Tilman Broicher
Research interests
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InterestsElectrophysiology, Neurophysiology, Neurobiology, Neuropharmacology, Patch-clamp electrophysiology, Ion Channels, Patch-Clamp Techniques, Dynamic-Clamp
Publications
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7.18Impact points
Membrane voltage fluctuations reduce spike frequency adaptation and preserve output gain in CA1 pyramidal neurons in a high-conductance state.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 03/2011; 31(10):3880-93.
Modulating the gain of the input-output function of neurons is critical for processing of stimuli and network dynamics. Previous gain control mechanisms have suggested that voltage fluctuations play a key role in determining neuronal gain in vivo. Here we show that, under increased membrane conducta... [more] Modulating the gain of the input-output function of neurons is critical for processing of stimuli and network dynamics. Previous gain control mechanisms have suggested that voltage fluctuations play a key role in determining neuronal gain in vivo. Here we show that, under increased membrane conductance, voltage fluctuations restore Na(+) current and reduce spike frequency adaptation in rat hippocampal CA1 pyramidal neurons in vitro. As a consequence, membrane voltage fluctuations produce a leftward shift in the frequency-current relationship without a change in gain, relative to an increase in conductance alone. Furthermore, we show that these changes have important implications for the integration of inhibitory inputs. Due to the ability to restore Na(+) current, hyperpolarizing membrane voltage fluctuations mediated by GABA(A)-like inputs can increase firing rate in a high-conductance state. Finally, our data show that the effects on gain and synaptic integration are mediated by voltage fluctuations within a physiologically relevant range of frequencies (10-40 Hz).
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3.70Impact points
A-type K+ currents in intralaminar thalamocortical relay neurons.
Pflügers Archiv : European journal of physiology. 03/2011; 461(5):545-56.
Transient A-type K+ currents (I(A)) are known to influence the firing pattern of a number of thalamic cell types, but have not been investigated in intralaminar thalamocortical (TC) relay neurons yet. We therefore combined whole-cell patch-clamp techniques, PCR analysis, and immunohistochemistry to ... [more] Transient A-type K+ currents (I(A)) are known to influence the firing pattern of a number of thalamic cell types, but have not been investigated in intralaminar thalamocortical (TC) relay neurons yet. We therefore combined whole-cell patch-clamp techniques, PCR analysis, and immunohistochemistry to investigate the voltage-dependent and pharmacological properties of I(A) and to determine its molecular basis in TC neurons from the centrolateral, paracentral, and centromedial thalamic nuclei. I(A) revealed half-maximal (V (h)) activation and inactivation at about -17 and -67 mV, respectively. At a concentration of 5-10 mM 4-aminopyridine (4-AP) completely blocked I(A). Furthermore, I(A) was nearly unaffected by two sea anemone toxins (blood depressing substances 1 and 2, BDS1 and BDS2; 6-8% block at a concentration of 1 μM) but strongly sensitive to the K(V)4 channel blocker Heteropoda venatoria toxin 2 (HpTx2; about 45% block at a concentration of 5 μM). PCR screening revealed the expression of K(V)4.1-4.3, with strongest expression for K(V)4.2 and weak expression for K(V)4.1. Accordingly K(V)4.1 was not detected in immunohistochemical staining. Furthermore, K(V)4.2 and K(V)4.3 revealed mainly dendritic and somatic staining, respectively. Together with current clamp recordings, these findings point to a scenario where the fast transient I(A) in intralaminar TC neurons has a depolarized threshold at potentials negative to -50 mV, is substantially generated by K(V)4.2 and K(V)4.3 channels, allows prominent burst firing at hyperpolarized potentials, prevents the generation of high-threshold potentials, generates a delayed onset of firing at more depolarized potentials, and allows fast tonic firing.
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Activity Modes in Thalamocortical Relay Neurons are Modulated by G(q)/G(11) Family G-proteins - Serotonergic and Glutamatergic Signaling.
Frontiers in cellular neuroscience. 01/2010; 4:132.
In thalamocortical relay (TC) neurons, G-protein-coupled receptors play an important part in the control of activity modes. A conditional Gα(q) knockout on the background of a constitutive Gα(11) knockout (Gα(q)/Gα(11) (-/-)) was used to determine the contribution of Gq/G11 family G-proteins to meta... [more] In thalamocortical relay (TC) neurons, G-protein-coupled receptors play an important part in the control of activity modes. A conditional Gα(q) knockout on the background of a constitutive Gα(11) knockout (Gα(q)/Gα(11) (-/-)) was used to determine the contribution of Gq/G11 family G-proteins to metabotropic serotonin (5-HT) and glutamate (Glu) function in the dorsal part of the lateral geniculate nucleus (dLGN). In control mice, current clamp recordings showed that α-m-5-HT induced a depolarization of V(rest) which was sufficient to suppress burst firing. This depolarization was concentration-dependent (100 μM: +6 ± 1 mV, n = 10; 200 μM: +10 ± 1 mV, n = 7) and had a conditioning effect on the activation of other Gα(q)-mediated pathways. The depolarization was significantly reduced in Gα(q)/Gα(11) (-/-) (100 μM: 3 ± 1 mV, n = 11; 200 μM: 5 ± 1 mV, n = 6) and was apparently insufficient to suppress burst firing. Activating Gα(q)-coupled muscarinic receptors affected the magnitude of α-m-5-HT-induced effects in a reciprocal manner. Furthermore, the depolarizing effect of mGluR1 agonists was significantly reduced in Gα(q)/Gα(11) (-/-) mice. Immunohistochemical stainings revealed binding of 5-HT(2C)R- and mGluR1α-, but not of 5-HT(2A)R-specific antibodies in the dLGN of Gα(q)/Gα(11) (-/-) mice. In conclusion, these findings demonstrate that transmitters of ascending brainstem fibers and corticofugal fibers both signal via a central element in the form of Gq/G11-mediated pathways to control activity modes in the TC system.
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3.29Impact points
Thalamic afferent activation of supragranular layers in auditory cortex in vitro: a voltage sensitive dye study.
Neuroscience. 10/2009;
We studied auditory thalamocortical interactions in vitro, using an auditory thalamocortical brain slice preparation. Cortical activity evoked by electrical stimulation of the medial geniculate nucleus (MGN) was investigated through field potential recordings and voltage sensitive dyes. Experiments ... [more] We studied auditory thalamocortical interactions in vitro, using an auditory thalamocortical brain slice preparation. Cortical activity evoked by electrical stimulation of the medial geniculate nucleus (MGN) was investigated through field potential recordings and voltage sensitive dyes. Experiments were performed in slices obtained from adult mice (9-14 weeks). Stimulus evoked activity was detected in the granular and supragranular layers after a short latency (5-6 ms). In 9-14 weeks old mice infragranular activity was detected in 10 of 24 preparations and was found to be increased in younger mice (p 31-64). In 14 of 24 slices a prominent horizontal spread was observed, which extended into cortical areas lateral to A1. In these experiments, the shortest onset latencies and largest signal amplitudes were located in the supragranular layers of A1. In areas lateral to A1, shortest onset latencies were located in the granular layer, while largest signal amplitudes were found in the supragranular layers. Evoked cortical activity was sensitive to removal of extracellular Ca(2+) or application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 muM). Short repetitive stimulation, resembling thalamic burst activity (three pulses at 100 Hz), resulted in an increase of signal amplitude and excited area by approximately 25%, without changing the overall spatiotemporal activity profile. Blockade of N-methyl-d-aspartate receptors by 2-amino-5-phosphonopentanoate (AP5, 50 muM) reduced amplitudes and excited area by approximately 15-30%, irrespective of stimulation frequency. Application of bicuculline (10 muM) greatly increased cortical responses to thalamic stimulation. Under these conditions, evoked activity displayed a pronounced horizontal spread in combination with a 2-3-fold increase in amplitude. In conclusion, afferent thalamic inputs primarily activate supragranular and granular layers in the auditory cortex of adult mice. This activation is predominantly mediated by non-NMDA receptors, while GABA(A) receptor-mediated inhibition limits the horizontal and vertical spread of activity.
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4.52Impact points
The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice.
Neurobiology of disease. 10/2008;
Oxygen depletion (O(2)) and a decrease in pH are initial pathophysiological events in stroke development, but secondary mechanisms of ischemic cell death are incompletely understood. By patch-clamp recordings of brain slice preparations we show that TASK1 and TASK3 channels are inhibited by pH-reduc... [more] Oxygen depletion (O(2)) and a decrease in pH are initial pathophysiological events in stroke development, but secondary mechanisms of ischemic cell death are incompletely understood. By patch-clamp recordings of brain slice preparations we show that TASK1 and TASK3 channels are inhibited by pH-reduction (42+/-2%) and O(2) deprivation (36+/-5%) leading to membrane depolarization, increased input resistance and a switch in action potential generation under ischemic conditions. In vivo TASK blockade by anandamide significantly increased infarct volumes at 24 h in mice undergoing 30 min of transient middle cerebral artery occlusion (tMCAO). Moreover, blockade of TASK channels accelerated stroke development. Supporting these findings TASK1(-/-) mice developed significantly larger infarct volumes after tMCAO accompanied by worse outcome in functional neurological tests compared to wild type mice. In conclusion, our data provide evidence for an important role of functional TASK channels in limiting tissue damage during cerebral ischemia.
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3.57Impact points
Correlation of T-channel coding gene expression, I(T), and the low threshold Ca(2+) spike in the thalamus of a rat model of absence epilepsy.
Molecular and cellular neurosciences. 08/2008;
T-type Ca(2+) current-dependent burst firing of thalamic neurons is thought to be involved in the hyper-synchronous activity observed during absence seizures. Here we investigate the correlation between the expression of T-channel coding genes (alpha1G, -H, -I), T-type Ca(2+) current, and the T-curr... [more] T-type Ca(2+) current-dependent burst firing of thalamic neurons is thought to be involved in the hyper-synchronous activity observed during absence seizures. Here we investigate the correlation between the expression of T-channel coding genes (alpha1G, -H, -I), T-type Ca(2+) current, and the T-current-dependent low threshold Ca(2+) spike in three functionally distinct thalamic nuclei (lateral geniculate nucleus; centrolateral nucleus; reticular nucleus) in a rat model of absence epilepsy, the WAG/Rij rats, and a non-epileptic control strain, the ACI rats. The lateral geniculate nucleus and centrolateral nucleus were found to primarily express alpha1G and alpha1I, while the reticular thalamic nucleus expressed alpha1H and alpha1I. Expression was higher in WAG/Rij when compared to ACI. The T-type Ca(2+) current properties matched the predictions derived from the expression pattern analysis. Current density was larger in all nuclei of WAG/Rij rats when compared to ACI and correlated with LTS size and the minimum LTS generating slope, while T-type Ca(2+) current voltage dependency correlated with the LTS onset potential.
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3.70Impact points
Muscarinic ACh receptor-mediated control of thalamic activity via G(q)/G (11)-family G-proteins.
Pflugers Archiv : European journal of physiology. 04/2008;
A genetic knock out was used to determine the specific contribution of G(q)/G(11)-family G-proteins to the function of thalamocortical relay (TC) neurons. Disruption of Galpha(q) function in a conditional forebrain-specific Galpha(q)/Galpha(11)-double-deficient mouse line [Formula: see text] had no ... [more] A genetic knock out was used to determine the specific contribution of G(q)/G(11)-family G-proteins to the function of thalamocortical relay (TC) neurons. Disruption of Galpha(q) function in a conditional forebrain-specific Galpha(q)/Galpha(11)-double-deficient mouse line [Formula: see text] had no effects on the resting membrane potential (V (rest)) and the amplitude of the standing outward current (I (SO)). Stimulation of muscarinic acetylcholine (ACh) receptors (mAChR; muscarine, 50 muM) induced a decrease in I (SO) amplitude in wild-type mice (36 +/- 4%, n = 5), a constitutive Galpha(11)-deficient mouse line ([Formula: see text]; 36 +/- 3%, n = 8), and [Formula: see text] (11 +/- 2%, n = 16). Current-clamp recordings revealed a muscarine-induced positive shift in V (rest) of 23 +/- 2 mV (n = 6), 18 +/- 5 mV (n = 5), and 2 +/- 1 mV (n = 9) in wild type, [Formula: see text], and [Formula: see text], respectively. This depolarization was associated with a change in TC neuron activity from burst to tonic firing in wild type and [Formula: see text], but not in [Formula: see text]. The use of specific antibodies and of pharmacological agents with preferred affinity points to the contribution of m(1)AChR and m(3)AChR. In conclusion, we present two novel aspects of the physiology of the thalamocortical system by demonstrating that the depolarization of TC neurons, which is induced by the action of transmitters of ascending brainstem fibers, is governed roughly equally by both m(1)AChR and m(3)AChR and is transduced by Galpha(q) but not by Galpha(11).
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3.57Impact points
Specific expression of low-voltage-activated calcium channel isoforms and splice variants in thalamic local circuit interneurons.
Molecular and cellular neurosciences. 11/2007; 36(2):132-45.
It has been suggested that the specific burst firing patterns of thalamic neurons reflect differential expression of low-voltage-activated (LVA) Ca(2+) channel subtypes and their splice variants. By combining electrophysiological, molecular biological, immunological, and computational modeling techn... [more] It has been suggested that the specific burst firing patterns of thalamic neurons reflect differential expression of low-voltage-activated (LVA) Ca(2+) channel subtypes and their splice variants. By combining electrophysiological, molecular biological, immunological, and computational modeling techniques we here show that diverging LVA Ca(2+) currents of thalamocortical relay (TC) and GABAergic interneurons of the dLGN correlate with a differential expression of LVA Ca(2+) channel splice variations and isoforms (alpha1G-a in TC; alpha1G-bc and alpha1I in interneurons). Implementation of the observed LVA Ca(2+) current differences into a TC neuron model changed the burst firing from TC-like to interneuron-like. We conclude that alternative splicing of the alpha1G isoform in dLGN TC and interneurons, and the exclusive expression of the alpha1I isoform in interneurons play a prominent role in setting the different LVA Ca(2+) current properties of TC and interneurons, which critically contribute to the diverging burst firing behavior of these neurons.
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3.91Impact points
T-current related effects of antiepileptic drugs and a Ca2+ channel antagonist on thalamic relay and local circuit interneurons in a rat model of absence epilepsy.
Neuropharmacology. 09/2007; 53(3):431-46.
Channel blocking, anti-oscillatory, and anti-epileptic effects of clinically used anti-absence substances (ethosuximide, valproate) and the T-type Ca2+ current (IT) blocker mibefradil were tested by analyzing membrane currents in acutely isolated local circuit interneurons and thalamocortical relay ... [more] Channel blocking, anti-oscillatory, and anti-epileptic effects of clinically used anti-absence substances (ethosuximide, valproate) and the T-type Ca2+ current (IT) blocker mibefradil were tested by analyzing membrane currents in acutely isolated local circuit interneurons and thalamocortical relay (TC) neurons, slow intrathalamic oscillations in brain slices, and spike and wave discharges (SWDs) occurring in vivo in Wistar Albino Glaxo rats from Rijswijk (WAG/Rij). Substance effects in vitro were compared between WAG/Rij and a non-epileptic control strain, the ACI rats. Ethosuximide (ETX) and valproate were found to block IT in acutely isolated thalamic neurons. Block of IT by therapeutically relevant ETX concentrations (0.25-0.75 mM) was stronger in WAG/Rij, although the maximal effect at saturating concentrations (>or=10 mM) was stronger in ACI. Ethosuximide delayed the onset of the low threshold Ca2+ spike (LTS) of neurons recorded in slice preparations. Mibefradil (>or=2 microM) completely blocked IT and the LTS, dampened evoked thalamic oscillations, and attenuated SWDs in vivo. Computational modeling demonstrated that the complete effect of ETX can be replicated by a sole reduction of IT. However, the necessary degree of IT reduction was not induced by therapeutically relevant ETX concentrations. A combined reduction of IT, the persistent sodium current, and the Ca2+ activated K+ current resulted in an LTS alteration resembling the experimental observations. In summary, these results support the hypothesis of IT reduction as part of the mechanism of action of anti-absence drugs and demonstrate the ability of a specific IT antagonist to attenuate rhythmic burst firing and SWDs.
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3.42Impact points
Modulation of neuronal activity by the endogenous pentapeptide QYNAD.
The European journal of neuroscience. 12/2003; 18(10):2697-706.
Inflammation and demyelination both contribute to the neurological deficits characteristic of multiple sclerosis. Neurological dysfunctions are attributable to inflammatory demyelination and, in addition, to soluble factors such as nitric oxide, cytokines and antibodies. QYNAD, an endogenous pentape... [more] Inflammation and demyelination both contribute to the neurological deficits characteristic of multiple sclerosis. Neurological dysfunctions are attributable to inflammatory demyelination and, in addition, to soluble factors such as nitric oxide, cytokines and antibodies. QYNAD, an endogenous pentapeptide identified in the cerebrospinal fluid of patients with demyelinating disorders, has been proposed to promote axonal dysfunction by blocking sodium channels. The present study aimed at characterizing the properties of QYNAD in acutely isolated thalamic neurons in vitro. QYNAD, but not a scrambled peptide (NYDQA), blocked sodium channels in neurons by shifting the steady-state inactivation to more negative potentials. Blocking properties followed a dose-response curve with a maximum effect at 10 microm. A fluorescently labelled QYNAD analogue with retained biological activity specifically stained thalamic neurons, positive for type II sodium channels, thus demonstrating the specificity of QYNAD binding. Our study confirms and extends previous observations describing QYNAD as a potent sodium channel-blocking agent. These data as well as our preliminary observations in in vivo experiments in an animal model of inflammatory CNS demyelination warrant further in vivo studies in order to clarify the exact pathogenetic role of QYNAD in inflammatory neurological diseases.
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7.18Impact points
Contribution of TWIK-related acid-sensitive K+ channel 1 (TASK1) and TASK3 channels to the control of activity modes in thalamocortical neurons.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 08/2003; 23(16):6460-9.
The thalamocortical network is characterized by rhythmic burst activity during natural sleep and tonic single-spike activity during wakefulness. The change between these two activity modes is partially governed by transmitters acting on leak K+ currents in the thalamus, although the nature of the co... [more] The thalamocortical network is characterized by rhythmic burst activity during natural sleep and tonic single-spike activity during wakefulness. The change between these two activity modes is partially governed by transmitters acting on leak K+ currents in the thalamus, although the nature of the constituting ion channels is not yet known. In the present study, the contribution of members of the two-pore domain K+ channel family to the leak current was investigated using whole-cell patch-clamp techniques and molecular biological techniques. RT-PCR and in situ hybridization revealed the expression of TWIK-related acid-sensitive K+ channel 1 (TASK 1) and TASK3 channels in the rat dLGN. Voltage-clamp recordings of thalamocortical relay neurons in slice preparations demonstrated the existence of a current component sensitive to the TASK channel blocker bupivacaine, which reversed at the presumed K+ equilibrium potential, showed outward rectification, and contributed approximately 40% to the standing outward current at depolarized values of the membrane potential (-28 mV). The pharmacological profile was indicative of TASK channels, in that the current was sensitive to changes in extracellular pH, reduced by muscarine and increased by halothane, and these effects were occluded by a near-maximal action of bupivacaine. Pharmacological manipulation of this current under current-clamp conditions resulted in a shift between burst and tonic firing modes. It is concluded that TASK1 and TASK3 channels contribute to the muscarine- and halothane-sensitive conductance in thalamocortical relay neurons, thereby contributing to the change in the activity mode of thalamocortical networks observed during the sleep-wake cycle and on application of inhalational anesthetics.
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Thalamic afferent activation of supragranular layers in auditory cortex in vitro: a voltage sensitive dye study
Neuroscience.
We studied auditory thalamocortical interactions in vitro, using an auditory thalamocortical brain slice preparation. Cortical activity evoked by electrical stimulation of the medial geniculate nucleus (MGN) was investigated through field potential recordings and voltage sensitive dyes. Experiments ... [more] We studied auditory thalamocortical interactions in vitro, using an auditory thalamocortical brain slice preparation. Cortical activity evoked by electrical stimulation of the medial geniculate nucleus (MGN) was investigated through field potential recordings and voltage sensitive dyes. Experiments were performed in slices obtained from adult mice (9–14 weeks). Stimulus evoked activity was detected in the granular and supragranular layers after a short latency (5–6 ms). In 9–14 weeks old mice infragranular activity was detected in 10 of 24 preparations and was found to be increased in younger mice (p 31–64). In 14 of 24 slices a prominent horizontal spread was observed, which extended into cortical areas lateral to A1. In these experiments, the shortest onset latencies and largest signal amplitudes were located in the supragranular layers of A1. In areas lateral to A1, shortest onset latencies were located in the granular layer, while largest signal amplitudes were found in the supragranular layers. Evoked cortical activity was sensitive to removal of extracellular Ca2+ or application of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10 μM). Short repetitive stimulation, resembling thalamic burst activity (three pulses at 100 Hz), resulted in an increase of signal amplitude and excited area by ∼25%, without changing the overall spatiotemporal activity profile. Blockade of N-methyl-d-aspartate receptors by 2-amino-5-phosphonopentanoate (AP5, 50 μM) reduced amplitudes and excited area by ∼15–30%, irrespective of stimulation frequency. Application of bicuculline (10 μM) greatly increased cortical responses to thalamic stimulation. Under these conditions, evoked activity displayed a pronounced horizontal spread in combination with a 2–3-fold increase in amplitude. In conclusion, afferent thalamic inputs primarily activate supragranular and granular layers in the auditory cortex of adult mice. This activation is predominantly mediated by non-NMDA receptors, while GABAA receptor-mediated inhibition limits the horizontal and vertical spread of activity.
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The neuroprotective impact of the leak potassium channel TASK1 on stroke development in mice
Neurobiology of Disease.
Oxygen depletion (O2) and a decrease in pH are initial pathophysiological events in stroke development, but secondary mechanisms of ischemic cell death are incompletely understood. By patch-clamp recordings of brain slice preparations we show that TASK1 and TASK3 channels are inhibited by pH-reducti... [more] Oxygen depletion (O2) and a decrease in pH are initial pathophysiological events in stroke development, but secondary mechanisms of ischemic cell death are incompletely understood. By patch-clamp recordings of brain slice preparations we show that TASK1 and TASK3 channels are inhibited by pH-reduction (42 ± 2%) and O2 deprivation (36 ± 5%) leading to membrane depolarization, increased input resistance and a switch in action potential generation under ischemic conditions. In vivo TASK blockade by anandamide significantly increased infarct volumes at 24 h in mice undergoing 30 min of transient middle cerebral artery occlusion (tMCAO). Moreover, blockade of TASK channels accelerated stroke development. Supporting these findings TASK1−/− mice developed significantly larger infarct volumes after tMCAO accompanied by worse outcome in functional neurological tests compared to wild type mice. In conclusion, our data provide evidence for an important role of functional TASK channels in limiting tissue damage during cerebral ischemia.
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Correlation of T-channel coding gene expression, IT, and the low threshold Ca2+ spike in the thalamus of a rat model of absence epilepsy
Molecular and Cellular Neuroscience.
T-type Ca2+ current-dependent burst firing of thalamic neurons is thought to be involved in the hyper-synchronous activity observed during absence seizures. Here we investigate the correlation between the expression of T-channel coding genes (α1G, -H, -I), T-type Ca2+ current, and the T-current-depe... [more] T-type Ca2+ current-dependent burst firing of thalamic neurons is thought to be involved in the hyper-synchronous activity observed during absence seizures. Here we investigate the correlation between the expression of T-channel coding genes (α1G, -H, -I), T-type Ca2+ current, and the T-current-dependent low threshold Ca2+ spike in three functionally distinct thalamic nuclei (lateral geniculate nucleus; centrolateral nucleus; reticular nucleus) in a rat model of absence epilepsy, the WAG/Rij rats, and a non-epileptic control strain, the ACI rats. The lateral geniculate nucleus and centrolateral nucleus were found to primarily express α1G and α1I, while the reticular thalamic nucleus expressed α1H and α1I. Expression was higher in WAG/Rij when compared to ACI. The T-type Ca2+ current properties matched the predictions derived from the expression pattern analysis. Current density was larger in all nuclei of WAG/Rij rats when compared to ACI and correlated with LTS size and the minimum LTS generating slope, while T-type Ca2+ current voltage dependency correlated with the LTS onset potential.
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Activity Modes in Thalamocortical Relay Neurons are Modulated by G(q)/G(11) Family G-proteins - Serotonergic and Glutamatergic Signaling
Front Cell Neurosci, v.4, 132.
In thalamocortical relay (TC) neurons, G-protein-coupled receptors play an important part in the control of activity modes. A conditional Galpha(q) knockout on the background of a constitutive Galpha(11) knockout (Galpha(q)/Galpha(11) (-/-)) was used to determine the contribution of Gq/G11 family G-... [more] In thalamocortical relay (TC) neurons, G-protein-coupled receptors play an important part in the control of activity modes. A conditional Galpha(q) knockout on the background of a constitutive Galpha(11) knockout (Galpha(q)/Galpha(11) (-/-)) was used to determine the contribution of Gq/G11 family G-proteins to metabotropic serotonin (5-HT) and glutamate (Glu) function in the dorsal part of the lateral geniculate nucleus (dLGN). In control mice, current clamp recordings showed that alpha-m-5-HT induced a depolarization of V(rest) which was sufficient to suppress burst firing. This depolarization was concentration-dependent (100 muM: +6 +/- 1 mV, n = 10; 200 muM: +10 +/- 1 mV, n = 7) and had a conditioning effect on the activation of other Galpha(q)-mediated pathways. The depolarization was significantly reduced in Galpha(q)/Galpha(11) (-/-) (100 muM: 3 +/- 1 mV, n = 11; 200 muM: 5 +/- 1 mV, n = 6) and was apparently insufficient to suppress burst firing. Activating Galpha(q)-coupled muscarinic receptors affected the magnitude of alpha-m-5-HT-induced effects in a reciprocal manner. Furthermore, the depolarizing effect of mGluR1 agonists was significantly reduced in Galpha(q)/Galpha(11) (-/-) mice. Immunohistochemical stainings revealed binding of 5-HT(2C)R- and mGluR1alpha-, but not of 5-HT(2A)R-specific antibodies in the dLGN of Galpha(q)/Galpha(11) (-/-) mice. In conclusion, these findings demonstrate that transmitters of ascending brainstem fibers and corticofugal fibers both signal via a central element in the form of Gq/G11-mediated pathways to control activity modes in the TC system.
Following (1)
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Fernando R Fernandez
University of Utah
Topics (7)
