Extrasynaptic Receptors Research Articles

Extrasynaptic Neurotransmission as a Way of Modulating Neuronal Functions

Extrasynaptic Neurotransmission as a Way of Modulating Neuronal Functions

Functional localization of neurotransmitter receptors and synaptic inputs to mature neurons of the medial superior olive

Neurons of the medial superior olive (MSO) code for the azimuthal location of low-frequency sound sources via a binaural coincidence detection system operating on microsecond time scales. These neurons are morphologically simple and stereotyped, and anatomical studies have indicated a functional segregation of excitatory and inhibitory inputs between cellular compartments. It is thought that this morphological arrangement holds important implications for the computational task of these cells. To date, however, there has been no functional investigation into synaptic input sites or functional receptor distributions on mature neurons of the MSO. Here, functional neurotransmitter receptor maps for amino-3-hydroxyl-5-methyl-4-isoxazole propionate (AMPA), N-methyl-D-aspartate (NMDA), glycine (Gly), and ionotropic γ-aminobutyric acid (GABA(A)) receptors (Rs) were compared and complemented by their corresponding synaptic input map. We find in MSO neurons from postnatal day 20-35 gerbils that AMPARs and their excitatory inputs target the soma and dendrites. Functional GlyRs and their inhibitory inputs are predominantly refined to the somata, although a pool of functional GlyRs is present extrasynaptically on MSO dendrites. GABA(A)R responses are present throughout the cell but lack direct synaptic contact indicating an involvement in volume transmission. NMDARs are present both synaptically and extrasynaptically with an overall distribution similar to GlyRs. Interestingly, even at physiological temperatures these functional NMDARs can be potentiated by synaptically released Gly. The functional receptor and synaptic input maps produced here led to the identification of a cross talk between transmitter systems and raises the possibility that extrasynaptic receptors could be modulating leak conductances as a homeostatic mechanism.

Glutamate transporter dysfunction associated with nerve injury-induced pain in mice

Dysfunction at glutamatergic synapses has been proposed as a mechanism in the development of neuropathic pain. Here we sought to determine whether peripheral nerve injury-induced neuropathic pain results in functional changes to primary afferent synapses. Signs of neuropathic pain as well as an induction of glial fibrillary acidic protein in immunostained spinal cord sections 4 days after partial ligation of the sciatic nerve indicated the induction of neuropathic pain. We found that following nerve injury, no discernable change to kinetics of dl-α-amino-3-hydroxy-5-methylisoxazole-propionic acid (AMPA) or N-methyl-d-aspartate receptor (NMDAR)-mediated evoked excitatory postsynaptic currents (eEPSCs) could be observed in dorsal horn (lamina I/II) neurons compared with those of naïve mice. However, we did find that nerve injury was accompanied by slowed decay of the early phase of eEPSCs in the presence of glutamate transporter inhibition by the competitive nontransportable inhibitor dl-threo-β-benzyloxyaspartic acid (TBOA). Concomitantly, expression patterns for the two major glutamate transporters in the spinal cord, excitatory amino acid transporters (EAAT) 1 and EAAT2, were found to be reduced at this time (4 days postinjury). We then sought to directly determine whether nerve injury results in glutamate spillover to NMDARs at dorsal horn synapses. By employing the use-dependent NMDAR blocker (±)MK-801 to block subsynaptic receptors, we found that although TBOA-induced spillover to extrasynaptic receptors trended to increased activation of these receptors after nerve injury, this was not significant compared with naïve mice. Together, these results suggest the development of neuropathic pain involves subtle changes to glutamate transporter expression and function that could contribute to neuropathic pain during excessive synaptic activity.

Glutamate Spillover Promotes the Generation of NMDA Spikes

NMDA spikes are prominent in the basal dendrites of cortical pyramidal neurons and greatly expand their ability to integrate synaptic inputs. Calcium (Ca) signals during these spikes are important for synaptic plasticity and fundamentally depend on activation of NMDA receptors. However, the factors that shape the activation of these receptors and the initiation of NMDA spikes remain unclear. Here we examine the properties of NMDA spikes in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two-photon imaging, we demonstrate that NMDA spikes evoke large Ca signals in both postsynaptic spines and nearby dendrites. We find that the dendrite Ca signals depend on NMDA and AMPA receptors but not sodium (Na) or Ca channels. Using voltage-clamp recordings, we show that activation of dendrite NMDA receptors is enhanced by concerted synaptic activity. Blocking glutamate reuptake further increases activation of these receptors and promotes the initiation of NMDA spikes. We conclude that glutamate spillover and recruitment of extrasynaptic receptors contribute to the initiation of NMDA spikes. These results have important implications for how synaptic activity generates both electrical and biochemical signals in dendrites and spines.

New insights on the molecular features and electrophysiological properties of dinotefuran, imidacloprid and acetamiprid neonicotinoid insecticides

Structural features and hydrogen-bond interactions of dinotefuran (DIN), imidacoloprid (IMI) and acetamiprid (ACE) have been investigated experimentally through analyses of new crystal structures and observations in structural databases, as well as by Density Functional Theory quantum chemical calculations. Several conformations are observed experimentally in the solid state, highlighting the large flexibility of these compounds. This feature is confirmed by the theoretical calculations in the gas phase, the numerous and different energetic minima of the three neonicotinoids being located within a 10kJ/mol range. Comparisons of the observed and simulated data sheds light on the hydrogen-bond (HB) strength of the functional group at the tip of the electronegative fragment of each pharmacophore (NO2 for DIN and IMI and CN for ACE). This effect originates in the ‘push–pull’ nature of these fragments and the related extensive electron delocalization. Molecular electrostatic potential calculations provide a ranking of the two fragments of the three neonicotinoid in terms of HB strength. Thus, the NO2 group of DIN is the strongest HB acceptor of the electronegative fragment, closely followed by the cyano group of ACE. These two groups are significantly more potent than the NO2 group of IMI. With respect to the other fragments of the three neonicotinoids, the nitrogen atom of the pyridine of IMI and ACE are stronger HB acceptors than the oxygen atom of the furanyl moiety of DIN. Finally, compared to electrophysiological studies obtained from cockroach synaptic and extrasynaptic receptors, DIN appears more effective than IMI and ACE because it strongly increases dose-dependently the ganglionic depolarisation and the currents amplitudes. These data suggest that DIN, IMI and ACE belong to two subgroups which act differently as agonists of insect nicotinic receptors.

Cerebellar Golgi cell inhibition gets slowly more complicated

The cellular architecture of the cerebellum that was so beautifully described by Ramon y Cajal (1899) offers one of the most complete systems for understanding how networks of excitatory and inhibitory neurons interact with one another to control the flow of sensory information in the mammalian brain. However, despite decades of anatomical and electrophysiological studies, this relatively simple and well-defined neuronal circuit still holds a few surprises. For example, in a recent issue of The Journal of Physiology, Holtzman and colleagues (2011) demonstrate some unusual features of cerebellar Golgi cell function. Our view of cerebellar Golgi cells has, in many respects, changed very little since Eccles first described the basic features of feed-forward and feed-back inhibition of granule cells by Golgi cell interneurons in the 1960s (Eccles, 1964). Cerebellar Golgi cells are one of the few cell types that can control granule cell firing within the cerebellar cortex due to their ability to release the inhibitory neurotransmitter γ-aminobutyric acid (GABA) onto both synaptic and extrasynaptic GABAA receptors that are expressed on granule cells (Brickley et al. 1996; Crowley et al. 2009). The current study is concerned with the excitatory drive onto Golgi cells that triggers the release of this GABA onto granule cells. Excitatory drive onto Golgi cells arises from glutamatergic mossy fibre inputs that convey sensory information into the cerebellar cortex (Kanichay & Silver, 2008), and from the glutamate released from granule cell axons that form the parallel fibre inputs onto Golgi cell dendrites (Dieudonne, 1998). It is this feedback loop involving the mossy-fibre → granule cell → Golgi cell → granule cell circuit that has been the focus of attention for the current study. Holtzmann et al. used in vivo recording techniques to monitor action potential firing patterns from Golgi cells during parallel fibre stimulation. In this way they confirmed an observation that was first made in an acute in vitro slice preparation of the cerebellum (Watanbe & Nakanishi, 2003) that the release of glutamate from granule cells leads to a decrease in Golgi cell firing through activation of mGluR2 receptors. This contradicts the classical view that granule cells serve only to excite Golgi cells. The decrease in Golgi firing that occurs following parallel fibre input lasts for hundreds of milliseconds, resulting in a conspicuous disinhibition of granule cells. This sustained depression of Golgi cell firing has been reported previously in vivo (Vos et al. 1999; Holtzman et al. 2006), but the authors have now confirmed the involvement of mGluR2 activation in this process. Moreover, the authors now show that it is possible to trigger this mGluR2-mediated disinhibition by modulating granule cell excitability through an enhancement of the tonic inhibition that is present on granule cells. In this study, tonic inhibition of granule cells was enhanced using the application of the GABA agonist gaboxadol (or THIP) that is known to have a selective action on extrasynaptic GABAA receptors that contain the delta subunit when used at sub-micromolar concentrations. Obviously, in an in vivo study of this type it is difficult to establish the effective concentration of the drug within the cerebellum, but it would appear that increased glutamate release from granule cells can lead to mGluR2 activation and, therefore, inhibition of Golgi cell firing. The authors further speculate that a spillover-type mechanism is involved in this glutamate activation of mGluR receptors on Golgi cells in an analogous manner to the GABA activation of extrasynaptic GABAA receptors. Spillover refers to the fact that glutamate diffuses out of the synaptic cleft to activate mGluR2 receptors located some distance away from the synapse. Binding of this ‘escaped’ glutamate to mGluR2 receptors is assumed to reduce Golgi cell firing due to an increased potassium permeability associated with activation of this G-protein-coupled receptor. However, an involvement of other mechanisms such as electrical coupling via gap-junctions cannot be ruled out at this stage (e.g. Vervaeke et al. 2010). Nevertheless, it is interesting to speculate that this form of slow intercellular signalling may support oscillations in granule cell firing such that modulation of granule cell activity levels over such slow time-scales are matched to incoming sensory inputs of the type observed during sleep and certain types of behaviour (Dugueet al. 2009; Roset al. 2009). Given the importance of the cerebellar cortex in the acquisition of new motor skills, an important challenge for the future will be to determine how these types of intercellular signalling mechanisms may impact upon granule cell firing during motor learning tasks.

Distribution pattern of extrasynaptic NMDA receptors is developmentally regulated

Distribution pattern of extrasynaptic NMDA receptors is developmentally regulated

Pathophysiology of Huntington's disease: time-dependent alterations in synaptic and receptor function.

Huntington's disease (HD) is a progressive, fatal neurological condition caused by an expansion of CAG (glutamine) repeats in the coding region of the Huntington gene. To date, there is no cure but great strides have been made to understand pathophysiological mechanisms. In particular, genetic animal models of HD have been instrumental in elucidating the progression of behavioral and physiological alterations, which had not been possible using classic neurotoxin models. Our groups have pioneered the use of transgenic HD mice to examine the excitotoxicity hypothesis of striatal neuronal dysfunction and degeneration, as well as alterations in excitation and inhibition in striatum and cerebral cortex. In this review, we focus on synaptic and receptor alterations of striatal medium-sized spiny (MSNs) and cortical pyramidal neurons in genetic HD mouse models. We demonstrate a complex series of alterations that are region-specific and time-dependent. In particular, many changes are bidirectional depending on the degree of disease progression, that is, early vs. late, and also on the region examined. Early synaptic dysfunction is manifested by dysregulated glutamate release in striatum followed by progressive disconnection between cortex and striatum. The differential effects of altered glutamate release on MSNs originating the direct and indirect pathways is also elucidated, with the unexpected finding that cells of the direct striatal pathway are involved early in the course of the disease. In addition, we review evidence for early N-methyl-D-aspartate receptor (NMDAR) dysfunction leading to enhanced sensitivity of extrasynaptic receptors and a critical role of GluN2B subunits. Some of the alterations in late HD could be compensatory mechanisms designed to cope with early synaptic and receptor dysfunctions. The main findings indicate that HD treatments need to be designed according to the stage of disease progression and should consider regional differences.

Upregulation of extrasynaptic GABAA receptors and PSD-95 in the nucleus accumbens may be responsible for animal model of major depressive disorder

Upregulation of extrasynaptic GABAA receptors and PSD-95 in the nucleus accumbens may be responsible for animal model of major depressive disorder

S17 * ALCOHOL AND GABAA RECEPTORS * S17.1 * EXTRASYNAPTIC GABAA-RS: PHARMACOLOGY AND REGULATION OF GENE EXPRESSION

S17 * ALCOHOL AND GABAA RECEPTORS * S17.1 * EXTRASYNAPTIC GABAA-RS: PHARMACOLOGY AND REGULATION OF GENE EXPRESSION

Effects of glial release and somatic receptors on bursting in synchronized neuronal networks

A model is constructed to study the phenomenon of bursting in cultured neuronal networks by considering the effects of glial release and the extrasynaptic receptors on neurons. In the frequently observed situations of synchronized bursting, the whole neuronal network can be described by a mean-field model. In this model, the dynamics of the synchronized network in the presence of glia is represented by an effective two-compartment neuron with stimulations on both the dendrite and soma. Numerical simulations of this model show that most of the experimental observations in bursting, in particular the high plateau and the slow repolarization, can be reproduced. Our findings suggest that the effects of glia release and extrasynaptic receptors, which are usually neglected in neuronal models, can become important in intense network activities. Furthermore, simulations of the model are also performed for the case of glia-suppressed cultures to compare with recent experimental results.

Alteration of Ethanol Drinking in Mice via Modulation of the GABAA Receptor with Ganaxolone, Finasteride, and Gaboxadol

Neurosteroids and other γ-aminobutyric acid(A) (GABA(A) ) receptor-modulating compounds have been shown to affect ethanol intake, although their mechanism remains unclear. This study examined how patterns of 24-hour ethanol drinking in mice were altered with the synthetic GABAergic neurosteroid ganaxolone (GAN), with an inhibitor of neurosteroid synthesis (finasteride [FIN]), or a GABA(A) receptor agonist with some selectivity at extrasynaptic receptors (gaboxadol HCL [THIP]). Male C57BL/6J mice had continuous access to a 10% v/v ethanol solution (10E) or water. Using lickometer chambers, drinking patterns were analyzed among mice treated in succession to GAN (0, 5, and 10 mg/kg), FIN (0 or 100 mg/kg), and THIP (0, 2, 4, 8, and 16 mg/kg). GAN shifted drinking in a similar but extended manner to previous reports using low doses of the neurosteroid allopregnanolone (ALLO); drinking was increased in hour 1, decreased in hours 2 and 3, and increased in hours 4 and 5 postinjection. THIP (8 mg/kg) and FIN both decreased 10E drinking during the first 5 hours postinjection by 30 and 53%, respectively, while having no effect on or increasing water drinking, respectively. All 3 drugs altered the initiation of drinking sessions in a dose-dependent fashion. FIN increased and GAN decreased time to first lick and first bout. THIP (8 mg/kg) decreased time to first lick but increased time to first bout and attenuated first bout size. The present findings support a role for the modulation of ethanol intake by neurosteroids and GABA(A) receptor-acting compounds and provide hints as to how drinking patterns are shifted. The ability of THIP to alter 10E drinking suggests that extrasynaptic GABA(A) receptors may be involved in the modulation of ethanol intake. Further, the consistent results with THIP to that seen previously with high doses of ALLO suggest that future studies should further examine the relationship between neurosteroids and extrasynaptic GABA(A) receptors, which could provide a better understanding of the mechanism by which neurosteroids influence ethanol intake.

Activity‐dependent γ‐aminobutyric acid release controls brain cortical tissue slice metabolism

Vigabatrin (γ-vinyl-GABA) is an irreversible inhibitor of the enzyme γ-aminobutyric acid (GABA) transaminase. It has been shown to increase levels of GABA in brain and result in increased release of GABA from nonsynaptic sources following activation. Here, we use a guinea pig cortical tissue slice model to identify the metabolic sequelae of vigabatrin when incubated with tissue slices alone or when the tissue slices were activated by ligands with targeted activating mechanisms. We show that incubation of slices with AMPA, the group II metabotropic glutamate antagonist EGLU [(2S)-α-ethylglutamic acid], or the GABA(B) R antagonist CGP 52432 in the presence of vigabatrin produces very similar metabolic profiles, consistent with the large-scale turning off of metabolic activity. This effect is blocked by the GABA(Arho) antagonist TPMPA [(1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid]. Taken together, these results suggest that GABA, released following activation, acts on extrasynaptic receptors consistent with GABA(Arho) and that these receptors act as a kind of "master switch" that is capable of turning off a range of differently induced activities.

Reduced postsynaptic GABAA receptor number and enhanced gaboxadol induced change in holding currents in Purkinje cells of the dystrophin-deficient mdx mouse

Duchenne muscular dystrophy (DMD) is caused by the absence of a functional transcript of the protein dystrophin. DMD is associated with a range of cognitive deficits that are thought to result from a lack of the protein dystrophin in brain structures involved in cognitive functions. The CNS involvement extends to an impairment of cognitive abilities, with many DMD boys having significant reduction in IQ. In the cerebellum, dystrophin is normally localized at the postsynaptic membrane of GABAergic synapses on Purkinje cells. Here, we investigate the effect of an absence of dystrophin on the number of GABAA channels located at the synapse in cerebellar Purkinje cells of the dystrophin-deficient mdx mouse. Whole-cell patch-clamp recordings of spontaneous miniature inhibitory postsynaptic currents (mIPSCs) were performed in cerebellar slices from mdx and littermate control mice. Our results showed that the number of receptors at GABAergic synapses in the cerebellar Purkinje cell was significantly reduced in mdx mice (38.38±2.95) compared to littermate controls (53.03±4.11). Furthermore, when gaboxadol was added to the bath, the change in holding current in mdx mice was significantly enhanced (65.01±5.89pA) compared to littermate controls (37.36±3.82pA). The single channel unitary conductance and the rise and decay time of mIPSCs were not significantly different in these two groups of mice, indicating that those GABAA channels located at the postsynaptic sites in the mdx mice function normally. Conclusion: There is a reduction in the number of functional receptors localized at GABAergic synapses in the cerebellar Purkinje cells of dystrophin-deficient mdx mice and an increase in a gaboxadol induced holding current, which is evidence for an increase in extrasynaptic GABAA receptors in mdx mice. We hypothesize that the absence of dystrophin, from mdx Purkinje cells, reduces the number of post-synaptic GABAA receptors and as a result there is an increase in extrasynaptic receptors. If similar changes occur in the CNS in boys with DMD, it will impact on the function of neural networks and may contribute to some of the motor, behavioral and cognitive impairment apparent in many boys with DMD.

Regulation of GABAA Receptor Dynamics by Interaction with Purinergic P2X2 Receptors

γ-Aminobutyric acid type A receptors (GABA(A)Rs) in the spinal cord are evolving as an important target for drug development against pain. Purinergic P2X(2) receptors (P2X(2)Rs) are also expressed in spinal cord neurons and are known to cross-talk with GABA(A)Rs. Here, we investigated a possible "dynamic" interaction between GABA(A)Rs and P2X(2)Rs using co-immunoprecipitation and fluorescence resonance energy transfer (FRET) studies in human embryonic kidney (HEK) 293 cells along with co-localization and single particle tracking studies in spinal cord neurons. Our results suggest that a significant proportion of P2X(2)Rs forms a transient complex with GABA(A)Rs inside the cell, thus stabilizing these receptors and using them for co-trafficking to the cell surface, where P2X(2)Rs and GABA(A)Rs are primarily located extra-synaptically. Furthermore, agonist-induced activation of P2X(2)Rs results in a Ca(2+)-dependent as well as an apparently Ca(2+)-independent increase in the mobility and an enhanced degradation of GABA(A)Rs, whereas P2X(2)Rs are stabilized and form larger clusters. Antagonist-induced blocking of P2XRs results in co-stabilization of this receptor complex at the cell surface. These results suggest a novel mechanism where association of P2X(2)Rs and GABA(A)Rs could be used for specific targeting to neuronal membranes, thus providing an extrasynaptic receptor reserve that could regulate the excitability of neurons. We further conclude that blocking the excitatory activity of excessively released ATP under diseased state by P2XR antagonists could simultaneously enhance synaptic inhibition mediated by GABA(A)Rs.

The ultrastructure of perisynaptic glia in the nucleus tractus solitarii of the adult rat: Comparison between single synapses and multisynaptic arrangements

Astrocytes are now considered as essential partners of neurons. In particular, they play important roles in glutamatergic transmission, including transmitter inactivation by uptake. Here, we investigated the organization of astroglia in the Nucleus Tractus Solitarii (NTS), a sensory nucleus located in the caudal medulla. Special attention was given to perisynaptic astroglial processes. Investigations were performed at the light and electron microscope levels, using immunodetection of glial glutamate transporters, stereological methods, and serial reconstruction. In the NTS, the main glutamate transporter expressed by astrocytes was GLT1. The volume fraction of astrocyte processes and the density of astrocyte membranes reached 15% and 2.8 μm(2) μm(-3) , respectively. In spite of the relative abundance of astrocyte processes, we found that NTS glutamatergic synapses were not entirely surrounded by glia. Measurements were performed on 43 reconstructed asymmetric junctions which were either single synapses (n = 22) or synapses involved in multisynaptic arrangements (n = 21). Single synapses had 58% of their perimeter contacted by astrocyte processes on average. In multisynaptic arrangement, glial coverage was restricted to the outer part of synaptic diameters and amounted to 50% of this outer part on average. Incomplete glial coverage of NTS synapses may allow glutamate to diffuse out of the synaptic cleft and to activate extrasynaptic receptors as well as receptors from neighboring synapses. Especially, in multisynaptic arrangements, the lack of intervening glia may favor functional coupling between individual contacts.

Tonic Extrasynaptic GABAA Receptor Currents Control Gonadotropin-Releasing Hormone Neuron Excitability in the Mouse

It is well established that the GABA(A) receptor plays an important role in regulating the electrical excitability of GnRH neurons. Two different modes of GABA(A) receptor signaling exist: one mediated by synaptic receptors generating fast (phasic) postsynaptic currents and the other mediated by extrasynaptic receptors generating a persistent (tonic) current. Using GABA(A) receptor antagonists picrotoxin, bicuculline methiodide, and gabazine, which differentiate between phasic and tonic signaling, we found that ∼50% of GnRH neurons exhibit an approximately 15-pA tonic GABA(A) receptor current in the acute brain slice preparation. The blockade of either neuronal (NO711) or glial (SNAP-5114) GABA transporter activity within the brain slice revealed the presence of tonic GABA signaling in ∼90% of GnRH neurons. The GABA(A) receptor δ subunit is only found in extrasynaptic GABA(A) receptors. Using single-cell RT-PCR, GABA(A) receptor δ subunit mRNA was identified in GnRH neurons and the δ subunit-specific agonist 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol was found to activate inward currents in GnRH neurons. Perforated-patch clamp studies showed that 4,5,6,7-tetrahydroisoxazolo [5,4-c] pyridin-3-ol exerted the same depolarizing or hyperpolarizing effects as GABA on juvenile and adult GnRH neurons and that tonic GABA(A) receptor signaling regulates resting membrane potential. Together, these studies reveal the presence of a tonic GABA(A) receptor current in GnRH neurons that controls their excitability. The level of tonic current is dependent, in part, on neuronal and glial GABA transporter activity and mediated by extrasynaptic δ subunit-containing GABA(A) receptors.

Extrasynaptic GABAA Receptors and Tonic Inhibition in Rat Auditory Thalamus

BackgroundNeural inhibition plays an important role in auditory processing and attentional gating. Extrasynaptic GABAA receptors (GABAAR), containing α4and δ GABAAR subunits, are thought to be activated by GABA spillover outside of the synapse following release resulting in a tonic inhibitory Cl− current which could account for up to 90% of total inhibition in visual and somatosensory thalamus. However, the presence of this unique type of inhibition has not been identified in auditory thalamus.Methodology/Principal FindingsThe present study used gaboxadol, a partially selective potent agonist for δ-subunit containing GABAA receptor constructs to elucidate the presence of extrasynaptic GABAARs using both a quantitative receptor binding assay and patch-clamp electrophysiology in thalamic brain slices. Intense [3H]gaboxadol binding was found to be localized to the MGB while whole cell recordings from MGB neurons in the presence of gaboxadol demonstrated the expression of δ-subunit containing GABAARs capable of mediating a tonic inhibitory Cl− current.Conclusions/SignificancePotent tonic inhibitory GABAAR responses mediated by extrasynaptic receptors may be important in understanding how acoustic information is processed by auditory thalamic neurons as it ascends to auditory cortex. In addition to affecting cellular behavior and possibly neurotransmission, functional extrasynaptic δ-subunit containing GABAARs may represent a novel pharmacological target for the treatment of auditory pathologies including temporal processing disorders or tinnitus.

Thyroid hormones modulate GABA A receptor-mediated currents in hippocampal neurons

Thyroid hormones (THs) play a crucial role in the maturation and functioning of mammalian central nervous system. Thyroxine (T4) and 3, 3′, 5- l-triiodothyronine (T3) are well known for their genomic effects, but recently attention has been focused on their non genomic actions as modulators of neuronal activity. In the present study we report that T4 and T3 reduce, in a non competitive manner, GABA-evoked currents in rat hippocampal cultures with IC 50s of 13 ± 4 μM and 12 ± 3 μM, respectively. The genomically inactive compound rev-T3 was also able to inhibit the currents elicited by GABA. Blocking PKC or PKA activity, chelating intracellular calcium, or antagonizing the integrin receptor αVβ3 with TETRAC did not affect THs modulation of GABA-evoked currents. THs affect also synaptic activity in hippocampal and cortical cultured neurons. T3 and T4 reduced to approximately 50% the amplitude and frequency of spontaneous inhibitory synaptic currents (sIPSCs), without altering their decay kinetic. Tonic currents evoked by low GABA concentrations were also reduced by T3 (40 ± 5%, n = 14), but not by T4. Similarly, T3 decreased currents elicited by low concentrations of THIP, a low affinity GABAA receptor agonist that preferentially activates extrasynaptic receptors, whereas T4 was ineffective. Thus, our data demonstrate that T3 and T4 selectively affect GABAergic phasic and tonic neurotransmission. Since THs concentrations can be regulated at the level of the synapses these data suggest that the network activity of the whole brain could be differently modulated depending on the relative amount of these two hormones. This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.

Virally mediated functional suppression of GABA-A receptors in the rodent thalamus

Event Abstract Back to Event Virally mediated functional suppression of GABA-A receptors in the rodent thalamus Z. Rovó1*, F. Mátyás1, P. Barthó1, A. Slézia1 and L. Acsády1 1 Hungarian Academy of Sciences, Institute of Experimental Medicine, Hungary GABAergic inhibition is essential for the normal function of thalamocortical networks. In addition beside the phasic inhibition mediated by synaptic GABA-A receptors, extrasynaptic GABA-A receptors also exert powerful tonic inhibition on thalamocortical cells. The nucleus specific role of synaptic inhibition is difficult to assess using the traditional pharmacological or KO methods due to the limited spatial and temporal control of their effects. Thus, in this study, we used stereotaxic injection of viral particles to focally knock down synaptic GABA-A receptors. All synaptic GABA-A receptors in the thalamus contain g2 subunit. Injection of AAV-Cre viral particles into the thalamus of g2 floxed mice results in the focal removal of the g2 gene. Successful removal of the g2 gene was identified by immunocytochemistry for g2 protein. Immunoreactivity of the other subunits of synaptic GABA-A receptors (a1, b2) as well as extrasynaptic receptors (alpha4) remained unchanged. Preliminary juxtacellular recording in anaesthetized mice demonstrated that it is possible to record, label and identify virally infected thalamocortical cells, which lack functional synaptic GABA-A receptors and to differentiate them from non-infected cells with intact inhibition. Our data demonstrate that the present method is an excellent tool to study the nucleus specific role of synaptic GABA-A receptor in cellular and network activity. Keywords: Neurophysiology, Neuroscience Conference: 13th Conference of the Hungarian Neuroscience Society (MITT), Budapest, Hungary, 20 Jan - 22 Jan, 2011. Presentation Type: Abstract Topic: Neurophysiology Citation: Rovó Z, Mátyás F, Barthó P, Slézia A and Acsády L (2011). Virally mediated functional suppression of GABA-A receptors in the rodent thalamus. Front. Neurosci. Conference Abstract: 13th Conference of the Hungarian Neuroscience Society (MITT). doi: 10.3389/conf.fnins.2011.84.00026 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Mar 2011; Published Online: 23 Mar 2011. * Correspondence: Dr. Z. Rovó, Hungarian Academy of Sciences, Institute of Experimental Medicine, Budapest, Hungary, rovozita@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Z. Rovó F. Mátyás P. Barthó A. Slézia L. Acsády Google Z. Rovó F. Mátyás P. Barthó A. Slézia L. Acsády Google Scholar Z. Rovó F. Mátyás P. Barthó A. Slézia L. Acsády PubMed Z. Rovó F. Mátyás P. Barthó A. Slézia L. Acsády Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.