: the degree of retinal convergence, the temporal pattern of retinal stimulation and the emergence of feed-forward inhibition. Before natural eye opening (postnatal day 14), the excitatory synaptic responses of relay cells receiving multiple retinal inputs summated in both the spatial and temporal domains to produce depolarizations sufficient to activate L-type activity. After eye opening, when inhibitory responses are fully developed, plateau activity was rarely evoked even with high temporal rates of OT stimulation. When the bulk of this inhibition was blocked by bath application of bicuculline, the incidence of plateau activity increased significantly. We also made use of a transgenic mouse that lacks the β3 subunit of the L-type Ca2+ channel. These mutants have far fewer membrane-bound Ca2+ channels and attenuated L-type activity. In β3 nulls, L-type plateau activity was rarely observed even at young ages when plateau activity prevails. Thus, in addition to the changing patterns of synaptic connectivity and retinal activity, the expression of L-type Ca2+ channels is a requisite component in the manifestation of plateau activity.
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Requirements for synaptically evoked plateau potentials in relay cells of the dorsal lateral geniculate nucleus of the mouse.
The Journal of physiology, 2010Co-Authors: Emily Dilger, Hee-sup Shin, William GuidoAbstract:In developing cells of the mouse dorsal lateral geniculate nucleus (dLGN), synaptic responses evoked by optic tract (OT) stimulation give rise to long-lasting, high-amplitude depolarizations known as plateau potentials. These events are mediated by L-type Ca2+ channels and occur during early postnatal life, a time when retinogeniculate connections are remodelling. To better understand the relationship between L-type activity and dLGN development we used an in vitro Thalamic Slice preparation which preserves the retinal connections and intrinsic circuitry in dLGN and examined how synaptic responses evoked by OT stimulation lead to the activation of plateau potentials. By varying the strength and temporal frequency of OT stimulation we identified at least three factors that contribute to the developmental regulation of plateau activity: the degree of retinal convergence, the temporal pattern of retinal stimulation and the emergence of feed-forward inhibition. Before natural eye opening (postnatal day 14), the excitatory synaptic responses of relay cells receiving multiple retinal inputs summated in both the spatial and temporal domains to produce depolarizations sufficient to activate L-type activity. After eye opening, when inhibitory responses are fully developed, plateau activity was rarely evoked even with high temporal rates of OT stimulation. When the bulk of this inhibition was blocked by bath application of bicuculline, the incidence of plateau activity increased significantly. We also made use of a transgenic mouse that lacks the β3 subunit of the L-type Ca2+ channel. These mutants have far fewer membrane-bound Ca2+ channels and attenuated L-type activity. In β3 nulls, L-type plateau activity was rarely observed even at young ages when plateau activity prevails. Thus, in addition to the changing patterns of synaptic connectivity and retinal activity, the expression of L-type Ca2+ channels is a requisite component in the manifestation of plateau activity.