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1.
Reduced tonic inhibition in the dentate gyrus contributes to chronic stress‐induced impairments in learning and memory
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It is well established that stress impacts the underlying processes of learning and memory. The effects of stress on memory are thought to involve, at least in part, effects on the hippocampus, which is particularly vulnerable to stress. Chronic stress induces hippocampal alterations, including but not limited to dendritic atrophy and decreased neurogenesis, which are thought to contribute to chronic stress‐induced hippocampal dysfunction and deficits in learning and memory. Changes in synaptic transmission, including changes in GABAergic inhibition, have been documented following chronic stress. Recently, our laboratory demonstrated shifts in EGABA in CA1 pyramidal neurons following chronic stress, compromising GABAergic transmission and increasing excitability of these neurons. Interestingly, here we demonstrate that these alterations are unique to CA1 pyramidal neurons, since we do not observe shifts in EGABA following chronic stress in dentate gyrus granule cells. Following chronic stress, there is a decrease in the expression of the GABAA receptor (GABAAR) δ subunit and tonic GABAergic inhibition in dentate gyrus granule cells, whereas there is an increase in the phasic component of GABAergic inhibition, evident by an increase in the peak amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). Given the numerous changes observed in the hippocampus following stress, it is difficult to pinpoint the pertinent contributing pathophysiological factors. Here we directly assess the impact of a reduction in tonic GABAergic inhibition of dentate gyrus granule cells on learning and memory using a mouse model with a decrease in GABAAR δ subunit expression specifically in dentate gyrus granule cells (Gabrd/Pomc mice). Reduced GABAAR δ subunit expression and function in dentate gyrus granule cells is sufficient to induce deficits in learning and memory. Collectively, these findings suggest that the reduction in GABAAR δ subunit‐mediated tonic inhibition in dentate gyrus granule cells contributes, at least in part, to deficits in learning and memory associated with chronic stress. These findings have significant implications regarding the pathophysiological mechanisms underlying impairments in learning and memory associated with stress and suggest a role for GABAAR δ subunit containing receptors in dentate gyrus granule cells. © 2016 Wiley Periodicals, Inc. 相似文献
2.
Febrile seizures are the most common seizure type in children, and hyperthermia may contribute to seizure generation during fever. We have previously demonstrated that hyperthermia suppressed γ‐aminobutyric acid (GABA)‐ergic synaptic transmission in CA1 neurons of immature rats. However, whether this suppression is age‐dependent is unknown. Moreover, it is unclear whether hyperthermia has differential effects on neuronal inhibition in CA1 pyramidal cells (PCs) and dentate gyrus granule cells (GCs). In this study, we investigated the effects of hyperthermia on GABAA and GABAB receptor‐mediated inhibitory postsynaptic currents (IPSCs) in CA1 and DG neurons from immature (11–17 days old) and mature (6–8 weeks old) rats using whole‐cell recordings in vitro. In immature rats, hyperthermia decreased the peak amplitude of GABAA receptor‐mediated IPSCs (GABAA IPSCs) in PCs but not in GCs. However, hyperthermia decreased the decay time constant of GABAA IPSCs to a similar extent in both PCs and GCs. In mature rats, hyperthermia decreased the peak amplitude but not the decay time constant of GABAA IPSCs in both PCs and GCs. Hyperthermia decreased charge transfer (area) of the GABAA IPSC of PCs more in immature than in mature rats. In contrast, hyperthermia decreased the GABAB receptor‐mediated IPSCs to the same degree in immature and mature rats, for either CA1 or DG neurons. Because the hippocampus has been found to be involved in hyperthermia‐induced behavioral seizures in immature rats, we suggest that the higher sensitivity of CA1 inhibitory synaptic function to hyperthermia in immature compared with mature rats might partially explain the higher susceptibility for febrile seizures in immature animals. © 2009 Wiley‐Liss, Inc. 相似文献
3.
Mai Marie Holm Jose Luis Nieto‐Gonzalez Irina Vardya Kim Henningsen Magdalena Niepsuj Jayatissa Ove Wiborg Kimmo Jensen 《Hippocampus》2011,21(4):422-433
In major depression, one line of research indicates that a dysfunctional GABAergic inhibitory system is linked to the appearance of depressive symptoms. However, as the mechanistic details of such GABAergic deficit are largely unknown, we undertook a functional investigation of the GABAergic system in the rat chronic mild stress model of depression. Adult rats were exposed to an eight‐week long stress protocol leading to anhedonic‐like behavior. In hippocampal brain slices, phasic, and tonic GABAA receptor‐mediated currents in dentate gyrus granule cells were examined using patch‐clamp recordings. In granule cells, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) was reduced to 41% in anhedonic‐like rats, which was associated with a reduced probability of evoked GABA release. Using immunohistochemical analysis, there was no change in the number of parvalbumin‐positive interneurons in the dentate gyrus. Notably, we observed a 60% increase in THIP‐activated tonic GABAA mediated current in anhedonic‐like rats, suggesting an upregulation of extrasynaptic GABAA receptors. Finally, five weeks treatment with the antidepressant escitalopram partially reversed the sIPSCs frequency. In summary, we have revealed a hippocampal dysfunction in the GABAergic system in the chronic mild stress model of depression in rats, caused by a reduction in action potential‐dependent GABA release. Since the function of the GABAergic system was improved by antidepressant treatment, in parallel with behavioral read outs, it suggests a role of the GABAergic system in the pathophysiology of depression. © 2010 Wiley‐Liss, Inc. 相似文献
4.
Tonic inhibition mediated by extrasynaptic GABAA receptors (GABAARs) is an important regulator of neuronal excitability. Phosphorylation by protein kinase C (PKC) provides a key mode of regulation for synaptic GABAARs underlying phasic inhibition; however, less attention has been focused on the plasticity of tonic inhibition and whether this can also be modulated by receptor phosphorylation. To address this issue, we used whole‐cell patch clamp recording in acute murine brain slices at both room and physiological temperatures to examine the effects of PKC‐mediated phosphorylation on tonic inhibition. Recordings from dentate gyrus granule cells in the hippocampus and dorsal lateral geniculate relay neurons in the thalamus demonstrated that PKC activation caused downregulation of tonic GABAAR‐mediated inhibition. Conversely, inhibition of PKC resulted in an increase in tonic GABAAR activity. These findings were corroborated by experiments on human embryonic kidney 293 cells expressing recombinant α4β2δ GABAARs, which represent a key extrasynaptic GABAAR isoform in the hippocampus and thalamus. Using bath application of low GABA concentrations to mimic activation by ambient neurotransmitter, we demonstrated a similar inhibition of receptor function following PKC activation at physiological temperature. Live cell imaging revealed that this was correlated with a loss of cell surface GABAARs. The inhibitory effects of PKC activation on α4β2δ GABAAR activity appeared to be mediated by direct phosphorylation at a previously identified site on the β2 subunit, serine 410. These results indicate that PKC‐mediated phosphorylation can be an important physiological regulator of tonic GABAAR‐mediated inhibition. 相似文献
5.
Ryuta Koyama 《Neuropathology》2013,33(4):475-479
Epilepsy is a nervous system disorder characterized by recurrent seizures. Among several types of epilepsy, which accounts for a significant portion of the disease worldwide, temporal lobe epilepsy (TLE) is one of the most common types of intractable epilepsy in adulthood. It has been suggested that complex febrile seizures in early life are associated with the development of TLE later in life; however, cellular and molecular links between febrile seizures and TLE remain unclear because of the lack of an appropriate in vitro system. Using rat hippocampal slice cultures, in which many features of native organotypic organization are retained, we found that the dentate granule cells exhibit aberrant migration in the dentate hilus via enhanced excitatory GABAA receptor (GABAA‐R) signaling, which results in granule cell ectopia that persists into adulthood. We further found that the granule cell ectopia is associated with spontaneous limbic seizures in adulthood. Importantly, both of these phenomena were prevented by inhibiting Na+K+2Cl? co‐transporter (NKCC1) which mediates the excitatory action of GABA. 相似文献
6.
Glial fibrillary acidic protein (GFAP)‐positive astrocytes with radial processes [radial glia (RG)‐like cells] in the postnatal dentate gyrus share many of the characteristics of embryonic radial glia and appear to act as precursor cells for adult dentate neurogenesis, a process important for pattern separation and hippocampus‐dependent learning. Although much work has delineated the mechanisms underlying activity‐neurogenesis coupling via gamma‐amino butyric acid (GABA)ergic neurotransmission on GFAP‐negative transient‐amplifying cells and neuroblasts, little is known regarding the effects of neurotransmitters on RG‐like cells. Conflicting evidence exists for both GABA and glutamate receptors on these cells. Here, using GFAP reporter mice, we show that the somatic membrane of RG‐like cells carries GABAA receptors and glutamate transporters but not ionotropic glutamate receptors, whereas 2‐amino‐3‐(hydroxyl‐5‐methylisoxazole‐4‐yl) propionic acid (AMPA) and GABAA receptors are expressed on the processes of these cells. Almost all RG‐like cells expressed the GluA2 subunit, which restricts the Ca2+ permeability of AMPA receptors. The glial GABAA receptors mainly comprised α2/α4, β1, and γ1/γ3. The selective presence of AMPA receptors on the radial processes may be important for sensing and responding to local activity‐driven glutamate release and supports the concept that RG‐like astrocytes are composed of functional and structural domains. 相似文献
7.
Inhibitory neurotransmission may play an important role in neuronal degeneration following transient cerebral ischemia. We studied the effect of transient forebrain ischemia on the GABAA receptor system in the gerbil hippocampus. Gerbils were subjected to 5 minutes of bilateral carotid occlusion and were sacrificed at various times over 4 days following reperfusion. There was a substantial loss of pyramidal cells in the CA1 area of the hippocampus, granule cell layer of the dentate gyrus, and ventroposterior medial and ventroposterior lateral nuclei of the thalamus at any time following ischemia. Examination of brain slices by in situ hybridization histochemistry revealed that a change in expression of the GABAA receptor α1 and β2 subunit mRNAs occurred in two phases following onset of reperfusion. The early phase (rapid) occurred within the first 4 hours following reperfusion. The expression of mRNAs significantly decreased (up to 25%) within 1 hour after occlusion in CA1 and CA3 pyramidal cell layers of the hippocampus and in the granule cell layer of the dentate gyrus. The expression of the mRNAs in these regions continued to decrease for 4 hours (up to 43%). In the second phase, which began between 4 and 12 hours following reperfusion, mRNA expression started to return to control levels in CA3 hippocampus and in the dentate. However, expression of both mRNAs continued to decline slowly in the CA1 pyramidal cell layer (up to 85%) over the next 3 days, concomitantly with degeneration of the CA1 pyramidal cells. Expression of mRNAs in the ventroposterior medial or ventroposterior lateral nuclei of the thalamus was similar to control values. To determine if a change in GABAA receptor distribution paralleled changes in receptor subunit mRNA expression, we also measured the binding of [35S]t-butylbicylophosphorothionate to GABAA receptor chloride channels. The t-butylibicyclophosphorothionate [35S] binding decreased between 1 and 4 days after reperfusion in the dendritic fields of CA1 pyramidal cells (strata oriens, radiatum, and lacunosum-moleculare) but not in the pyramidal cell body layer. These results indicate that expression of GABAA receptor subunit mRNAs decrease well before CA1 pyramidal cell degeneration and loss of GABAA receptors. At present, it is not clear if an early loss of mRNA expression after an ischemic insult leads to a functional defect in GABAA receptors. If so, a loss of GABA neurotransmission may contribute to the development of neuronal degeneration following cerebral ischemia. The maintenance of normal GABA neurotransmission in surviving cells may explain their resistance to ischemia-induced neuronal death. 相似文献
8.
Partial inactivation of GABAA receptors containing the α5 subunit affects the development of adult‐born dentate gyrus granule cells
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Amalia Floriou‐Servou Carlos Lafourcade Uwe Rudolph Shiva K. Tyagarajan Jean‐Marc Fritschy 《The European journal of neuroscience》2016,44(5):2258-2271
Alterations of neuronal activity due to changes in GABAA receptors (GABAAR) mediating tonic inhibition influence different hippocampal functions. Gabra5‐null mice and α5 subunit(H105R) knock‐in mice exhibit signs of hippocampal dysfunction, but are capable of improved performance in several learning and memory tasks. Accordingly, alleviating abnormal GABAergic tonic inhibition in the hippocampal formation by selective α5‐GABAAR modulators represents a possible therapeutic approach for several intellectual deficit disorders. Adult neurogenesis in the dentate gyrus is an important facet of hippocampal plasticity; it is regulated by tonic GABAergic transmission, as shown by deficits in proliferation, migration and dendritic development of adult‐born neurons in Gabra4‐null mice. Here, we investigated the contribution of α5‐GABAARs to granule cell development, using retroviral vectors expressing eGFP for labeling precursor cells in the subgranular zone. Global α5‐GABAAR knockout (α5‐KO) mice showed no alterations in migration and morphological development of eGFP‐positive granule cells. However, upregulation of α1 subunit‐immunoreactivity was observed in the hippocampal formation and cerebral cortex. In contrast, partial gene inactivation in α5‐heterozygous (α5‐het) mice, as well as single‐cell deletion of Gabra5 in newborn granule cells from α5‐floxed mice, caused severe alterations of migration and dendrite development. In α5‐het mice, retrovirally mediated overexpression of Cdk5 resulted in normal migration and dendritic branching, suggesting that Cdk5 cooperates with α5‐GABAARs to regulate neuronal development. These results show that minor imbalance of α5‐GABAAR‐mediated transmission may have major consequences for neuronal plasticity; and call for caution upon chronic therapeutic use of negative allosteric modulators acting at these receptors. 相似文献
9.
Carmen Vale M. Teresa Vilar Eduardo Rodríguez‐Farr Cristina Suol 《Journal of neuroscience research》1999,57(1):95-105
The effects of the GABA analogues, cis‐ and trans‐4‐aminocrotonic acid (ACA) on GABAA receptor function and GABA uptake, together with the presence of ρ‐1 subunit mRNA and putative GABAC receptors, were studied in primary cultures of neocortical neurons and cerebellar granule cells. Both isomers induced a Cl‐ influx, which was inhibited by bicuculline, t‐butylbicyclophosphorothionate (TBPS), picrotoxinin (PTX), and γ‐hexachlorocyclohexane (γ‐HCH or lindane). [3H]‐flunitrazepam binding was also increased by both isomers and this increase was inhibited by bicuculline. In neocortical neurons, the trans‐isomer completely inhibited the [3H]GABA uptake, whereas the cis‐isomer produced only a 25% inhibition at the highest concentration used. The possible presence of GABAC receptors was investigated only in neocortical cultures by using RT‐PCR in order to detect the presence of the mRNA encoding the ρ‐1 subunit which assembles to form homooligomeric Cl‐ channels. The results presented here show that ρ‐1 subunits, and thus GABAC receptors, may represent a very minor population of GABA receptors in these neuronal preparations. We conclude that both GABA analogues may act as agonists at the GABAA receptors, although with very different potencies. J. Neurosci. Res. 57:95–105, 1999. © 1999 Wiley‐Liss, Inc. 相似文献
10.
Helmut K. Wolf Matthias Spänle Marianne B. Müller Christian E. Elger Johannes Schramm Otmar D. Wiestler 《Acta neuropathologica》1994,88(4):313-319
Alterations of gamma aminobutyric acid (GABA)-mediated neurotransmission have been implicated in the pathogenesis of epilepsies. Here we examine the distribution of the GABAA receptor in the hippocampus of 78 surgical specimens from patients with chronic pharmacoresistant focal epilepsies. The receptor was localized immunohistochemically with the monoclonal antibody bd-24 which selectively recognizes the 1 subunit of the GABAA receptor. The results were compared with the receptor distribution of 28 normal hippocampal specimens obtained at autopsy. In the great majority of the surgical specimens a loss of GABAA receptor immunoreactivity was present in CA1 (92.3%), CA4 (78.2%), the dentate granular cell layer (70.5%) and the molecular layer of the dentate gyrus (65.4%). The subiculum revealed a normal staining pattern in all but 4 cases. In no instance did we observe an increase of immunoreactivity in any region or cell population. The decrease of GABAA receptor immunoreactivity was closely related to neuronal loss in the respective specimen and to Ammon's horn sclerosis. There was no correlation between GABAA receptor loss and the patient's age at surgery, duration of seizures, age at onset of seizures and to the presence or absence of secondary generalized tonic clonic seizures. The data suggest that the observed loss of GABAA receptor immunoreactivity is a secondary phenomenon rather than an event that is relevant for the pathogenesis of epileptic seizures. 相似文献
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13.
Kristy M. McClellan Matthew S. Stratton Stuart A. Tobet 《The Journal of comparative neurology》2010,518(14):2710-2728
The development of the hypothalamic paraventricular nucleus (PVN) involves several factors that work together to establish a cell group that regulates neuroendocrine functions and behaviors. Several molecular markers were noted within the developing PVN, including estrogen receptors (ER), neuronal nitric oxide synthase (nNOS), and brain‐derived neurotrophic factor (BDNF). By contrast, immunoreactive γ‐aminobutyric acid (GABA) was found in cells and fibers surrounding the PVN. Two animal models were used to test the hypothesis that GABA works through GABAA and GABAB receptors to influence the development of the PVN. Treatment with bicuculline to decrease GABAA receptor signaling from embryonic day (E) 10 to E17 resulted in fewer cells containing immunoreactive (ir) ERα in the region of the PVN vs. control. GABABR1 receptor subunit knockout mice were used to examine the PVN at P0 without GABAB signaling. In female but not male GABABR1 subunit knockout mice, the positions of cells containing ir ERα shifted from medial to lateral compared with wild‐type controls, whereas the total number of ir ERα‐containing cells was unchanged. In E17 knockout mice, ir nNOS cells and fibers were spread over a greater area. There was also a significant decrease in ir BDNF in the knockout mice in a region‐dependent manner. Changes in cell position and protein expression subsequent to disruption of GABA signaling may be due, in part, to changes in nNOS and BDNF signaling. Based on the current study, the PVN can be added as another site where GABA exerts morphogenetic actions in development. J. Comp. Neurol. 518:2710–2728, 2010. © 2010 Wiley‐Liss, Inc. 相似文献
14.
γ‐Aminobutyric acid (GABA)‐ and serotonin (5‐HT)‐mediated cell signaling, neuronal survival enhancement, and reduced neuronal death in brainstem during liver injury followed by active liver regeneration have a critical role in maintaining routine bodily functions. In the present study, GABAB and 5‐HT2A receptor functional regulation, interrelated actions of neuronal survival factors, and expression of apoptotic factors in the brainstem during GABA and 5‐HT chitosan nanoparticles‐induced active liver regeneration in partially hepatectomized rats were evaluated. Partially hepatectomized rats were treated with the nanoparticles, and receptor assays and confocal microscopic studies of GABAB and 5‐HT2A receptors, gene expression studies of GABAB and 5‐HT2A receptors, nuclear factor‐κB (NF‐κB), tumor necrosis factor‐α (TNF‐α), Akt‐1, phospholipase C, Bax, and caspase‐8 were performed with the brainstems of experimental animals. A significant decrease in GABAB and 5‐HT2A receptor numbers and gene expressions denoted a homeostatic adjustment by the brain to trigger the sympathetic innervations during elevated DNA synthesis in the liver. The neuronal apoptosis resulting from the loss of liver function after partial hepatectomy was minimized by nanoparticle treatment in rats compared with rats with no treatment during regeneration. This was confirmed from the gene expression patterns of NF‐κB, TNF‐α, Akt‐1, phospholipase C, Bax, and caspase‐8. The present study revealed the potential of GABA and 5‐HT chitosan nanoparticles for increasing neuronal survival in the brainstem during liver injury following regeneration, which avoids many neuropsychiatric problems. © 2013 Wiley Periodicals, Inc. 相似文献
15.
Cocaine withdrawal reduces GABABR transmission at entopeduncular nucleus – lateral habenula synapses
Dorine Tan Alvaro Nuno‐Perez Manuel Mameli Frank J. Meye 《The European journal of neuroscience》2019,50(3):2124-2133
Lateral habenula (LHb) hyperactivity plays a pivotal role in the emergence of negative emotional states, including those occurring during withdrawal from addictive drugs. We have previously implicated cocaine‐driven adaptations at synapses from the entopeduncular nucleus (EPN) to the LHb in this process. Specifically, ionotropic GABAA receptor (R)‐mediated neurotransmission at EPN‐to‐LHb synapses is reduced during cocaine withdrawal, due to impaired vesicle filling. Recent studies have shown that metabotropic GABABR signaling also controls LHb activity, although its role at EPN‐to‐LHb synapses during drug withdrawal is unknown. Here, we predicted that cocaine treatment would reduce GABABR‐mediated neurotransmission at EPN‐to‐LHb synapses. We chronically treated mice with saline or cocaine, prepared brain slices after two days of withdrawal and performed voltage‐clamp recordings from LHb neurons whilst optogenetically stimulating EPN terminals. Compared with controls, mice in cocaine withdrawal exhibited reduced GABAAR‐mediated input to LHb neurons, and a reduced occurrence of GABABR‐signaling at EPN‐to‐LHb synapses. We then assessed the underlying mechanism of this decrease. Application of GABABR agonist baclofen evoked similar postsynaptic responses in EPN‐innervated LHb neurons in saline‐ and cocaine‐treated mice. Release probability at EPN‐to‐LHb GABAergic synapses was also comparable between groups. However, incubating brain slices in glutamine to facilitate GABA vesicle filling, normalized GABABR‐currents at EPN‐to‐LHb synapses in cocaine‐treated mice. Overall, we show that during cocaine withdrawal, together with reduced GABAAR transmission, also GABABR‐mediated inhibitory signaling is diminished at EPN‐to‐LHb synapses, likely via the same presynaptic deficit. In concert, these alterations are predicted to contribute to the emergence of drug withdrawal symptoms, facilitating drug relapse. 相似文献
16.
Activation of 5‐HT receptors inhibits GABAergic transmission by pre‐and post‐synaptic mechanisms in layer II/III of the juvenile rat auditory cortex
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Lu Dinh Luis Galindo‐Charles Elsy Arlene Pérez Padilla Juan Carlos Pineda Marco Atzori Humberto Salgado 《Synapse (New York, N.Y.)》2015,69(3):115-127
The specific mechanisms by which serotonin (5‐HT) modulates synaptic transmission in the auditory cortex are still unknown. In this work, we used whole‐cell recordings from layer II/III of pyramidal neurons in rat brain slices to characterize the influence of 5‐HT on inhibitory synaptic activity in the auditory cortex after pharmacological blockade of excitatory glutamatergic transmission. We found that bath application of 5‐HT (5 µM) reduced the frequency and amplitude of both spontaneous and miniature inhibitory postsynaptic currents (IPSCs), reduced the amplitude of evoked IPSCs, and enhanced facilitation of paired pulse ratio (PPR), suggesting presynaptic inhibition. To determine which the serotonin receptors were involved in this effect, we studied the influence of specific 5‐HT receptor agonists and antagonists on ?‐aminobutyric acid (GABA)ergic synaptic transmission. The inhibiting influence of 5‐HT in the GABAergic synaptic activity was mimicked by using the selective agonists of the 5‐HT1A and 5‐HT2A receptors, 8(OH)‐DPAT (10 µM) and DOI (10 µM), respectively; and it was prevented by their respective antagonists NAN‐190 (1 µM) and ritanserin (1 μM). Furthermore, the application of the selective agonist of 5‐HT1A receptors, 8‐(OH)‐DPAT (10 µM), produced PPR facilitation, while DOI application (5‐HT2A agonist) did not change the PPR. Moreover, the 5‐HT2A agonist reduced the amplitude of the IPSCs evoked by application of the selective GABA agonist, muscimol. These results suggest a presynaptic and postsynaptic reduction of GABAergic transmission mediated by 5‐HT1A and 5‐HT2A serotonergic receptors, respectively. Synapse 69:115–127, 2015. © 2014 Wiley Periodicals, Inc. 相似文献
17.
Nadine I. Holter Maura M. Zylla Nadine Zuber Claus Bruehl Andreas Draguhn 《The European journal of neuroscience》2010,32(8):1300-1309
The dentate gyrus is the main hippocampal input structure receiving strong excitatory cortical afferents via the perforant path. Therefore, inhibition at this ‘hippocampal gate’ is important, particularly during postnatal development, when the hippocampal network is prone to seizures. The present study describes the development of tonic GABAergic inhibition in mouse dentate gyrus. A prominent tonic GABAergic component was already present at early postnatal stages (postnatal day 3), in contrast to the slowly developing phasic postsynaptic GABAergic currents. Tonic currents were mediated by GABAA receptors containing α5‐ and δ‐subunits, which are sensitive to low ambient GABA concentrations. The extracellular GABA level was determined by synaptic GABA release and GABA uptake via the GABA transporter 1. The contribution of these main regulatory components was surprisingly stable during postnatal granule cell maturation. Throughout postnatal development, tonic GABAergic signals were inhibitory. They increased the action potential threshold of granule cells and reduced network excitability, starting as early as postnatal day 3. Thus, tonic inhibition is already functional at early developmental stages and plays a key role in regulating the excitation/inhibition balance of both the adult and the maturing dentate gyrus. 相似文献
18.
Changik Lee Kayoung Joo Myung‐Jun Kim Duck‐Joo Rhie Hyun‐Jong Jang 《Journal of neuroscience research》2015,93(9):1405-1412
In the visual cortex, synaptic plasticity is very high during the early developmental stage known as the critical period and declines with development after the critical period. Changes in the properties of N‐methyl‐D‐aspartate receptor (NMDAR) and γ‐aminobutyric acid type A receptor (GABAAR) have been suggested to underlie the changes in the characteristics of plasticity. However, it is largely unknown how the changes in the two receptors interact to regulate synaptic plasticity. The present study investigates the changes in the properties of NMDAR and GABAAR from 3 to 5 weeks of age in layer 2/3 pyramidal neurons of the rat visual cortex. The impact of these changes on the characteristics of long‐term potentiation (LTP) is also investigated. The amplitude and decay time constant of GABAAR‐mediated currents increased during this period. However, the decay time constant of NMDAR‐mediated currents decreased as a result of the decrease in the proportion of the GluN2B subunit‐mediated component. Induction of NMDAR‐dependent LTP at 3 weeks depended on the GluN2B subunit, but LTP at 5 weeks did not. Enhancement of GABAAR‐mediated inhibition suppressed the induction of LTP only at 5 weeks. However, partial inhibition of the GluN2B subunit with a low concentration of ifenprodil allowed the GABAAR‐mediated suppression of LTP at 3 weeks. These results suggest that changes in the properties of NMDAR‐ and GABAAR‐mediated synaptic transmission interact to determine the characteristics of synaptic plasticity during the critical period in the visual cortex. © 2015 Wiley Periodicals, Inc. 相似文献
19.
Ying Wang Florian B. Neubauer Hans‐Rudolf Lüscher Kay Thurley 《The European journal of neuroscience》2010,31(9):1582-1594
GABA (γ‐aminobutyric acid) can mediate inhibition via pre‐ and post/extrasynaptic GABA receptors. In this paper we demonstrate potentially post/extrasynaptic GABAB receptor‐dependent tonic inhibition in L2/3 pyramidal cells of rat medial prefrontal cortex (mPFC) in vitro. First, we show via voltage‐clamp experiments the presence of a tonic GABAB receptor‐dependent outward current in these neurons. This GABABergic current could be induced by ambient GABA when present at sufficient concentrations. To increase ambient GABA levels in the usually silent slice preparation, we amplified network activity and hence synaptic GABA release with a modified artificial cerebrospinal fluid. The amplitude of tonic GABAB current was similar at different temperatures. In addition to the tonic GABAB current, we found presynaptic GABAB effects, GABAB‐mediated inhibitory postsynaptic currents and tonic GABAA currents. Second, we performed current‐clamp experiments to evaluate the functional impact of GABAB receptor‐mediated inhibition in the mPFC. Activating or inactivating GABAB receptors led to rightward (reduction of excitability) or leftward (increase of excitability) shifts, respectively, of the input–output function of mPFC L2/3 pyramidal cells without effects on the slope. Finally, we showed in electrophysiological recordings and epifluorescence Ca2+‐imaging that GABAB receptor‐mediated tonic inhibition is capable of regulating network activity. Blocking GABAB receptors increased the frequency of excitatory postsynaptic currents impinging on a neuron and prolonged network upstates. These results show that ambient GABA via GABAB receptors is powerful enough to modulate neuronal excitability and the activity of neural networks. 相似文献
20.
Sara Trowbridge Sophie Scotto‐Lomassese Felix B. Kleine Borgmann Sebastian Jessberger Bruno Giros Luc Maroteaux Evan Deneris Patricia Gaspar 《The European journal of neuroscience》2013,38(5):2650-2658
Increased adult neurogenesis is a major neurobiological correlate of the beneficial effects of antidepressants. Indeed, selective serotonin (5‐HT) re‐uptake inhibitors, which increase 5‐HT transmission, enhance adult neurogenesis in the dentate gyrus (DG) of the hippocampus. However, the consequences of 5‐HT depletion are still unclear as studies using neurotoxins that target serotonergic neurons reached contradictory conclusions on the role of 5‐HT on DG cell proliferation. Here, we analysed two genetic models of 5‐HT depletion, the Pet1?/? and the VMAT2f/f; SERTcre/+ mice, which have, respectively, 80 and 95% reductions in hippocampal 5‐HT. In both models, we found unchanged cell proliferation of the neural precursors in the DG subgranular zone, whereas a significant increase in the survival of newborn neurons was noted 1 and 4 weeks after BrdU injections. This pro‐survival trait was phenocopied pharmacologically with 5‐HT synthesis inhibitor PCPA treatment in adults, indicating that this effect was not developmental. Furthermore, a 1‐week administration of the 5‐HT1A receptor agonist 8‐OH‐DPAT in Pet1?/? and PCPA‐treated mice normalised hippocampal cell survival. Overall, our results indicate that constitutive 5‐HT depletion does not alter the proliferation of neural precursors in the DG but promotes the survival of newborn cells, an effect which involves activation of postsynaptic 5‐HT1A receptors. The role of 5‐HT in selective neuronal elimination points to a new facet in its multiple effects in controlling neural circuit maturation. 相似文献