Presynaptic GABAB Receptors Functionally Uncouple Somatostatin Interneurons from the Active Hippocampal Network

Information processing in cortical neuronal networks relies on properly balanced excitatory and inhibitory neurotransmission. A ubiquitous motif for maintaining this balance is the somatostatin interneuron (SOM-IN) feedback microcircuit. Here, we investigated the modulation of this microcircuit by presynaptic GABAB receptors (GABABRs) in the rodent hippocampus. Whole-cell recordings from SOM-INs revealed that both excitatory and inhibitory synaptic inputs are strongly inhibited by GABABRs, while optogenetic activation of the interneurons shows that their inhibitory output is also strongly suppressed. Electron microscopic analysis of immunogold-labelled freeze-fracture replicas confirms that GABABRs are highly expressed presynaptically at both input and output synapses of SOM-INs. Activation of GABABRs selectively suppresses the recruitment of SOM-INs during gamma oscillations induced in vitro. Thus, axonal GABABRs are positioned to efficiently control the input and output synapses of SOM-INs and can functionally uncouple them from local network with implications for rhythmogenesis and the balance of entorhinal versus intrahippocampal afferents

Expression of GABAergic Receptors in Mouse Taste Receptor Cells

) while it is terminated by the re-uptake of GABA through transporters (GATs).- immunoreactivity were detected in the peripheral taste receptor cells. We also used transgenic mice that express green fluorescent protein (GFP) in either the Type II taste cells, which can respond to bitter, sweet or umami taste stimuli, or in the Type III GAD67 expressing taste cells. Thus, we were able to identify that GABAergic receptors are expressed in some Type II and Type III taste cells. Mouse GAT4 labeling was concentrated in the cells surrounding the taste buds with a few positively labeled TRCs at the margins of the taste buds.The presence of GABAergic receptors localized on Type II and Type III taste cells suggests that GABA is likely modulating evoked taste responses in the mouse taste bud

Spatial Distribution of the Cannabinoid Type 1 and Capsaicin Receptors May Contribute to the Complexity of Their Crosstalk

Angelika Varga has been supported by a European Union Marie Curie Intra-European Fellowship (254661), a Hungarian Social Renewal Operation Program (TÁMOP 4.1.2.E-13/1/KONV-2013-0010) and the Hungarian Brain Research program (KTIA_NAP_13-2-2014-0005) of the Hungarian Government. Agnes Jenes has been supported by a BJA/RCoA Project Grant. This work has also been supported, in part, by the BIOSS-2 Grant, Project A6.

GABAB receptor auxiliary subunits modulate Cav2.3-mediated release from medial habenula terminals

The synaptic connection from medial habenula (MHb) to interpeduncular nucleus (IPN) is critical for emotion-related behaviors and uniquely expresses R-type Ca2+ channels (Cav2.3) and auxiliary GABAB receptor (GBR) subunits, the K+-channel tetramerization domain-containing proteins (KCTDs). Activation of GBRs facilitates or inhibits transmitter release from MHb terminals depending on the IPN subnucleus, but the role of KCTDs is unknown. We therefore examined the localization and function of Cav2.3, GBRs, and KCTDs in this pathway in mice. We show in heterologous cells that KCTD8 and KCTD12b directly bind to Cav2.3 and that KCTD8 potentiates Cav2.3 currents in the absence of GBRs. In the rostral IPN, KCTD8, KCTD12b, and Cav2.3 co-localize at the presynaptic active zone. Genetic deletion indicated a bidirectional modulation of Cav2.3-mediated release by these KCTDs with a compensatory increase of KCTD8 in the active zone in KCTD12b-deficient mice. The interaction of Cav2.3 with KCTDs therefore scales synaptic strength independent of GBR activation

Nanodomain coupling between Ca2+ channels and Ca2+ sensors promotes fast and efficient transmitter release at a cortical GABAergic synapse

It is generally thought that transmitter release at mammalian central synapses is triggered by Ca²⁺ microdomains, implying loose coupling between presynaptic Ca²⁺ channels and Ca²⁺ sensors of exocytosis. Here we show that Ca²⁺ channel subunit immunoreactivity is highly concentrated in the active zone of GABAergic presynaptic terminals of putative parvalbumin-containing basket cells in the hippocampus. Paired recording combined with presynaptic patch pipette perfusion revealed that GABA release at basket cell-granule cell synapses is sensitive to millimolar concentrations of the fast Ca²⁺ chelator BAPTA but insensitive to the slow Ca²⁺ chelator EGTA. These results show that Ca²⁺ source and Ca²⁺ sensor are tightly coupled at this synapse, with distances in the range of 10–20 nm. Models of Ca²⁺ inflow-exocytosis coupling further reveal that the tightness of coupling increases efficacy, speed, and temporal precision of transmitter release. Thus, tight coupling contributes to fast feedforward and feedback inhibition in the hippocampal network

Cyclin D1 is required for proliferation of Olig2-expressing progenitor cells in the injured cerebral cortex

Little is known about the molecular mechanisms driving proliferation of glial cells after an insult to the central nervous system (CNS). To test the hypothesis that the G1 regulator cyclin D1 is critical for injury-induced cell division of glial cells, we applied an injury model that causes brain damage within a well-defined region. For this, we injected the neurotoxin ibotenic acid into the prefrontal cortex of adult mice, which leads to a local nerve cell loss but does not affect the survival of glial cells. Here, we show that cyclin D1 immunoreativity increases drastically after neurotoxin injection. We find that the cyclin D1-immunopositive (cyclin D1+) cell population within the lesioned area consists to a large extent of Olig2+ oligodendrocyte progenitor cells. Analysis of cyclin D1-deficient mice demonstrates that the proliferation rate of Olig2+ cells diminishes upon loss of cyclin D1. Further, we show that cyclin-dependent kinase (cdk) 4, but not cdk6 or cdk2, is essential for driving cell division of Olig2-expressing cells in our injury model. These data suggest that distinct cell cycle proteins regulate proliferation of Olig2+ progenitor cells following a CNS insult

Channels and Ca 2+ Sensors Promotes Fast and Efficient Transmitter Release at a Cortical GABAergic Synapse

inflow-exocytosis coupling further reveal that the tightness of coupling increases efficacy, speed, and temporal precision of transmitter release. Thus, tight coupling contributes to fast feedforward and feedback inhibition in the hippocampal network

Expression and distribution of metabotropic GABA receptor subtypes GABABR1 and GABABR2 during rat neocortical development

To understand the possible contribution of metabotropic γ-aminobutyric acid receptors (GABABR) in cortical development, we investigated the expression pattern and the cellular and subcellular localization of the GABABR1 and GABABR2 subtypes in the rat neocortex from embryonic day 14 (E14) to adulthood. At the light microscopic level, both GABABR1 and GABABR2 were detected as early as E14. During prenatal development, both subtypes were expressed highly in the cortical plate. Using double immunofluorescence, GABABR1 colocalized with GABABR2 in neurons of the marginal zone and subplate, indicating that these proteins are coexpressed and could be forming functional GABABRs during prenatal development in vivo. In contrast, only GABABR1 but not GABABR2 was detected in the tangentially migratory cells in the lower intermediate zone. During postnatal development, immunoreactivity for GABABR1 and GABABR2 was distributed mainly in pyramidal cells. Discrete GABABR1-immunopositive cell bodies of interneurons were present throughout the neocortex. In addition, GABABR1 but not GABABR2 was found in identified Cajal-Retzius cells in layer I. At the electron microscopic level, immunoreactivity for GABABR1 and GABABR2 was found in dendritic spines and dendritic shafts at extrasynaptic and perisynaptic sites throughout postnatal development. We further demonstrated the presynaptic localization of GABABR1 and GABABR2, as well as the association of the receptors with asymmetrical synaptic junctions. These results indicate potentially important roles for the GABABRs in the regulation of migratory processes during corticogenesis and in the modulation of synaptic transmission during early development of cortical circuitry.This work was made possible by grants from the European Community (QLG3-CT-1999–00192, R.L) and the Spanish Ministry of Science and Technology (PB97-0582-CO2-01, A.F).Peer reviewe

Distribution of metabotropic GABA receptor subunits GABAB1a/b and GABAB2 in the rat hippocampus during prenatal and postnatal development

Metabotropic γ-aminobutyric acid receptors (GABAB) play modulatory roles in central synaptic transmission and are involved in controlling neuronal migration during development. We used immunohistochemical methods to elucidate the expression pattern as well as the cellular and the precise subcellular localization of the GABAB1a/b and GABAB2 subunits in the rat hippocampus during prenatal and postnatal development. At the light microscopic level, both GABAB1a/b and GABAB2 were expressed in the hippocampal primordium from embryonic day E14. During postnatal development, immunoreactivity for GABAB1a/b and GABAB2 was distributed mainly in pyramidal cells, with discrete GABAB1a/b-immunopositive cell bodies of interneurons present throughout the hippocampus. Using double immunofluorescence, we demonstrated that during the second week of postnatal development, GABAB1a/b but not GABAB2 was expressed in glial cells throughout the hippocampal formation. At the electron microscopic level, GABAB1a/b and GABAB2 showed a similar distribution pattern during postnatal development. Thus, at all ages the two receptor subunits were located postsynaptically in dendritic spines and shafts at extrasynaptic and perisynaptic sites in both pyramidal and nonpyramidal cells. We further demonstrated that the two subunits were localized presynaptically along the extrasynaptic plasma membrane of axon terminals and along the presynaptic active zone in both asymmetrical and, to a lesser extent, symmetrical synapses. These results suggest that GABAB receptors are widely expressed in the hippocampus throughout development and that GABAB1a/b and GABAB2 form both pre- and postsynaptic receptors.Grant sponsor: Universidad de Castilla-La Mancha and JJCC; Grant sponsor: Human Frontier Science Program; Grant number: RGP107/2001; Grantsponsor: Deutsche Forschungsgemeinschaft; Grant number: SFB 505;Grant number: TP B5; Grant sponsor: Alexander von Humboldt Foundation.Peer reviewe

Stage-specific requirement for cyclin D1 in glial progenitor cells of the cerebral cortex

Despite the vast abundance of glial progenitor cells in the mouse brain parenchyma, little is known about the molecular mechanisms driving their proliferation in the adult. Here we unravel a critical role of the G1 cell cycle regulator cyclin D1 in controlling cell division of glial cells in the cortical grey matter. We detect cyclin D1 expression in Olig2-immunopositive (Olig2+) oligodendrocyte progenitor cells, as well as in Iba1+ microglia and S100β+ astrocytes in cortices of 3-month-old mice. Analysis of cyclin D1-deficient mice reveals a cell and stage-specific molecular control of cell cycle progression in the various glial lineages. While proliferation of fast dividing Olig2+ cells at early postnatal stages becomes gradually dependent on cyclin D1, this particular G1 regulator is strictly required for the slow divisions of Olig2+/NG2+ oligodendrocyte progenitors in the adult cerebral cortex. Further, we find that the population of mature oligodendrocytes is markedly reduced in the absence of cyclin D1, leading to a significant decrease in the number of myelinated axons in both the prefrontal cortex and the corpus callosum of 8-month-old mutant mice. In contrast, the pool of Iba1+ cells is diminished already at postnatal day 3 in the absence of cyclin D1, while the number of S100β+ astrocytes remains unchanged in the mutant