Non-synaptic receptors and transporters involved in brain functions and targets of drug treatment

Abstract

Beyond direct synaptic communication, neurons are able to talk to each other without making synapses. They are able to send chemical messages by means of diffusion to target cells via the extracellular space, provided that the target neurons are equipped with high-affinity receptors. While synaptic transmission is responsible for the 'what' of brain function, the 'how' of brain function (mood, attention, level of arousal, general excitability, etc.) is mainly controlled non-synaptically using the extracellular space as communication channel. It is principally the 'how' that can be modulated by medicine. In this paper, we discuss different forms of non-synaptic transmission, localized spillover of synaptic transmitters, local presynaptic modulation and tonic influence of ambient transmitter levels on the activity of vast neuronal populations. We consider different aspects of non-synaptic transmission, such as synaptic-extrasynaptic receptor trafficking, neuron-glia communication and retrograde signalling. We review structural and functional aspects of non-synaptic transmission, including (i) anatomical arrangement of non-synaptic release sites, receptors and transporters, (ii) intravesicular, intra- and extracellular concentrations of neurotransmitters, as well as the spatiotemporal pattern of transmitter diffusion. We propose that an effective general strategy for efficient pharmacological intervention could include the identification of specific non-synaptic targets and the subsequent development of selective pharmacological tools to influence them.

Figure 1

Scheme of the arborization of different neurons in the hippocampus. Arrows indicate varicosities, while the arrowheads show the bifurcation of branches. The average length of axonal arborization (mm) per cell body, number of boutons per cell body, percentage of non-synaptic boutons and density of boutons are given (10⁶·mm⁻³). ¹Aznavour et al. (2002), ²Descarries et al. (1997), ³Umbriaco et al. (1995), ⁴Vizi and Kiss (1998), ⁵Hökfelt (1968), ⁶Oleskevich et al. (1989), ⁷Descarries et al. (1990), ⁸Gulyas et al. (1993), ⁹Olah et al. (2009). The inset shows axonal varicosities of a GABAergic interneuron from the rat hippocampus (A. Barth, N. Hájos and E.S. Vizi, Institute of Experimental Medicine, unpublished data) using a two-photon laser-scanning microscope (for method see Rozsa et al. 2004 and Vizi et al., 2004a). Scale bars are 10 and 50 µm, as indicated.

Figure 2

Subcellular localization of mGlu receptors at synaptic and non-synaptic (perisynaptic or extrasynaptic) sites. Group I mGlu receptors are concentrated at the postsynaptic membrane in a perisynaptic annulus, but are also present extrasynaptically. Group II mGlu receptors are located extrasynaptically along axons and axon terminals, while group III mGlu receptors are expressed in the presynaptic active zone. ¹Lujan et al. (1996), ²Ohishi et al. (1994), ³Petralia et al. (1996), ⁴Lujan et al. (1997), ⁵Corti et al. (2002), ⁶Shigemoto et al. (1997), ⁷Baude et al. (1993), ⁸Bradley et al. (1996), ⁹Tamaru et al. (2001), ¹⁰Uchigashima et al. (2007). *mGlu3 can be found in a postsynaptic localization in the hippocampus and striatum but not in the ventrobasal nuclear complex of the thalamus.

Figure 3

Relevance of NMDA receptor localization composed of NR1/NR2A or NR1/NR2B assemblies. It was proposed that NR1/NR2A receptors, which have a lower affinity for glutamate and glycine than NR1/NR2B receptors (Yamakura and Shimoji, 1999), reside in the synapse, while NR1/NR2B receptors are located at extrasynaptic sites. However, it has been shown that this separation evolves only during postnatal development when the NR1/NR2B receptors exchange for NR1/NR2A receptors in the synapse (Tovar and Westbrook, 1999). This dynamic view of NMDA receptor subtypes was completed by the observation that NMDA receptors can move laterally between synaptic and extrasynaptic sites within the plasma membrane (Tovar and Westbrook, 2002; Triller and Choquet, 2005). Groc et al. have shown that NR1/NR2A assemblies diffuse laterally more than two order of magnitude slower than NR1/NR2B receptors (Groc et al., 2009; Groc et al., 2006; see thick purple and thin green arrows representing the mobility of NR1/NR2A and NR1/NR2B assemblies, respectively). The different subcellular locations of NR1/NR2A and NR1/NR2B assemblies determine the source of glutamate being able to activate these receptors. While the NR1/NR2A assemblies are activated by glutamate released in the synapse, the origin of glutamate activating NR1/NR2B assemblies can be: (i) the spillover of synaptic glutamate following high frequency stimulation (Huang, 1998; Vizi and Mike, 2006), (ii) the reversal of glutamate transporters (EAAT1-4) mainly in neurons (Rossi et al., 2007), (iii) the vesicular glutamate release from glial processes in the tripartite synapses (Haydon and Carmignoto, 2006; Perea et al., 2009). The latter is the basis of glia-neuron interaction and can affect both the presynaptic and postsynaptic NR1/NR2B assemblies and either enhances synaptic strength or mediates slow inward currents, respectively (Fellin et al., 2004; Jourdain et al., 2007). Functions of synaptic NR1/NR2A and extrasynaptic NR1/NR2B receptors are opposing to some extent (Haydon and Carmignoto, 2006): (i) NR1/NR2A promote, while NR1/NR2B inhibit AMPA receptor trafficking (Kim et al., 2005), (ii) NR1/NR2A induces the neuroprotective CREB (cAMP response element binding protein) pathway, while NR1/NR2B shuts it down and promotes neuronal death (Hardingham et al., 2002), (iii) NR1/NR2A induces long-term potentiation, while NR1/NR2B seems to be relevant in long-term depression (Liu et al., 2004a; Massey et al., 2004).

Figure 4

Scheme of different types of chemical communication, including synaptic transmission when the transmitter released into the synaptic gap acts on postsynaptic low affinity receptors located in the synaptic gap, and non-synaptic communication when the transmitter spills over from the synaptic gap or is released from a bouton without making synaptic contact and reaches its target non-synaptic (perisynaptic or extrasynaptic) receptors by diffusion. The distance could be from a few hundred nm to a few hundred µm. Note the significant difference in concentration in the vesicle (∼100 mM), in the synaptic gap (∼1 mM) and in the extrasynaptic space (∼0.01–3 µM). Concentrations in the figure are approximate values from the literature (see Table 4).