Metabotropic glutamate receptors and striatal synaptic plasticity: implications for neurological diseases
Introduction
Basal ganglia (BG) represent a richly interconnected group of brain nuclei that communicate with elements of the sensory, motor, cognitive, and motivational apparatus of the brain (Fig. 1). The observation of humans afflicted with neurodegenerative diseases affecting the BG, such as Parkinson's disease (PD) and Huntington's disease (HD), has provided the most widely accepted view of the function of these structures. Thus, BG appear to play a key role in the subtle regulation of voluntary and purposive movements (Albin et al., 1989, DeLong, 1990). Among the structures of the BG, the striatum represents the main input station from other brain structures, in particular the cortex and the thalamus. Corticostriatal afferents are the main glutamatergic extrinsic pathway of the BG, while the subthalamic nucleus (STN) represents the principal intrinsic glutamatergic structure of these brain nuclei. Another crucial input to the striatum arises from the substantia nigra pars compacta (SNc), whose fibers represent the main source of dopamine (DA) in the brain. The neuronal population of the striatum is constituted mainly (>95%) by GABAergic medium spiny neurons (10–18 μm soma diameter) projecting to the globus pallidus (GP) and the substantia nigra pars reticulata (SNr), two other key structures of the BG. There are two groups of these neurons: those of the “direct” pathway, which utilize substance P and express D1-like DA receptors, and those of the “indirect” pathway, utilizing enkephalin and bearing D2-like DA receptors (Preston et al., 1979, Park et al., 1980, Wilson and Groves, 1980, Smith and Bolam, 1990). See Fig. 1 for a schematic representation of BG circuitry and neurotransmitters. The striatum contains also three subclasses of interneurons (Kawaguchi, 1993, Kawaguchi et al., 1995): (i) fast-spiking, parvalbumin-containing, GABAergic interneurons; (ii) burst firing, NADPH-diaphorase/somatostatin-positive GABAergic; (iii) cholinergic large aspiny interneurons (20–50 μm soma diameter), which are probably the best characterized (Kawaguchi, 1993, Kawaguchi et al., 1995, Levy et al., 1997, Wilson et al., 1990). Thus, the information arising from several brain areas is integrated in the striatum, whose role is central in the BG and in the regulation of several processes of motor function and motor learning, as well as some forms of associative/visual learning (Groves, 1983, Bouyer et al., 1984, Freund et al., 1984, Graybiel, 1990, Smith and Bolam, 1990, Kotter, 1994, Sesack et al., 1994, Ariano et al., 1997). Changes in striatal synaptic transmission efficacy, i.e. striatal synaptic plasticity, are supposed to be the cellular basis for such complex integrative functions (Albin et al., 1989, Graybiel et al., 1994, Calabresi et al., 1992a, Calabresi et al., 1992b, Calabresi et al., 1996, Calabresi et al., 1997a, Lovinger et al., 1993, Walsh, 1993, Parker and Gaffan, 1998, Gubellini et al., 2001, Gubellini et al., 2003, Nieoullon, 2002). Moreover, both clinical and experimental evidence shows that short- and long-term changes in corticostriatal synaptic transmission may play a role in some pathophysiological conditions, such as PD and HD (Albin et al., 1989, Calabresi et al., 1993a, Calabresi et al., 1996, Calabresi et al., 1998c, Calabresi et al., 2001a, Calabresi et al., 2001b, Calabresi et al., 2002, Gubellini et al., 2002, Picconi et al., 2003).
Electrophysiological recordings performed in vivo have shown that striatal spiny neurons present an irregular firing, associated to wide fluctuations of the membrane potential (“up” and “down” states) lasting some seconds. This activity pattern seems to be triggered by the cortical and/or thalamic glutamatergic input, rather than being induced by intrinsic membrane properties of these cells (Wilson and Groves, 1980, Calabresi et al., 1990a, Calabresi et al., 1990b, Cowan and Wilson, 1994, Wilson and Kawaguchi, 1996, Stern et al., 1998). Over the last 15 years, the use of in vitro corticostriatal slices and the availability of more selective pharmacological compounds have allowed to better understand the role of the different neurotransmitters implicated in the control of the electrophysiological activity of striatal neurons (Akins et al., 1990, Calabresi et al., 1987, Cepeda et al., 1994, Howe and Surmeier, 1995). In addition, these compounds can be tested more efficiently and easily since they can be dissolved in the physiological solution perfusing the slice. In such in vitro preparation, which includes both cortex and striatum, as well as DAergic terminals, medium spiny neurons are generally at hyperpolarized potentials (around −85 mV) and quiet in terms of firing activity and membrane potential fluctuations. When recorded intracellularly, these cells have a membrane input resistance around 40 MΩ (measured at resting membrane potential by negative current steps) and show tonic action potentials of wide amplitude (around 100 mV) and short duration (1.1–1.3 ms) (Wilson and Groves, 1980, Calabresi et al., 1992a, Cepeda et al., 1994, Stern et al., 1998). Besides, cholinergic large aspiny interneurons have a less hyperpolarized membrane potential (about −61 mV) and a higher input resistance, and show a non-tonic firing, quickly inactivated and followed by a peculiar after-hyperpolarization. If hyperpolarized by a negative current step, these cells show a peculiar time-dependent hyperpolarized-activated cation current, the Ih current. Moreover, they sometimes have an irregular spontaneous firing activity at a frequency of 1–10 Hz (Wilson et al., 1990, Kawaguchi, 1993, Kawaguchi et al., 1995). In this in vitro slice preparation, intracellular or patch-clamp recordings from striatal neurons can show excitatory post-synaptic potentials (EPSPs) that can be evoked by means of electrically stimulating corticostriatal fibers. These EPSPs are mediated by glutamate, since in the presence of CNQX and AP-V (antagonists of AMPA and NMDA ionotropic glutamate receptor, respectively) they are inhibited. In particular, medium spiny neurons show an EPSP mediated mainly by AMPA receptor, since in these neurons the ionic channel of NMDA receptor is obstructed by Mg2+, due to their spontaneous hyperpolarized potential: when this receptor is de-inactivated by depolarizing the cell, or by utilizing a Mg2+-free perfusing solution, a NMDA component can be unmasked. Further electrophysiological studies have shown that the responses of striatal medium spiny neurons to the activation of their different receptors are more complex that a mere depolarization (excitation) or hyperpolarization (inhibition). Many neurotransmitters, in fact, such as DA or acetylcholine (ACh), while playing a key role in the integrative activity of the striatum, do not provoke themselves any remarkable effect on the basic membrane properties (resting potential, resistance, firing, etc.) of spiny neurons. However, these neurotransmitters can interact, exerting a modulatory action on striatal synaptic transmission through pre- and post-synaptic mechanisms, and thus also affecting the function of glutamate system (Mitchell and Doggett, 1980, Rowlands and Roberts, 1980, Brown and Arbuthnott, 1983, Kerkerian et al., 1987, Nishi et al., 1990, Garcia-Munoz et al., 1991, Cepeda et al., 1993, Yan et al., 1997, Calabresi et al., 2000b, Centonze et al., 2001b, Kulagina et al., 2001).
Section snippets
Long-term depression and long-term potentiation in the striatum
The two “classic” forms of synaptic plasticity, long-term depression (LTD) and long-term potentiation (LTP), have been described at corticostriatal synapse on medium spiny neurons, both in vitro (Calabresi et al., 1992a, Calabresi et al., 1992b, Lovinger et al., 1993, Walsh, 1993, Lovinger and Tyler, 1996, Wickens et al., 1996, Partridge et al., 2000, Lovinger et al., 2000) and in vivo (Charpier and Deniau, 1997, Reynolds and Wickens, 2000, Charpier et al., 1999, Mahon et al., 2004). This
The family of mGluRs
Pharmacological and molecular observations have shown, beside ionotropic glutamate receptors consisting in ligand-activated ionic channels (Sommer and Seeburg, 1992), the existence of glutamate receptors coupled to second-messenger systems through G-proteins. These glutamate G-protein coupled receptors (GPCRs) where initially pharmacologically characterized by their ability to be activated by (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; Schoepp et al., 1990, Schoepp and Conn,
Metabotropic glutamate receptors and corticostriatal LTD
Several studies have shown that mGluRs play a role in the induction of in vitro corticostriatal LTD: for example, broad spectrum mGluRs antagonists, such as l-2-amino-3-phosphonopropionate (l-AP3, Calabresi et al., 1992a, Calabresi et al., 1993b) or MCPG (Lovinger et al., 1999) can suppress this form of synaptic plasticity in rat slices. However, only the recent pharmacology and molecular biology advancements have given the opportunity to discern which mGluR subtype is selectively involved in
Metabotropic glutamate receptors and corticostriatal LTP
The induction of corticostriatal LTP on brain slices requires a strong glutamatergic signal through NMDA receptors, which in our conditions is de-inactivated by omitting Mg2+ from the solution perfusing the slice (see above; Calabresi et al., 1990b, Calabresi et al., 1992b). In these conditions, the pharmacological blockade of mGluR1 by LY 367385 cannot prevent the induction of LTP, but it can decrease its amplitude by about 50%. Blocking mGluR5 by MPEP reduces LTP amplitude in a similar way,
Group I mGluRs and NMDA responses in the striatum and in other brain areas
In the striatum, the activation of group I mGluRs leads to the enhancement of NMDA receptor-mediated responses recorded electrophysiologically from medium spiny neurons. This phenomenon can be obtained by incubating corticostriatal slices in 1S,3R-ACPD, as well as in 3,5-DHPG, and can be blocked by pre-incubation in MCPG. Moreover, group II or III agonists, such as DCG-IV or l-SOP have not such an effect. This potentiation of NMDA receptor by group I mGluRs activation can be mimicked by
Pathological forms of synaptic plasticity in the striatum
According to their proposed role in the cellular mechanisms of motor behavior and motor learning, LTD and LTP are considered as “physiological” forms of synaptic plasticity (Albin et al., 1989, Graybiel et al., 1994, Calabresi et al., 1992a, Calabresi et al., 1992b, Calabresi et al., 1996, Calabresi et al., 1997a, Calabresi et al., 2000d, Lovinger et al., 1993, Walsh, 1993, Parker and Gaffan, 1998, Gubellini et al., 2001, Gubellini et al., 2003, Nieoullon, 2002). Beside “physiological” LTD and
Metabotropic glutamate receptors as a potential target for Parkinson's disease
The symptoms characterizing PD are tremor, rigidity and bradykinesia. This highly disabling pathology is caused by the loss of DAergic neurons of SNc (see Fig. 10 for a description of the BG circuitry changes in PD, and Wichmann and DeLong, 2003). Since the early 1970s, the most effective therapies for PD are based on DA-mimetic treatments, primarily utilizing the DA precursor l-DOPA or other DAergic agents replacing the loss of this neurotransmitter. Unfortunately, these treatments, at
Conclusions
The understanding of BG's circuitry and function, and in particular of the striatum, has considerably evolved during these last 15 years. Part of these progresses are due to the study of the modulation and plasticity of corticostriatal synaptic transmission. Recently, the discovery and the molecular and pharmacological characterization of mGluRs have introduced a new and important element in these studies. While this element may represent a further challenge for the researchers involved in
Acknowledgements
We wish to thank Professor A. Nieoullon and Dr. C. Baunez for kindly reading, discussing and helping with the manuscript. This work was supported by a CNRS “C.R.A.” (year 2003) contract to P.G., and by Telethon (GP 02035) and F.I.R.B. 2001 grants to P.C.
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