@article{19498,
  abstract     = {A dynamic interplay between fast synaptic signals and slower neuromodulatory signals controls the excitatory/inhibitory (E/I) balance within neuronal circuits. The mechanisms by which neuropeptide signaling is regulated to maintain E/I balance remain uncertain. We designed a genetic screen to isolate genes involved in the peptidergic maintenance of the E/I balance in the C. elegans motor circuit. This screen identified the C. elegans orthologs of the presynaptic phosphoprotein synapsin (snn-1) and the protein phosphatase 1 (PP1) regulatory subunit PHACTR1 (phac-1). We demonstrate that both phac-1 and snn-1 alter the motor behavior of C. elegans, and genetic interactions suggest that SNN-1 contributes to PP1-PHAC-1 holoenzyme signaling. De novo variants of human PHACTR1, associated with early-onset epilepsies [developmental and epileptic encephalopathy 70 (DEE70)], when expressed in C. elegans resulted in constitutive PP1-PHAC-1 holoenzyme activity. Unregulated PP1-PHAC-1 signaling alters the synapsin and actin cytoskeleton and increases neuropeptide release by cholinergic motor neurons, which secondarily affects the presynaptic vesicle cycle. Together, these results clarify the dominant mechanisms of action of the DEE70 alleles and suggest that altered neuropeptide release may alter E/I balance in DEE70.},
  author       = {Stratigi, Aikaterini and Soler-García, Miguel and Krout, Mia and Shukla, Shikha and De Bono, Mario and Richmond, Janet E. and Laurent, Patrick},
  issn         = {1529-2401},
  journal      = {Journal of Neuroscience},
  number       = {13},
  publisher    = {Society for Neuroscience},
  title        = {{Neuroendocrine control of synaptic transmission by PHAC-1 in C. elegans}},
  doi          = {10.1523/JNEUROSCI.1767-23.2024},
  volume       = {45},
  year         = {2025},
}

@article{17092,
  abstract     = {Memories are thought to be stored in neural ensembles known as engrams that are specifically reactivated during memory recall. Recent studies have found that memory engrams of two events that happened close in time tend to overlap in the hippocampus and the amygdala, and these overlaps have been shown to support memory linking. It has been hypothesized that engram overlaps arise from the mechanisms that regulate memory allocation itself, involving neural excitability, but the exact process remains unclear. Indeed, most theoretical studies focus on synaptic plasticity and little is known about the role of intrinsic plasticity, which could be mediated by neural excitability and serve as a complementary mechanism for forming memory engrams. Here, we developed a rate-based recurrent neural network that includes both synaptic plasticity and neural excitability. We obtained structural and functional overlap of memory engrams for contexts that are presented close in time, consistent with experimental and computational studies. We then investigated the role of excitability in memory allocation at the network level and unveiled competitive mechanisms driven by inhibition. This work suggests mechanisms underlying the role of intrinsic excitability in memory allocation and linking, and yields predictions regarding the formation and the overlap of memory engrams.},
  author       = {Delamare, Geoffroy and Feitosa Tomé, Douglas and Clopath, Claudia},
  issn         = {1529-2401},
  journal      = {Journal of Neuroscience},
  number       = {21},
  publisher    = {Society for Neuroscience},
  title        = {{Intrinsic neural excitability biases allocation and overlap of memory engrams}},
  doi          = {10.1523/JNEUROSCI.0846-23.2024},
  volume       = {44},
  year         = {2024},
}

@article{13202,
  abstract     = {Phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) plays an essential role in neuronal activities through interaction with various proteins involved in signaling at membranes. However, the distribution pattern of PI(4,5)P2 and the association with these proteins on the neuronal cell membranes remain elusive. In this study, we established a method for visualizing PI(4,5)P2 by SDS-digested freeze-fracture replica labeling (SDS-FRL) to investigate the quantitative nanoscale distribution of PI(4,5)P2 in cryo-fixed brain. We demonstrate that PI(4,5)P2 forms tiny clusters with a mean size of ∼1000 nm2 rather than randomly distributed in cerebellar neuronal membranes in male C57BL/6J mice. These clusters show preferential accumulation in specific membrane compartments of different cell types, in particular, in Purkinje cell (PC) spines and granule cell (GC) presynaptic active zones. Furthermore, we revealed extensive association of PI(4,5)P2 with CaV2.1 and GIRK3 across different membrane compartments, whereas its association with mGluR1α was compartment specific. These results suggest that our SDS-FRL method provides valuable insights into the physiological functions of PI(4,5)P2 in neurons.},
  author       = {Eguchi, Kohgaku and Le Monnier, Elodie and Shigemoto, Ryuichi},
  issn         = {1529-2401},
  journal      = {The Journal of Neuroscience},
  number       = {23},
  pages        = {4197--4216},
  publisher    = {Society for Neuroscience},
  title        = {{Nanoscale phosphoinositide distribution on cell membranes of mouse cerebellar neurons}},
  doi          = {10.1523/JNEUROSCI.1514-22.2023},
  volume       = {43},
  year         = {2023},
}

@article{10051,
  abstract     = {Rab-interacting molecule (RIM)-binding protein 2 (BP2) is a multidomain protein of the presynaptic active zone (AZ). By binding to RIM, bassoon (Bsn), and voltage-gated Ca2+ channels (CaV), it is considered to be a central organizer of the topography of CaV and release sites of synaptic vesicles (SVs) at the AZ. Here, we used RIM-BP2 knock-out (KO) mice and their wild-type (WT) littermates of either sex to investigate the role of RIM-BP2 at the endbulb of Held synapse of auditory nerve fibers (ANFs) with bushy cells (BCs) of the cochlear nucleus, a fast relay of the auditory pathway with high release probability. Disruption of RIM-BP2 lowered release probability altering short-term plasticity and reduced evoked EPSCs. Analysis of SV pool dynamics during high-frequency train stimulation indicated a reduction of SVs with high release probability but an overall normal size of the readily releasable SV pool (RRP). The Ca2+-dependent fast component of SV replenishment after RRP depletion was slowed. Ultrastructural analysis by superresolution light and electron microscopy revealed an impaired topography of presynaptic CaV and a reduction of docked and membrane-proximal SVs at the AZ. We conclude that RIM-BP2 organizes the topography of CaV, and promotes SV tethering and docking. This way RIM-BP2 is critical for establishing a high initial release probability as required to reliably signal sound onset information that we found to be degraded in BCs of RIM-BP2-deficient mice in vivo. SIGNIFICANCE STATEMENT: Rab-interacting molecule (RIM)-binding proteins (BPs) are key organizers of the active zone (AZ). Using a multidisciplinary approach to the calyceal endbulb of Held synapse that transmits auditory information at rates of up to hundreds of Hertz with submillisecond precision we demonstrate a requirement for RIM-BP2 for normal auditory signaling. Endbulb synapses lacking RIM-BP2 show a reduced release probability despite normal whole-terminal Ca2+ influx and abundance of the key priming protein Munc13-1, a reduced rate of SV replenishment, as well as an altered topography of voltage-gated (CaV)2.1 Ca2+ channels, and fewer docked and membrane proximal synaptic vesicles (SVs). This hampers transmission of sound onset information likely affecting downstream neural computations such as of sound localization.},
  author       = {Butola, Tanvi and Alvanos, Theocharis and Hintze, Anika and Koppensteiner, Peter and Kleindienst, David and Shigemoto, Ryuichi and Wichmann, Carolin and Moser, Tobias},
  issn         = {1529-2401},
  journal      = {Journal of Neuroscience},
  number       = {37},
  pages        = {7742--7767},
  publisher    = {Society for Neuroscience},
  title        = {{RIM-binding protein 2 organizes Ca<sup>21</sup> channel topography and regulates release probability and vesicle replenishment at a fast central synapse}},
  doi          = {10.1523/JNEUROSCI.0586-21.2021},
  volume       = {41},
  year         = {2021},
}

@article{9073,
  abstract     = {The sensory and cognitive abilities of the mammalian neocortex are underpinned by intricate columnar and laminar circuits formed from an array of diverse neuronal populations. One approach to determining how interactions between these circuit components give rise to complex behavior is to investigate the rules by which cortical circuits are formed and acquire functionality during development. This review summarizes recent research on the development of the neocortex, from genetic determination in neural stem cells through to the dynamic role that specific neuronal populations play in the earliest circuits of neocortex, and how they contribute to emergent function and cognition. While many of these endeavors take advantage of model systems, consideration will also be given to advances in our understanding of activity in nascent human circuits. Such cross-species perspective is imperative when investigating the mechanisms underlying the dysfunction of early neocortical circuits in neurodevelopmental disorders, so that one can identify targets amenable to therapeutic intervention.},
  author       = {Hanganu-Opatz, Ileana L. and Butt, Simon J. B. and Hippenmeyer, Simon and De Marco García, Natalia V. and Cardin, Jessica A. and Voytek, Bradley and Muotri, Alysson R.},
  issn         = {1529-2401},
  journal      = {The Journal of Neuroscience},
  keywords     = {General Neuroscience},
  number       = {5},
  pages        = {813--822},
  publisher    = {Society for Neuroscience},
  title        = {{The logic of developing neocortical circuits in health and disease}},
  doi          = {10.1523/jneurosci.1655-20.2020},
  volume       = {41},
  year         = {2021},
}

@article{8084,
  abstract     = {Origin and functions of intermittent transitions among sleep stages, including brief awakenings and arousals, constitute a challenge to the current homeostatic framework for sleep regulation, focusing on factors modulating sleep over large time scales. Here we propose that the complex micro-architecture characterizing sleep on scales of seconds and minutes results from intrinsic non-equilibrium critical dynamics. We investigate θ- and δ-wave dynamics in control rats and in rats where the sleep-promoting ventrolateral preoptic nucleus (VLPO) is lesioned (male Sprague-Dawley rats). We demonstrate that bursts in θ and δ cortical rhythms exhibit complex temporal organization, with long-range correlations and robust duality of power-law (θ-bursts, active phase) and exponential-like (δ-bursts, quiescent phase) duration distributions, features typical of non-equilibrium systems self-organizing at criticality. We show that such non-equilibrium behavior relates to anti-correlated coupling between θ- and δ-bursts, persists across a range of time scales, and is independent of the dominant physiologic state; indications of a basic principle in sleep regulation. Further, we find that VLPO lesions lead to a modulation of cortical dynamics resulting in altered dynamical parameters of θ- and δ-bursts and significant reduction in θ–δ coupling. Our empirical findings and model simulations demonstrate that θ–δ coupling is essential for the emerging non-equilibrium critical dynamics observed across the sleep–wake cycle, and indicate that VLPO neurons may have dual role for both sleep and arousal/brief wake activation. The uncovered critical behavior in sleep- and wake-related cortical rhythms indicates a mechanism essential for the micro-architecture of spontaneous sleep-stage and arousal transitions within a novel, non-homeostatic paradigm of sleep regulation.},
  author       = {Lombardi, Fabrizio and Gómez-Extremera, Manuel and Bernaola-Galván, Pedro and Vetrivelan, Ramalingam and Saper, Clifford B. and Scammell, Thomas E. and Ivanov, Plamen Ch.},
  issn         = {1529-2401},
  journal      = {Journal of Neuroscience},
  number       = {1},
  pages        = {171--190},
  publisher    = {Society for Neuroscience},
  title        = {{Critical dynamics and coupling in bursts of cortical rhythms indicate non-homeostatic mechanism for sleep-stage transitions and dual role of VLPO neurons in both sleep and wake}},
  doi          = {10.1523/jneurosci.1278-19.2019},
  volume       = {40},
  year         = {2020},
}

@article{7339,
  abstract     = {Cytoskeletal filaments such as microtubules (MTs) and filamentous actin (F-actin) dynamically support cell structure and functions. In central presynaptic terminals, F-actin is expressed along the release edge and reportedly plays diverse functional roles, but whether axonal MTs extend deep into terminals and play any physiological role remains controversial. At the calyx of Held in rats of either sex, confocal and high-resolution microscopy revealed that MTs enter deep into presynaptic terminal swellings and partially colocalize with a subset of synaptic vesicles (SVs). Electrophysiological analysis demonstrated that depolymerization of MTs specifically prolonged the slow-recovery time component of EPSCs from short-term depression induced by a train of high-frequency stimulation, whereas depolymerization of F-actin specifically prolonged the fast-recovery component. In simultaneous presynaptic and postsynaptic action potential recordings, depolymerization of MTs or F-actin significantly impaired the fidelity of high-frequency neurotransmission. We conclude that MTs and F-actin differentially contribute to slow and fast SV replenishment, thereby maintaining high-frequency neurotransmission.},
  author       = {Piriya Ananda Babu, Lashmi and Wang, Han Ying and Eguchi, Kohgaku and Guillaud, Laurent and Takahashi, Tomoyuki},
  issn         = {1529-2401},
  journal      = {Journal of neuroscience},
  number       = {1},
  pages        = {131--142},
  publisher    = {Society for Neuroscience},
  title        = {{Microtubule and actin differentially regulate synaptic vesicle cycling to maintain high-frequency neurotransmission}},
  doi          = {10.1523/JNEUROSCI.1571-19.2019},
  volume       = {40},
  year         = {2020},
}

@article{2018,
  abstract     = {Synaptic cell adhesion molecules are increasingly gaining attention for conferring specific properties to individual synapses. Netrin-G1 and netrin-G2 are trans-synaptic adhesion molecules that distribute on distinct axons, and their presence restricts the expression of their cognate receptors, NGL1 and NGL2, respectively, to specific subdendritic segments of target neurons. However, the neural circuits and functional roles of netrin-G isoform complexes remain unclear. Here, we use netrin-G-KO and NGL-KO mice to reveal that netrin-G1/NGL1 and netrin-G2/NGL2 interactions specify excitatory synapses in independent hippocampal pathways. In the hippocampal CA1 area, netrin-G1/NGL1 and netrin-G2/NGL2 were expressed in the temporoammonic and Schaffer collateral pathways, respectively. The lack of presynaptic netrin-Gs led to the dispersion of NGLs from postsynaptic membranes. In accord, netrin-G mutant synapses displayed opposing phenotypes in long-term and short-term plasticity through discrete biochemical pathways. The plasticity phenotypes in netrin-G-KOs were phenocopied in NGL-KOs, with a corresponding loss of netrin-Gs from presynaptic membranes. Our findings show that netrin-G/NGL interactions differentially control synaptic plasticity in distinct circuits via retrograde signaling mechanisms and explain how synaptic inputs are diversified to control neuronal activity.},
  author       = {Matsukawa, Hiroshi and Akiyoshi Nishimura, Sachiko and Zhang, Qi and Luján, Rafael and Yamaguchi, Kazuhiko and Goto, Hiromichi and Yaguchi, Kunio and Hashikawa, Tsutomu and Sano, Chie and Shigemoto, Ryuichi and Nakashiba, Toshiaki and Itohara, Shigeyoshi},
  issn         = {1529-2401},
  journal      = {Journal of Neuroscience},
  number       = {47},
  pages        = {15779 -- 15792},
  publisher    = {Society for Neuroscience},
  title        = {{Netrin-G/NGL complexes encode functional synaptic diversification}},
  doi          = {10.1523/JNEUROSCI.1141-14.2014},
  volume       = {34},
  year         = {2014},
}

@article{6126,
  abstract     = {Aerobic animals constantly monitor and adapt to changes in O2 levels. The molecular mechanisms involved in sensing O2 are, however, incompletely understood. Previous studies showed that a hexacoordinated globin called GLB-5 tunes the dynamic range of O2-sensing neurons in natural C. elegans isolates, but is defective in the N2 lab reference strain (McGrath et al., 2009; Persson et al., 2009). GLB-5 enables a sharp behavioral switch when O2 changes between 21 and 17%. Here, we show that GLB-5 also confers rapid behavioral and cellular recovery from exposure to hypoxia. Hypoxia reconfigures O2-evoked Ca2+ responses in the URX O2 sensors, and GLB-5 enables rapid recovery of these responses upon re-oxygenation. Forward genetic screens indicate that GLB-5's effects on O2 sensing require PDL-1, the C. elegans ortholog of mammalian PrBP/PDE6δ protein. In mammals, PDE6δ regulates the traffic and activity of prenylated proteins (Zhang et al., 2004; Norton et al., 2005). PDL-1 promotes localization of GCY-33 and GCY-35, atypical soluble guanylate cyclases that act as O2 sensors, to the dendritic endings of URX and BAG neurons, where they colocalize with GLB-5. Both GCY-33 and GCY-35 are predicted to be prenylated. Dendritic localization is not essential for GCY-35 to function as an O2 sensor, but disrupting pdl-1 alters the URX neuron's O2 response properties. Functional GLB-5 can restore dendritic localization of GCY-33 in pdl-1 mutants, suggesting GCY-33 and GLB-5 are in a complex. Our data suggest GLB-5 and the soluble guanylate cyclases operate in close proximity to sculpt O2 responses.},
  author       = {Gross, E. and Soltesz, Z. and Oda, S. and Zelmanovich, V. and Abergel, Z. and de Bono, Mario},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {50},
  pages        = {16726--16738},
  publisher    = {Society for Neuroscience},
  title        = {{GLOBIN-5-dependent O2 responses are regulated by PDL-1/PrBP that targets prenylated soluble guanylate cyclases to dendritic endings}},
  doi          = {10.1523/jneurosci.5368-13.2014},
  volume       = {34},
  year         = {2014},
}

@article{8025,
  abstract     = {Chandelier (axoaxonic) cells (ChCs) are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells. However, their circuit role and the function of their clearly defined anatomical specificity remain unclear. Recent work has demonstrated that chandelier cells can produce depolarizing GABAergic PSPs, occasionally driving postsynaptic targets to spike. On the other hand, other work suggests that ChCs are hyperpolarizing and may have an inhibitory role. These disparate functional effects may reflect heterogeneity among ChCs. Here, using brain slices from transgenic mouse strains, we first demonstrate that, across different neocortical areas and genetic backgrounds, upper Layer 2/3 ChCs belong to a single electrophysiologically and morphologically defined population, extensively sampling Layer 1 inputs with asymmetric dendrites. Consistent with being a single cell type, we find electrical coupling between ChCs. We then investigate the effect of chandelier cell activation on pyramidal neuron spiking in several conditions, ranging from the resting membrane potential to stimuli designed to approximate in vivo membrane potential dynamics. We find that under quiescent conditions, chandelier cells are capable of both promoting and inhibiting spike generation, depending on the postsynaptic membrane potential. However, during in vivo-like membrane potential fluctuations, the dominant postsynaptic effect was a strong inhibition. Thus, neocortical chandelier cells, even from within a homogeneous population, appear to play a dual role in the circuit, helping to activate quiescent pyramidal neurons, while at the same time inhibiting active ones.},
  author       = {Woodruff, A. R. and McGarry, L. M. and Vogels, Tim P and Inan, M. and Anderson, S. A. and Yuste, R.},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {49},
  pages        = {17872--17886},
  publisher    = {Society for Neuroscience},
  title        = {{State-dependent function of neocortical chandelier cells}},
  doi          = {10.1523/jneurosci.3894-11.2011},
  volume       = {31},
  year         = {2011},
}

@article{3826,
  abstract     = {Gamma frequency (30-100 Hz) oscillations in the mature cortex underlie higher cognitive functions. Fast signaling in GABAergic interneuron networks plays a key role in the generation of these oscillations. During development of the rodent brain, gamma activity appears at the end of the first postnatal week, but frequency and synchrony reach adult levels only by the fourth week. However, the mechanisms underlying the maturation of gamma activity are unclear. Here we demonstrate that hippocampal basket cells (BCs), the proposed cellular substrate of gamma oscillations, undergo marked changes in their morphological, intrinsic, and synaptic properties between postnatal day 6 (P6) and P25. During maturation, action potential duration, propagation time, duration of the release period, and decay time constant of IPSCs decreases by approximately 30-60%. Thus, postnatal development converts BCs from slow into fast signaling devices. Computational analysis reveals that BC networks with young intrinsic and synaptic properties as well as reduced connectivity generate oscillations with moderate coherence in the lower gamma frequency range. In contrast, BC networks with mature properties and increased connectivity generate highly coherent activity in the upper gamma frequency band. Thus, late postnatal maturation of BCs enhances coherence in neuronal networks and will thereby contribute to the development of cognitive brain functions.},
  author       = {Doischer, Daniel and Hosp, Jonas and Yanagawa, Yuchio and Obata, Kunihiko and Jonas, Peter M and Vida, Imre and Bartos, Marlene},
  issn         = {1529-2401},
  journal      = {The Journal of Neuroscience},
  number       = {48},
  pages        = {12956 -- 68},
  publisher    = {Society for Neuroscience},
  title        = {{Postnatal differentiation of basket cells from slow to fast signaling devices}},
  doi          = {10.1523/JNEUROSCI.2890-08.2008},
  volume       = {28},
  year         = {2008},
}

@article{8028,
  abstract     = {Transmission of signals within the brain is essential for cognitive function, but it is not clear how neural circuits support reliable and accurate signal propagation over a sufficiently large dynamic range. Two modes of propagation have been studied: synfire chains, in which synchronous activity travels through feedforward layers of a neuronal network, and the propagation of fluctuations in firing rate across these layers. In both cases, a sufficient amount of noise, which was added to previous models from an external source, had to be included to support stable propagation. Sparse, randomly connected networks of spiking model neurons can generate chaotic patterns of activity. We investigate whether this activity, which is a more realistic noise source, is sufficient to allow for signal transmission. We find that, for rate-coded signals but not for synfire chains, such networks support robust and accurate signal reproduction through up to six layers if appropriate adjustments are made in synaptic strengths. We investigate the factors affecting transmission and show that multiple signals can propagate simultaneously along different pathways. Using this feature, we show how different types of logic gates can arise within the architecture of the random network through the strengthening of specific synapses.},
  author       = {Vogels, Tim P and Abbott, L. F.},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {46},
  pages        = {10786--10795},
  publisher    = {Society for Neuroscience},
  title        = {{Signal propagation and logic gating in networks of integrate-and-fire neurons}},
  doi          = {10.1523/jneurosci.3508-05.2005},
  volume       = {25},
  year         = {2005},
}

@article{3804,
  abstract     = {Kv3 channels are thought to be essential for the fast-spiking (FS) phenotype in GABAergic interneurons, but how these channels confer the ability to generate action potentials (APs) at high frequency is unknown. To address this question, we developed a fast dynamic-clamp system (approximately 50 kHz) that allowed us to add a Kv3 model conductance to CA1 oriens alveus (OA) interneurons in hippocampal slices. Selective pharmacological block of Kv3 channels by 0.3 mm 4-aminopyridine or 1 mm tetraethylammonium ions led to a marked broadening of APs during trains of short stimuli and a reduction in AP frequency during 1 sec stimuli. The addition of artificial Kv3 conductance restored the original AP pattern. Subtraction of Kv3 conductance by dynamic clamp mimicked the effects of the blockers. Application of artificial Kv3 conductance also led to FS in OA interneurons after complete K+ channel block and even induced FS in hippocampal pyramidal neurons in the absence of blockers. Adding artificial Kv3 conductance with altered deactivation kinetics revealed a nonmonotonic relationship between mean AP frequency and deactivation rate, with a maximum slightly above the original value. Insertion of artificial Kv3 conductance with either lowered activation threshold or inactivation also led to a reduction in the mean AP frequency. However, the mechanisms were distinct. Shifting the activation threshold induced adaptation, whereas adding inactivation caused frequency-dependent AP broadening. In conclusion, Kv3 channels are necessary for the FS phenotype of OA interneurons, and several of their gating properties appear to be optimized for high-frequency repetitive activity.},
  author       = {Lien, Cheng and Jonas, Peter M},
  issn         = {1529-2401},
  journal      = {Journal of Neuroscience},
  keywords     = {Kv3 channels, dynamic clamp, fast spiking, deactivation kinetics, OA interneurons, hippocampal slices, two electrode current clamp},
  number       = {6},
  pages        = {2058 -- 68},
  publisher    = {Society for Neuroscience},
  title        = {{Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons}},
  doi          = {10.1523/JNEUROSCI.23-06-02058.2003},
  volume       = {23},
  year         = {2003},
}

@article{2635,
  abstract     = {Metabotropic GABAB receptors mediate slow inhibitory effects presynaptically and postsynaptically. Using preembedding immunohistochemical methods combined with quantitative analysis of GABAB receptor subunit immunoreactivity, this study provides a detailed description of the cellular and subcellular localization of GABAB1a/b and GABA B2 in the rat hippocampus. At the light microscopic level, an overlapping distribution of GABAB1a/b and GABAB2 was revealed in the dendritic layers of the hippocampus. In addition, expression of the GABAB1a/b subunit was found in somata of CA1 pyramidal cells and of a subset of GABAergic interneurons. At the electron microscopic level, immunoreactivity for both subunits was observed on presynaptic and, more abundantly, on postsynaptic elements. Presynaptically, subunits were mainly detected in the extrasynaptic membrane and occasionally over the presynaptic membrane specialization of putative glutamatergic and, to a lesser extent, GABAergic axon terminals. Postsynaptically, the majority of GABAB receptor subunits were localized to the extrasynaptic plasma membrane of spines and dendritic shafts of principal cells and shafts of interneuron dendrites. Quantitative analysis revealed enrichment of GABAB1a/b around putative glutamatergic synapses on spines and an even distribution on dendritic shafts of pyramidal cells contacted by GABAergic boutons. The association of GABAB receptors with glutamatergic synapses at both presynaptic and postsynaptic sides indicates their intimate involvement in the modulation of glutamatergic neurotransmission. The dominant extrasynaptic localization of GABAB receptor subunits suggests that their activation is dependent on spillover of GABA requiring simultaneous activity of populations of GABAergic cells as it occurs during population oscillations or epileptic seizures.},
  author       = {Kulik, Ákos and Vida, Imre and Luján, Rafael and Haas, Carola and López Bendito, Guillermina and Shigemoto, Ryuichi and Frotscher, Michael},
  issn         = {1529-2401},
  journal      = {Journal of Neuroscience},
  number       = {35},
  pages        = {11026 -- 11035},
  publisher    = {Society for Neuroscience},
  title        = {{Subcellular Localization of Metabotropic GABAB Receptor Subunits GABAB1a/b and GABAB2 in the Rat Hippocampus}},
  doi          = {10.1523/JNEUROSCI.23-35-11026.2003},
  volume       = {23},
  year         = {2003},
}

@article{2613,
  abstract     = {In this investigation, we report identification and characterization of a 95 kDa postsynaptic density protein (PSD-95)/discs-large/ ZO-1 (PDZ) domain-containing protein termed tamalin, also recently named GRP1-associated scaffold protein (GRASP), that interacts with group 1 metabotropic glutamate receptors (mGluRs). The yeast two-hybrid system and in vitro pull-down assays indicated that the PDZ domain-containing, amino-terminal half of tamalin directly binds to the class I PDZ-binding motif of group 1 mGluRs. The C-terminal half of tamalin also bound to cytohesins, the members of guanine nucleotide exchange factors (GEFs) specific for the ADP-ribosylation factor (ARF) family of small GTP-binding proteins. Tamalin mRNA is expressed predominantly in the telencephalic region and highly overlaps with the expression of group 1 mGluR mRNAs. Both tamalin and cytohesin-2 were enriched and codistributed with mGluR1a in postsynaptic membrane fractions. Importantly, recombinant and native mGluR1a/tamalin/cytohesin-2 complexes were coimmunoprecipitated from transfected COS-7 cells and rat brain tissue, respectively. Transfection of tamalin and mutant tamalin lacking a cytohesin-binding domain caused an increase and decrease in cell-surface expression of mGluR1a in COS-7 cells, respectively. Furthermore, adenovirus-mediated expression of tamalin and dominant-negative tamalin facilitated and reduced the neuritic distribution of endogenous mGluR5 in cultured hippocampal neurons, respectively. The results indicate that tamalin plays a key role in the association of group 1 mGluRs with the ARF-specific GEF proteins and contributes to intracellular trafficking and the macromolecular organization of group 1 mGluRs at synapses.},
  author       = {Kitano, Jun and Kimura, Kouji and Yamazaki, Yoshimitsu and Soda, Takeshi and Shigemoto, Ryuichi and Nakajima, Yoshiaki and Nakanishi, Shigetada},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {4},
  pages        = {1280 -- 1289},
  publisher    = {Society for Neuroscience},
  title        = {{Tamalin, a PDZ domain-containing protein, links a protein complex formation of group 1 metabotropic glutamate receptors and the guanine nucleotide exchange factor cytohesins}},
  doi          = {10.1523/JNEUROSCI.22-04-01280.2002},
  volume       = {22},
  year         = {2002},
}

@article{3802,
  abstract     = {The presynaptic Ca2+ signal is a key determinant of transmitter release at chemical synapses. In cortical synaptic terminals, however, little is known about the kinetic properties of the presynaptic Ca2+ channels. To investigate the timing and magnitude of the presynaptic Ca2+ inflow, we performed whole-cell patch-clamp recordings from mossy fiber boutons (MFBs) in rat hippocampus. MFBs showed large high-voltage-activated Ca(2+) currents, with a maximal amplitude of approximately 100 pA at a membrane potential of 0 mV. Both activation and deactivation were fast, with time constants in the submillisecond range at a temperature of approximately 23 degrees C. An MFB action potential (AP) applied as a voltage-clamp command evoked a transient Ca2+ current with an average amplitude of approximately 170 pA and a half-duration of 580 microsec. A prepulse to +40 mV had only minimal effects on the AP-evoked Ca2+ current, indicating that presynaptic APs open the voltage-gated Ca2+ channels very effectively. On the basis of the experimental data, we developed a kinetic model with four closed states and one open state, linked by voltage-dependent rate constants. Simulations of the Ca2+ current could reproduce the experimental data, including the large amplitude and rapid time course of the current evoked by MFB APs. Furthermore, the simulations indicate that the shape of the presynaptic AP and the gating kinetics of the Ca2+ channels are tuned to produce a maximal Ca2+ influx during a minimal period of time. The precise timing and high efficacy of Ca2+ channel activation at this cortical glutamatergic synapse may be important for synchronous transmitter release and temporal information processing.},
  author       = {Bischofberger, Josef and Geiger, Jörg and Jonas, Peter M},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {24},
  pages        = {10593 -- 10602},
  publisher    = {Society for Neuroscience},
  title        = {{Timing and efficacy of Ca(2+) channel activation in hippocampal mossy fiber boutons}},
  doi          = {10.1523/JNEUROSCI.22-24-10593.2002},
  volume       = {22},
  year         = {2002},
}

@article{2610,
  abstract     = {To study the role of mGlu7 receptors (mGluR7), we used homologous recombination to generate mice lacking this metabotropic receptor subtype (mGluR7 -/-). After the serendipitous discovery of a sensory stimulus-evoked epileptic phenotype, we tested two convulsant drugs, pentylenetetrazole (PTZ) and bicuculline. In animals aged 12 weeks and older, subthreshold doses of these drugs induced seizures in mGluR7 -/-, but not in mGluR7 +/-, mice. PTZ-induced seizures were inhibited by three standard anticonvulsant drugs, but not by the group III selective mGluR agonist (R,S)-4-phosphonophenylglycine (PPG). Consistent with the lack of signs of epileptic activity in the absence of specific stimuli, mGluR7 -/- mice showed no major changes in synaptic properties in two slice preparations. However, slightly increased excitability was evident in hippocampal slices. In addition, there was slower recovery from frequency facilitation in cortical slices, suggesting a role for mGluR7 as a frequency-dependent regulator in presynaptic terminals. Our findings suggest that mGluR7 receptors have a unique role in regulating neuronal excitability and that these receptors may be a novel target for the development of anticonvulsant drugs.},
  author       = {Sansig, Gilles and Bushell, Trevor and Clarke, Vernon and Rozov, Andrei and Burnashev, Nail and Portet, Chantal and Gasparini, Fabrizio and Schmutz, Markus and Klebs, Klaus and Shigemoto, Ryuichi and Flor, Peter and Kühn, Rainer and Knoepfel, Thomas and Schroeder, Markus and Hampson, David and Collett, Valerie and Zhang, Congxiao and Duvoisin, Robert and Collingridge, Graham and Van Der Putten, Herman},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {22},
  pages        = {8734 -- 8745},
  publisher    = {Society for Neuroscience},
  title        = {{Increased seizure susceptibility in mice lacking metabotropic glutamate receptor 7}},
  doi          = {10.1523/JNEUROSCI.21-22-08734.2001},
  volume       = {21},
  year         = {2001},
}

@article{3494,
  abstract     = {Mutual synaptic interactions between GABAergic interneurons are thought to be of critical importance for the generation of network oscillations and for temporal encoding of information in the hippocampus. However, the functional properties of synaptic transmission between hippocampal interneurons are largely unknown. We have made paired recordings from basket cells (BCs) in the dentate gyrus of rat hippocampal slices, followed by correlated light and electron microscopical analysis. Unitary GABAAreceptor-mediated IPSCs at BC–BC synapses recorded at the soma showed a fast rise and decay, with a mean decay time constant of 2.5 ± 0.2 msec (32°C). Synaptic transmission at BC–BC synapses showed paired-pulse depression (PPD) (32 ± 5% for 10 msec interpulse intervals) and multiple-pulse depression during repetitive stimulation. Detailed passive cable model simulations based on somatodendritic morphology and localization of synaptic contacts further indicated that the conductance change at the postsynaptic site was even faster, decaying with a mean time constant of 1.8 ± 0.6 msec. Sequential triple recordings revealed that the decay time course of IPSCs at BC–BC synapses was approximately twofold faster than that at BC–granule cell synapses, whereas the extent of PPD was comparable. To examine the consequences of the fast postsynaptic conductance change for the generation of oscillatory activity, we developed a computational model of an interneuron network. The model showed robust oscillations at frequencies &gt;60 Hz if the excitatory drive was sufficiently large. Thus the fast conductance change at interneuron–interneuron synapses may promote the generation of high-frequency oscillations observed in the dentate gyrusin vivo. },
  author       = {Bartos, Marlene and Vida, Imre and Frotscher, Michael and Geiger, Jörg and Jonas, Peter M},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {8},
  pages        = {2687 -- 2698},
  publisher    = {Society for Neuroscience},
  title        = {{Rapid signaling at inhibitory synapses in a dentate gyrus interneuron network.}},
  doi          = {10.1523/JNEUROSCI.21-08-02687.2001},
  volume       = {21},
  year         = {2001},
}

@article{3546,
  abstract     = {Local versus distant coherence of hippocampal CA1 pyramidal cells was investigated in the behaving rat. Temporal cross-correlation of pyramidal cells revealed a significantly stronger relationship among local (&lt;140 &lt;mu&gt;m) pyramidal neurons compared with distant (&gt;300 mum) neurons during non-theta-associated immobility and sleep but not during theta-associated running and walking. In contrast, cross-correlation between local pyramidal cell-interneuron pairs was significantly stronger than between distant pairs during theta oscillations but were similar during non-theta-associated behaviors. We suggest that network state-dependent functional clustering of neuronal activity emerges because of the differential contribution of the main excitatory inputs, the perforant path, and Schaffer collaterals during theta and non-theta behaviors.},
  author       = {Hirase, Hajima and Leinekugel, Xavier and Csicsvari, Jozsef L and Czurkó, András and Buzsáki, György},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {10},
  publisher    = {Society for Neuroscience},
  title        = {{Behavior-dependent states of the hippocampal network affect functional clustering of neurons}},
  doi          = {10.1523/JNEUROSCI.21-10-j0003.2001},
  volume       = {21},
  year         = {2001},
}

@article{2602,
  abstract     = {Although presynaptic localization of mGluR7 is well established, the mechanism by which the receptor may control Ca2+ channels in neurons is still unknown. We show here that cultured cerebellar granule cells express native metabotropic glutamate receptor type 7 (mGluR7) in neuritic processes, whereas transfected mGluR7 was also expressed in cell bodies. This allowed us to study the effect of the transfected receptor on somatic Ca2+ channels. In transfected neurons, mGuR7 selectively inhibited P/Q-type Ca2+ channels. The effect was mimicked by GTPγS and blocked by pertussis toxin (PTX) or a selective antibody raised against the G-protein αo subunit, indicating the involvement of a G(o)-like protein. The mGuR7 effect did not display the characteristics of a direct interaction between G-protein βγ subunits and the α1A Ca2+ channel subunit, but was abolished by quenching βγ subunits with specific intracellular peptides. Intracellular dialysis of G-protein βγ subunits did not mimic the action of mGluR7, suggesting that both G-protein βγ and αo subunits were required to mediate the effect. Inhibition of phospholipase C (PLC) blocked the inhibitory action of mGluR7, suggesting that a coincident activation of PLC by the G-protein βγ with αo subunits was required. The Ca2+ chelator BAPTA, as well as inhibition of either the inositol trisphosphate (IP3) receptor or protein kinase C (PKC) abolished the mGluR7 effect. Moreover, activation of native mGluR7 induced a PTX-dependent IP3 formation. These results indicated that IP3-mediated intracellular Ca2+ release was required for PKC-dependent inhibition of the Ca2+ channels. Possible control of synaptic transmission by the present mechanisms is discussed.},
  author       = {Perroy, Julie and Prezèau, Laurent and De Waard, Michel and Shigemoto, Ryuichi and Bockaërt, Joël and Fagni, Laurent},
  issn         = {0270-6474},
  journal      = {Journal of Neuroscience},
  number       = {21},
  pages        = {7896 -- 7904},
  publisher    = {Society for Neuroscience},
  title        = {{Selective blockade of P/Q-type calcium channels by the metabotropic glutamate receptor type 7 involves a phospholipase C pathway in neurons}},
  doi          = {10.1523/JNEUROSCI.20-21-07896.2000},
  volume       = {20},
  year         = {2000},
}