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Can diffuse extrasynaptic signaling form a guiding template?
Neurochemistry International 52 (2008) 31–33 www.elsevier.com/locate/neuint
Can diffuse extrasynaptic signaling form a guiding template? Alexey Semyanov a,b,* a
RIKEN Brain Science Institute (BSI), Neuronal Circuit Mechanisms Research Group, Semyanov Research Unit, Japan b Department of Neurodynamics and Neurobiology, Nizhny Novgorod State University, Russia Received 26 February 2007; received in revised form 24 July 2007; accepted 25 July 2007 Available online 8 August 2007
Abstract Brain functions such as information processing, learning and memory are commonly associated with changes in synaptic strength, the synaptic plasticity. Extrasynaptic diffusion of transmitters thought to mediate only a modulatory effect. Here I suggest a hypothesis that concentration profile of signaling molecules in the extracellular space can form a ‘‘diffuse guiding template’’ for signal propagation through neuronal network. Such template can be potentially involved in information processing and storage. This hypothesis requires further experimental investigation and, thus, provides a framework for future studies in the field of non-synaptic transmission in the brain. # 2007 Elsevier Ltd. All rights reserved. Keywords: Extrasynaptic communication; Volume transmission; Spillover; GABA; Glutamate; Astrocytes; Information processing
The idea of extrasynaptic communication in the brain was initially ignited by the concept of volume transmission (Vizi, 1984; Bunin and Wightman, 1999; Agnati et al., 2006). It was proposed that neurons function in synaptic and volume transmission modes (Agnati et al., 1995). The slow volume transmission mode was opposed to the fast synaptic (wiring) transmission. This concept was based on the fact that neurons are surrounded by moderate concentrations of various signaling molecules that may affect their properties by acting on both synaptic and extrasynaptic receptors. Because of its slow nature, volume transmission was considered to be a modulatory mechanism, while the synaptic signaling was proposed to be solely responsible for information processing. There were at least three main reasons for that. First, sensory information arrives into the brain through a chain of synaptic connections. Second, the information processing has to be fast to ensure adequate reaction of the animal to changes in the environment. Being fast, the synaptic signaling is therefore a better candidate for the basic mechanism of information processing than slow volume transmission. Third, the discovery of long term * Correspondence address: RIKEN Brain Science Institute (BSI), Neuronal Circuit Mechanisms Research Group, Semyanov Research Unit, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. E-mail address: [email protected]. URL: http://semyanov.brain.riken.jp/ 0197-0186/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2007.07.021
synaptic plasticity LTP (Bliss and Lomo, 1973) and LTD (Ito and Kano, 1982) fueled the concept that information is coded in the synaptic networks by changes in synaptic strength. 1. Fast action of extrasynaptic transmitters Several observations made later pointed to the fact that extrasynaptic signals are actually more complex than slow changes in ambient concentrations of neuromodulators. First, glutamate can escape the synaptic cleft and possibly reach high affinity glutamate receptors in the neighbouring synapses (Asztely et al., 1997). This phenomenon was named ‘‘spillover’’ and initially proposed to be a mechanism of intersynaptic crosstalk (Rusakov et al., 1999). These days, spillover of neurotransmitters is also considered to play a role in activation of high affinity extrasynaptic receptors. Glutamate spillover can activate extrasynaptic NMDA receptors (Lozovaya et al., 2004), kainate receptors (Semyanov and Kullmann, 2001), and mGluRs (Semyanov and Kullmann, 2000). GABA escaping from the synaptic cleft acts on extrasynaptic GABAB receptors (Scanziani, 2000) and is responsible for tonic activation of extrasynaptic GABAA receptors (Semyanov et al., 2004). Another important observation was that not only neurons, but also astrocytes can release glutamate and GABA (Parpura et al., 1994; Kozlov et al., 2006). The mechanisms of such release are largely unknown. Calcium dependent vesicular
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A. Semyanov / Neurochemistry International 52 (2008) 31–33
release of glutamate has been suggested (Montana et al., 2006, but see Fiacco et al., 2007). Interestingly the astrocytes also possess various receptors that can initiate calcium transients in them (Fiacco and McCarthy, 2006), and thus can participate in bi-directional diffuse communication with neurons. In case of synaptic spillover and vesicular release by astrocytes, the actions of glutamate and GABA are fast, as opposed to the original concept of slow volume transmission. The speed and the spatial restriction of these actions are determined by narrowness of extrasynaptic cleft, proximal location of extrasynaptic/astrocytic receptors and effective uptake. Indeed both slow volume transmission and fast extrasynaptic actions of glutamate and GABA can modulate synaptic signaling and the properties of neuronal membranes. Changes in ambient levels of such signaling molecules can synchronize activity of neighboring neurons (Carmignoto and Fellin, 2006) and/or affect neuronal network excitability (Semyanov et al., 2003). Noticeably, the fast extrasynaptic signaling can go beyond simple modulation of synaptic networks. For instance activation of kainate receptors in hippocampal interneurons either due to glutamate spillover (Semyanov and Kullmann, 2001) or release by astrocytes (Liu et al., 2004) can make cells to fire ectopic action potentials. This phenomenon corresponds to the classical definition of signal transmission rather than modulation. Thus, diffuse communication among brain cells (including neurons and glia) possess both modulatory and signaling functions. 2. Hypothesis of ‘‘extrasynaptic guiding template’’ The classical ‘‘synaptocentric’’ view holds that the signals that enter neuronal networks are transformed into new signals after passing through local synaptic connections. The type of the modification depends on the balance of excitatory and inhibitory synapses and the state of their plasticity (LTD/LTP) at a given moment of time. These days the concept of synaptic organization of the brain evolves into a more complex concept of the brain as a neuron–glial information network that also includes extrasynaptic diffuse action of transmitters (Vizi, 2000). I propose a schematic which describes this information processing network as a multilayer structure (Fig. 1). It includes layers of synaptic networks and layers of extrasynaptic sources of signaling molecules. Extrasynaptic signaling molecules can affect the properties of the synaptic network by acting on synapses or extrasynaptic neuronal membranes. Distributed sources of signaling molecules (synaptic spillover, nonsynaptic neuronal release, astrocytes) spatially co-exist with synaptic networks and form a concentration profile of ambient agonists of extrasynaptic neuronal and glial receptors. This profile is shaped by anisotropy of diffusion (Sykova, 2004) and anisotropy of uptake (Lehre and Rusakov, 2002) in the extracellular space. The effect of spatially and temporary inhomogeneous extrasynaptic signals depends on cell types and cell compartment specific distributions of extrasynaptic receptors (Semyanov, 2003; Semyanov et al., 2004). Thus, distributed sources of extrasynaptic signaling molecules, uptake, properties of extracellular space, and localization of
Fig. 1. Schematic representation of multilayer information processing network of brain cells. Principle neurons receive synaptic input of rate coded or phase locked information. This information is being transformed within the local networks of interneurons. The properties of the synaptic network are affected by temporarily and spatially heterogeneous concentration profile of extrasynaptic signaling molecules. This profile is formed due to activation of distributed release sources (e.g. active synapses, astrocytes, etc.), due to properties of extracellular space (diffusion coefficient, anisotropy, etc.) and uptake.
extrasynaptic receptors may form a template that guides the information propagation in the synaptic networks. Such hypothetic ‘‘guiding template’’ could be potentially as important as synaptic plasticity for information processing in the brain. Fast changes in extrasynaptic signal, which are thought to be essential for information processing are not required in this case. Extrasynaptic ‘‘guiding templates’’ being applied over the synaptic network have to be quasi-stationary for at least the time of signal propagation through entire synaptic network. However, contributions of individual players (immediate synaptic signals, receptor activation by escaped and ambient transmitters, release from glia, etc.) to signal transfer within a particular neuronal circuit could change substantially, in a state- and/or use-dependent way, thus, giving additional degree of complexity to the system and prompting further studies. Acknowledgement The work is supported by HFSP grant RGP0050/2006-C. References Agnati, L.F., Bjelke, B., Fuxe, K., 1995. Volume versus wiring transmission in the brain: a new theoretical frame for neuropsychopharmacology. Med. Res. Rev. 15, 33–45. Agnati, L.F., Leo, G., Zanardi, A., Genedani, S., Rivera, A., Fuxe, K., Guidolin, D., 2006. Volume transmission and wiring transmission from cellular to molecular networks: history and perspectives. Acta Physiol. (Oxford) 187, 329–344. Asztely, F., Erdemli, G., Kullmann, D.M., 1997. Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron 18, 281–293. Bliss, T.V., Lomo, T., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356. Bunin, M.A., Wightman, R.M., 1999. Paracrine neurotransmission in the CNS: involvement of 5-HT. Trends Neurosci. 22, 377–382.
A. Semyanov / Neurochemistry International 52 (2008) 31–33 Carmignoto, G., Fellin, T., 2006. Glutamate release from astrocytes as a nonsynaptic mechanism for neuronal synchronization in the hippocampus. J. Physiol. Paris 99, 98–102. Fiacco, T.A., Agulhon, C., Taves, S.R., Petravicz, J., Casper, K.B., Dong, X., Chen, J., McCarthy, K.D., 2007. Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron 54, 611–626. Fiacco, T.A., McCarthy, K.D., 2006. Astrocyte calcium elevations: properties, propagation, and effects on brain signaling. Glia 54, 676–690. Ito, M., Kano, M., 1982. Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci. Lett. 33, 253–258. Kozlov, A.S., Angulo, M.C., Audinat, E., Charpak, S., 2006. Target cell-specific modulation of neuronal activity by astrocytes. Proc. Natl. Acad. Sci. U.S.A. 103, 10058–10063. Lehre, K.P., Rusakov, D.A., 2002. Asymmetry of glia near central synapses favors presynaptically directed glutamate escape. Biophys. J. 83, 125–134. Liu, Q.S., Xu, Q., Arcuino, G., Kang, J., Nedergaard, M., 2004. Astrocytemediated activation of neuronal kainate receptors. Proc. Natl. Acad. Sci. U.S.A. 101, 3172–3177. Lozovaya, N.A., Grebenyuk, S.E., Tsintsadze, T., Feng, B., Monaghan, D.T., Krishtal, O.A., 2004. Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape ‘superslow’ afterburst EPSC in rat hippocampus. J. Physiol. 558, 451–463. Montana, V., Malarkey, E.B., Verderio, C., Matteoli, M., Parpura, V., 2006. Vesicular transmitter release from astrocytes. Glia 54, 700–715. Parpura, V., Basarsky, T.A., Liu, F., Jeftinija, K., Jeftinija, S., Haydon, P.G., 1994. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747.
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Rusakov, D.A., Kullmann, D.M., Stewart, M.G., 1999. Hippocampal synapses: do they talk to their neighbours? Trends Neurosci. 22, 382–388. Scanziani, M., 2000. GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity. Neuron 25, 673–681. Semyanov, A., 2003. Cell type specificity of GABA(A) receptor mediated signaling in the hippocampus. Curr. Drug Targets CNS Neurol. Disord. 2, 240–247. Semyanov, A., Kullmann, D.M., 2000. Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25, 663–672. Semyanov, A., Kullmann, D.M., 2001. Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat. Neurosci. 4, 718–723. Semyanov, A., Walker, M.C., Kullmann, D.M., 2003. GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat. Neurosci. 6, 484–490. Semyanov, A., Walker, M.C., Kullmann, D.M., Silver, R.A., 2004. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269. Sykova, E., 2004. Extrasynaptic volume transmission and diffusion parameters of the extracellular space. Neuroscience 129, 861–876. Vizi, E.S., 1984. Non-Synaptic Interactions Between Neurons: Modulation of Neurochemical Transmission. Pharmacological and Clinical Aspects. John Wiley & Sons. Vizi, E.S., 2000. Role of high-affinity receptors and membrane transporters in nonsynaptic communication and drug action in the central nervous system. Pharmacol. Rev. 52, 63–89.
Can diffuse extrasynaptic signaling form a guiding template? Alexey Semyanov a,b,* a
RIKEN Brain Science Institute (BSI), Neuronal Circuit Mechanisms Research Group, Semyanov Research Unit, Japan b Department of Neurodynamics and Neurobiology, Nizhny Novgorod State University, Russia Received 26 February 2007; received in revised form 24 July 2007; accepted 25 July 2007 Available online 8 August 2007
Abstract Brain functions such as information processing, learning and memory are commonly associated with changes in synaptic strength, the synaptic plasticity. Extrasynaptic diffusion of transmitters thought to mediate only a modulatory effect. Here I suggest a hypothesis that concentration profile of signaling molecules in the extracellular space can form a ‘‘diffuse guiding template’’ for signal propagation through neuronal network. Such template can be potentially involved in information processing and storage. This hypothesis requires further experimental investigation and, thus, provides a framework for future studies in the field of non-synaptic transmission in the brain. # 2007 Elsevier Ltd. All rights reserved. Keywords: Extrasynaptic communication; Volume transmission; Spillover; GABA; Glutamate; Astrocytes; Information processing
The idea of extrasynaptic communication in the brain was initially ignited by the concept of volume transmission (Vizi, 1984; Bunin and Wightman, 1999; Agnati et al., 2006). It was proposed that neurons function in synaptic and volume transmission modes (Agnati et al., 1995). The slow volume transmission mode was opposed to the fast synaptic (wiring) transmission. This concept was based on the fact that neurons are surrounded by moderate concentrations of various signaling molecules that may affect their properties by acting on both synaptic and extrasynaptic receptors. Because of its slow nature, volume transmission was considered to be a modulatory mechanism, while the synaptic signaling was proposed to be solely responsible for information processing. There were at least three main reasons for that. First, sensory information arrives into the brain through a chain of synaptic connections. Second, the information processing has to be fast to ensure adequate reaction of the animal to changes in the environment. Being fast, the synaptic signaling is therefore a better candidate for the basic mechanism of information processing than slow volume transmission. Third, the discovery of long term * Correspondence address: RIKEN Brain Science Institute (BSI), Neuronal Circuit Mechanisms Research Group, Semyanov Research Unit, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. E-mail address: [email protected]. URL: http://semyanov.brain.riken.jp/ 0197-0186/$ – see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuint.2007.07.021
synaptic plasticity LTP (Bliss and Lomo, 1973) and LTD (Ito and Kano, 1982) fueled the concept that information is coded in the synaptic networks by changes in synaptic strength. 1. Fast action of extrasynaptic transmitters Several observations made later pointed to the fact that extrasynaptic signals are actually more complex than slow changes in ambient concentrations of neuromodulators. First, glutamate can escape the synaptic cleft and possibly reach high affinity glutamate receptors in the neighbouring synapses (Asztely et al., 1997). This phenomenon was named ‘‘spillover’’ and initially proposed to be a mechanism of intersynaptic crosstalk (Rusakov et al., 1999). These days, spillover of neurotransmitters is also considered to play a role in activation of high affinity extrasynaptic receptors. Glutamate spillover can activate extrasynaptic NMDA receptors (Lozovaya et al., 2004), kainate receptors (Semyanov and Kullmann, 2001), and mGluRs (Semyanov and Kullmann, 2000). GABA escaping from the synaptic cleft acts on extrasynaptic GABAB receptors (Scanziani, 2000) and is responsible for tonic activation of extrasynaptic GABAA receptors (Semyanov et al., 2004). Another important observation was that not only neurons, but also astrocytes can release glutamate and GABA (Parpura et al., 1994; Kozlov et al., 2006). The mechanisms of such release are largely unknown. Calcium dependent vesicular
32
A. Semyanov / Neurochemistry International 52 (2008) 31–33
release of glutamate has been suggested (Montana et al., 2006, but see Fiacco et al., 2007). Interestingly the astrocytes also possess various receptors that can initiate calcium transients in them (Fiacco and McCarthy, 2006), and thus can participate in bi-directional diffuse communication with neurons. In case of synaptic spillover and vesicular release by astrocytes, the actions of glutamate and GABA are fast, as opposed to the original concept of slow volume transmission. The speed and the spatial restriction of these actions are determined by narrowness of extrasynaptic cleft, proximal location of extrasynaptic/astrocytic receptors and effective uptake. Indeed both slow volume transmission and fast extrasynaptic actions of glutamate and GABA can modulate synaptic signaling and the properties of neuronal membranes. Changes in ambient levels of such signaling molecules can synchronize activity of neighboring neurons (Carmignoto and Fellin, 2006) and/or affect neuronal network excitability (Semyanov et al., 2003). Noticeably, the fast extrasynaptic signaling can go beyond simple modulation of synaptic networks. For instance activation of kainate receptors in hippocampal interneurons either due to glutamate spillover (Semyanov and Kullmann, 2001) or release by astrocytes (Liu et al., 2004) can make cells to fire ectopic action potentials. This phenomenon corresponds to the classical definition of signal transmission rather than modulation. Thus, diffuse communication among brain cells (including neurons and glia) possess both modulatory and signaling functions. 2. Hypothesis of ‘‘extrasynaptic guiding template’’ The classical ‘‘synaptocentric’’ view holds that the signals that enter neuronal networks are transformed into new signals after passing through local synaptic connections. The type of the modification depends on the balance of excitatory and inhibitory synapses and the state of their plasticity (LTD/LTP) at a given moment of time. These days the concept of synaptic organization of the brain evolves into a more complex concept of the brain as a neuron–glial information network that also includes extrasynaptic diffuse action of transmitters (Vizi, 2000). I propose a schematic which describes this information processing network as a multilayer structure (Fig. 1). It includes layers of synaptic networks and layers of extrasynaptic sources of signaling molecules. Extrasynaptic signaling molecules can affect the properties of the synaptic network by acting on synapses or extrasynaptic neuronal membranes. Distributed sources of signaling molecules (synaptic spillover, nonsynaptic neuronal release, astrocytes) spatially co-exist with synaptic networks and form a concentration profile of ambient agonists of extrasynaptic neuronal and glial receptors. This profile is shaped by anisotropy of diffusion (Sykova, 2004) and anisotropy of uptake (Lehre and Rusakov, 2002) in the extracellular space. The effect of spatially and temporary inhomogeneous extrasynaptic signals depends on cell types and cell compartment specific distributions of extrasynaptic receptors (Semyanov, 2003; Semyanov et al., 2004). Thus, distributed sources of extrasynaptic signaling molecules, uptake, properties of extracellular space, and localization of
Fig. 1. Schematic representation of multilayer information processing network of brain cells. Principle neurons receive synaptic input of rate coded or phase locked information. This information is being transformed within the local networks of interneurons. The properties of the synaptic network are affected by temporarily and spatially heterogeneous concentration profile of extrasynaptic signaling molecules. This profile is formed due to activation of distributed release sources (e.g. active synapses, astrocytes, etc.), due to properties of extracellular space (diffusion coefficient, anisotropy, etc.) and uptake.
extrasynaptic receptors may form a template that guides the information propagation in the synaptic networks. Such hypothetic ‘‘guiding template’’ could be potentially as important as synaptic plasticity for information processing in the brain. Fast changes in extrasynaptic signal, which are thought to be essential for information processing are not required in this case. Extrasynaptic ‘‘guiding templates’’ being applied over the synaptic network have to be quasi-stationary for at least the time of signal propagation through entire synaptic network. However, contributions of individual players (immediate synaptic signals, receptor activation by escaped and ambient transmitters, release from glia, etc.) to signal transfer within a particular neuronal circuit could change substantially, in a state- and/or use-dependent way, thus, giving additional degree of complexity to the system and prompting further studies. Acknowledgement The work is supported by HFSP grant RGP0050/2006-C. References Agnati, L.F., Bjelke, B., Fuxe, K., 1995. Volume versus wiring transmission in the brain: a new theoretical frame for neuropsychopharmacology. Med. Res. Rev. 15, 33–45. Agnati, L.F., Leo, G., Zanardi, A., Genedani, S., Rivera, A., Fuxe, K., Guidolin, D., 2006. Volume transmission and wiring transmission from cellular to molecular networks: history and perspectives. Acta Physiol. (Oxford) 187, 329–344. Asztely, F., Erdemli, G., Kullmann, D.M., 1997. Extrasynaptic glutamate spillover in the hippocampus: dependence on temperature and the role of active glutamate uptake. Neuron 18, 281–293. Bliss, T.V., Lomo, T., 1973. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356. Bunin, M.A., Wightman, R.M., 1999. Paracrine neurotransmission in the CNS: involvement of 5-HT. Trends Neurosci. 22, 377–382.
A. Semyanov / Neurochemistry International 52 (2008) 31–33 Carmignoto, G., Fellin, T., 2006. Glutamate release from astrocytes as a nonsynaptic mechanism for neuronal synchronization in the hippocampus. J. Physiol. Paris 99, 98–102. Fiacco, T.A., Agulhon, C., Taves, S.R., Petravicz, J., Casper, K.B., Dong, X., Chen, J., McCarthy, K.D., 2007. Selective stimulation of astrocyte calcium in situ does not affect neuronal excitatory synaptic activity. Neuron 54, 611–626. Fiacco, T.A., McCarthy, K.D., 2006. Astrocyte calcium elevations: properties, propagation, and effects on brain signaling. Glia 54, 676–690. Ito, M., Kano, M., 1982. Long-lasting depression of parallel fiber-Purkinje cell transmission induced by conjunctive stimulation of parallel fibers and climbing fibers in the cerebellar cortex. Neurosci. Lett. 33, 253–258. Kozlov, A.S., Angulo, M.C., Audinat, E., Charpak, S., 2006. Target cell-specific modulation of neuronal activity by astrocytes. Proc. Natl. Acad. Sci. U.S.A. 103, 10058–10063. Lehre, K.P., Rusakov, D.A., 2002. Asymmetry of glia near central synapses favors presynaptically directed glutamate escape. Biophys. J. 83, 125–134. Liu, Q.S., Xu, Q., Arcuino, G., Kang, J., Nedergaard, M., 2004. Astrocytemediated activation of neuronal kainate receptors. Proc. Natl. Acad. Sci. U.S.A. 101, 3172–3177. Lozovaya, N.A., Grebenyuk, S.E., Tsintsadze, T., Feng, B., Monaghan, D.T., Krishtal, O.A., 2004. Extrasynaptic NR2B and NR2D subunits of NMDA receptors shape ‘superslow’ afterburst EPSC in rat hippocampus. J. Physiol. 558, 451–463. Montana, V., Malarkey, E.B., Verderio, C., Matteoli, M., Parpura, V., 2006. Vesicular transmitter release from astrocytes. Glia 54, 700–715. Parpura, V., Basarsky, T.A., Liu, F., Jeftinija, K., Jeftinija, S., Haydon, P.G., 1994. Glutamate-mediated astrocyte-neuron signalling. Nature 369, 744–747.
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Rusakov, D.A., Kullmann, D.M., Stewart, M.G., 1999. Hippocampal synapses: do they talk to their neighbours? Trends Neurosci. 22, 382–388. Scanziani, M., 2000. GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity. Neuron 25, 673–681. Semyanov, A., 2003. Cell type specificity of GABA(A) receptor mediated signaling in the hippocampus. Curr. Drug Targets CNS Neurol. Disord. 2, 240–247. Semyanov, A., Kullmann, D.M., 2000. Modulation of GABAergic signaling among interneurons by metabotropic glutamate receptors. Neuron 25, 663–672. Semyanov, A., Kullmann, D.M., 2001. Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat. Neurosci. 4, 718–723. Semyanov, A., Walker, M.C., Kullmann, D.M., 2003. GABA uptake regulates cortical excitability via cell type-specific tonic inhibition. Nat. Neurosci. 6, 484–490. Semyanov, A., Walker, M.C., Kullmann, D.M., Silver, R.A., 2004. Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci. 27, 262–269. Sykova, E., 2004. Extrasynaptic volume transmission and diffusion parameters of the extracellular space. Neuroscience 129, 861–876. Vizi, E.S., 1984. Non-Synaptic Interactions Between Neurons: Modulation of Neurochemical Transmission. Pharmacological and Clinical Aspects. John Wiley & Sons. Vizi, E.S., 2000. Role of high-affinity receptors and membrane transporters in nonsynaptic communication and drug action in the central nervous system. Pharmacol. Rev. 52, 63–89.