Brain Research Reviews 40 (2002) 9–18www.elsevier.com/ locate/brainresrev

Review

M etabotropic glutamate receptors provide intrinsic modulation of thelamprey locomotor network

*Abdeljabbar El Manira , Petronella Kettunen, Dietmar Hess, Patrik KriegerNobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden

Abstract

Spinal networks generate the motor pattern underlying locomotion. These are subject to modulatory systems that influence theiroperation and thereby result in a flexible network organization. In this review, we have summarized the mechanisms by which thedifferent metabotropic glutamate receptor subtypes fine-tune the cellular and synaptic properties and thus underlie intrinsic modulation ofthe activity of the locomotor network in the lamprey. 2002 Elsevier Science B.V. All rights reserved.

21Keywords: Metabotropic glutamate receptors; Locomotion; Presynaptic inhibition; Ca oscillations; Modulation

Contents

1 . Introduction ............................................................................................................................................................................................ 92 . Presynaptic group II and III mGluRs inhibit synaptic transmission .............................................................................................................. 103 . Mechanisms of presynaptic inhibition mediated by mGluRs ....................................................................................................................... 124 . Postsynaptic group I mGluRs regulate the excitability of spinal neurons ...................................................................................................... 125 . Cellular action of group I mGluR subtypes, mGluR1 and mGluR5 .............................................................................................................. 126 . Group I mGluRs may facilitate synaptic transmission in larval lampreys ..................................................................................................... 137 . Presynaptic group III mGluRs modulate the burst frequency and synaptic transmission from network neurons ............................................... 138 . Endogenous activation of mGluR1 during locomotor activity...................................................................................................................... 149 . Presynaptic facilitation does not contribute to the modulation of the locomotor rhythm by mGluR1............................................................... 151 0. Endogenous activation of mGluR5 produces effects opposite to mGluR1 on the locomotor rhythm.............................................................. 161 1. Concluding remarks ............................................................................................................................................................................... 16Acknowledgements ...................................................................................................................................................................................... 17References................................................................................................................................................................................................... 17

1 . Introduction generated by spinal networks whose activity can beinitiated from supraspinal centers (networks) in the brain-

The activity in the central nervous system emerges from stem and forebrain [17,26,40,41,52,57]. To understand thedistinct networks, which control different functions rang- cellular mechanisms underlying motor behavior we need toing from sensory-motor processing to complex cognitive define the different types of neurons involved, theirtasks. The large building blocks in many control systems connectivity, the receptor and channel subtypes theyare similar in all vertebrates from cyclostomes to mam- possess, and their modulation by various transmitters. Themals. With regard to locomotion, the basic motor pattern is intrinsic mode of operation of spinal networks is now

being revealed using amenable model systems such as thefrog embryo [5,15,47,55], the lamprey [9,20,21] and theneonatal rat spinal cord [11,30,50]. In the lamprey, thebasic circuitry responsible for the generation of the un-*Corresponding author. Tel.:146-8-728-6911; fax:146-8-349-544.

E-mail address: abdel.elmanira@neuro.ki.se(A. El Manira). dulatory swimming activity consists of ipsilaterally pro-

0165-0173/02/$ – see front matter 2002 Elsevier Science B.V. All rights reserved.PI I : S0165-0173( 02 )00184-4

10 A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18

jecting excitatory interneurons and contralaterally project- 2 . Presynaptic group II and III mGluRs inhibiting inhibitory interneurons. The latter underlie reciprocal synaptic transmissioninhibition and thus allows for alternation of activitybetween the left and right side. The spinal network is The modulation of the lamprey spinal locomotor net-subject to influence from various modulators, which act work by mGluRs involves activation of both presynapticthrough specific receptors to regulate ion channels, ionot- and postsynaptic receptors. The localization and cellularropic receptors in soma/dendrites or the efficacy of effects of the receptor subtypes were first characterized atsynaptic transmission. This type of control results in a very the reticulospinal synapse in the spinal cord. Reticulospinalflexible network organization that allows a fine-tuning of neurons are responsible for the initiation of locomotionthe locomotor network to meet different environmental [40]. Their axons make monosynaptic en passant synapsesdemands. with motoneurons, excitatory and inhibitory interneurons

Fine-tuning of the activity of the spinal networks and provide glutamatergic EPSPs via ionotropic NMDAinvolves usually an activation of G-protein-coupled and AMPA receptors to trigger the activity of themetabotropic receptors, which have a comparatively slow locomotor network [44,48,53].onset of action, while their effects may last from seconds, The mGluR subtypes modulating the reticulospinalto hours or even days. The modulation of neuronal transmission were characterized by using paired intracellu-properties allows the nervous system not only to adapt its lar recordings from single reticulospinal axons and their

21output to relatively brief changes in the environment, but postsynaptic target neurons in vitro in high Ca , high21also provides the means for long-lasting changes in Mg solution to minimize polysynaptic transmission [32].

behavior [16,22,27,42,43]. Extrinsic neuromodulation cor- Activation of presynaptic group II mGluRs byL-CCG-I orresponds to fine-tuning mediated by transmitters released ACPD (which also acts on group I mGluRs) and the groupfrom neurons not being part of the network. In contrast, III mGluRs byL-AP4 both reduced the amplitude of theintrinsic neuromodulation is mediated by transmitters reticulospinal EPSP (Fig. 1). TheL-AP4-induced depres-released from network neurons that act on receptors to sion of the reticulospinal synaptic transmission was coun-shape the ongoing activity of the network. In this review, teracted by the group III antagonist MAP4 (Fig. 1A, C).we will summarize the mechanisms by which the different This antagonist did, however, not affect ACPD-mediatedmetabotropic glutamate receptor (mGluR) subtypes under- presynaptic inhibition, which is most likely mediated bylie intrinsic modulation of the activity of the locomotor group II mGluRs (Fig. 1A, B).network in the lamprey. Glutamate is of particular impor- The ACPD- andL-AP4-induced inhibition of synaptictance since it is the main excitatory transmitter in the CNS transmission occurred without any change in the electricalof all vertebrates. component of the EPSP, which provides a measure of the

Glutamate acts both as a fast transmitter and neuro- input resistance at the synaptic site (Fig. 1B, C). Inmodulator depending on the receptors activated. Ionotropic addition, these agonists had no effect on the input resist-NMDA and AMPA receptors mediate fast synaptic trans- ance measured in the soma of postsynaptic neurons,mission within the spinal locomotor network [20,25,29,56]. indicating that the decrease in the EPSP amplitude is notGlutamate also activates mGluRs, which through activa- due to activation of conductances in the postsynaptiction of G-proteins can modulate neuronal activity. Eight neurons. Furthermore, the sensitivity of the postsynapticmGluR subtypes, mGluR1–8, have been cloned in mam- AMPA receptors mediating the monosynaptic EPSPs wasmals [13,46], and some of these have also been found inC. not affected by the mGluR agonists ACPD andL-AP4. Theelegans [7], Drosophila [45] and salmon [37]. Interesting- group II and group III mGluRs are thus co-localized only, the sequences of the cloned mGluRs are highly single reticulospinal axons and inhibit synaptic transmis-conserved across species. mGluRs are subdivided into sion by presynaptic mechanisms (Fig. 2). These twothree groups based on the amino acid sequence homology receptors (group II and III mGluRs) are distinct from theand the signal transduction pathways. Group I consists of group I mGluRs located postsynaptically on the soma/mGluR1 and mGluR5 that mediate an increase in phos- dendrites of spinal neurons (Fig. 2). Since this synapse ispholipase C (PLC), leading to IP formation. Group II and glutamatergic, the activation of the presynaptic mGluRs3

group III mGluRs consist of mGluR2 and 3, and mGluR4, may be caused by glutamate released from the synapse6, 7 and 8, respectively, and the receptors of both groups itself. This presynaptic inhibition by mGluRs may thusare negatively coupled to adenylyl cyclase. Several re- serve as a form of autoinhibition [19,59]. It is also possibleviews have addressed the pharmacology and role of that these mGluRs are activated by overflow (spillover) ofmGluRs in synaptic plasticity [4,8]. The present review glutamate from neighboring synapses [6,38,49]. A highwill focus on the action of group I, II and III mGluRs on level of activity at the same synapse or adjacent synapsessingle neurons and synaptic transmission, and their role for could therefore lead to a subsequent depression of trans-the intrinsic modulation of the locomotor network in the mission at the reticulospinal synapse.lamprey spinal cord. Synaptic transmission from the cutaneous sensory neu-

A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18 11

Fig. 1. Group II and III mGluRs mediate presynaptic inhibition of reticulospinal synaptic transmission. (A) Activation of group II mGluRs by ACPD andthe group III mGluRs byL-AP4 decreases the amplitude of the reticulospinal-evoked EPSP. (B) The decrease in the monosynaptic EPSP amplitude byACPD is not antagonized by the group III antagonist MAP4. (C) TheL-AP4-induced decrease of the monosynaptic EPSP is antagonized by MAP4. NeitherACPD norL-AP4 affects the electrical component (indicated by an arrow in B and C) of the EPSP or the input resistance of the postsynaptic target neuron.

Fig. 2. Pre- and postsynaptic distribution of mGluRs in the lamprey spinal cord. Group I mGluRs (mGluR1 and mGluR5) are located postsynaptically andcan be activated by the specific agonist DHPG and the broad-spectrum agonist ACPD. The antagonist CPCCOEt blocks specifically mGluR1, while MPEPblocks mGluR5. Group II mGluRs are presynaptic and are activated by ACPD. Group III mGluRs are also presynaptic and are activated byL-AP4 andblocked by MAP4.

12 A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18

1rons, dorsal cells, and from sensory axons projecting in the of action potentials by activation of a 4-AP-sensitive Kdorsal column is also presynaptically inhibited by activa- current is a mechanism underlying the presynaptic inhibi-tion of group III mGluRs [31]. The inhibition of dorsal cell tion of reticulospinal transmission. Instead these results,transmission, however, required higher concentrations of together with those showing that mGluR agonists do not

21the group III agonistL-AP4 compared to that of the dorsal depress presynaptic Ca currents, indicate that the pre-column axons. This can be due to a difference in the group synaptic group II and III mGluRs may act directly on theIII mGluR subtypes involved in modulating sensory trans- release machinery to inhibit synaptic transmission at themission from neurons with different modalities. In addi- reticulospinal synapse.tion, synaptic inputs from vestibulospinal axons to re-ticulospinal neurons in the brainstem are modulated viapresynaptic activation of mGluRs, which may correspond 4 . Postsynaptic group I mGluRs regulate theto group II receptors [2]. excitability of spinal neurons

Group I mGluRs are present postsynaptically on the3 . Mechanisms of presynaptic inhibition mediated by soma and dendrites of neurons in the locomotor networkmGluRs [32]. In the spinal cord in vitro, activation of these

receptors by the group I mGluR agonist DHPG or by theThe presynaptic group II and III mGluRs can act on broad spectrum agonist ACPD increases the spontaneous

different cellular targets to mediate inhibition of synaptic synaptic activity in motoneurons and interneurons, elicitstransmission from reticulospinal axons. These potential membrane potential oscillations, and causes ventral root

21mechanisms include inhibition of Ca channels, shunting bursting [32,33]. The membrane potential oscillations areof the presynaptic action potentials, or an effect on the network-induced since they are always blocked by ionot-exocytotic release machinery. In the lamprey, blockade of ropic glutamate receptor antagonists [33,36]. The increase

21N-type Ca channels, which predominantly contribute to in the excitability of spinal neurons and ventral roottransmitter release at the reticulospinal synapse [34], did activity induced by DHPG and ACPD are blocked by thenot occlude group III mGluR-induced inhibition of synap- group I antagonists CPCCOEt and MCPG. The latter

21tic transmission. An effect on P/Q- and R-type Ca antagonist does not block the ACPD-induced depression ofchannels might also contribute to the mGluR-mediated reticulospinal transmission mediated by activation of grouppresynaptic inhibition, but this was found not to be the II mGluRs by ACPD that has been described above. These

21case [34]. Furthermore,L-AP4 had no effect on the Ca results show that group I mGluRs are located postsynapti-component of action potentials in reticulospinal axons or cally and increase the excitability of locomotor network

21on the Ca current measured in cell bodies of reticulospi- neurons in the lamprey (Fig. 2). In turtle, group I mGluRsnal neurons [34]. Similarly, activation of group II mGluRs increase the excitability of motoneurons by potentiating

21 21by ACPD had no effect on Ca currents recorded in L-type Ca channels underlying plateau potentials [23].reticulospinal axons [12]. The presynaptic action ofmGluRs on reticulospinal transmission thus appears to be

21independent of a depression of the Ca influx. 5 . Cellular action of group I mGluR subtypes,In adult lampreys, mGluR activation does not produce mGluR1 and mGluR5

any change in the amplitude or duration of the actionpotentials recorded in reticulospinal axons. This indicates Group I mGluRs involve two receptor subtypes,that presynaptic mGluRs do not mediate presynaptic mGluR1 and mGluR5, the cellular effects of which haveinhibition by shunting mechanisms [36]. In larval lam- been investigated in dissociated neurons and in the spinalpreys, however, group II and III mGluRs have been cord in vitro. Activation of group I mGluRs by DHPG

21suggested to induce a shunt of the presynaptic action enhanced NMDA receptor current and Ca responses in1potentials via an increased K conductance, which is dissociated spinal motoneurons and network interneurons

1blocked by the K channel blocker 4-AP [12]. If shunting (Fig. 7) [35]. It also increased the NMDA-induced depo-is the mechanism underlying presynaptic inhibition by larizations in neurons in the intact spinal cord [33]. The

1mGluRs, it is expected that a blockade of K channels potentiation in dissociated neurons is blocked by theshould occlude the depression of synaptic transmission by mGluR1 antagonist CPCCOEt and required activation ofmGluR agonists. We examined this possibility in adult G-proteins, but not protein kinase A, C or G activationlampreys by comparing the degree of inhibition of synaptic [35]. At the concentration used, CPCCOEt has been showntransmission byL-AP4 in the absence and presence of the to antagonize specifically mGluR1 [3,10,39]. The potentia-

1K channel blocker 4-AP [36]. The degree of depression tion of NMDA receptors thus appears to be mediated byof synaptic transmission was similar in the absence or mGluR1.

1presence of the K channel blocker. Our results do not The consequences of the interaction between mGluR1support the notion of group III mGluR-mediated shunting and NMDA receptors were further investigated on mem-

A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18 13

reticulospinal axons by electrical stimulation. This en-21hancement of the Ca transient was inhibited by

ryanodine [12].The consequence of this increase in the presynaptic21Ca transient was then tested on the amplitude of EPSPs

elicited in postsynaptic neurons with a paired-pulse proto-col [12]. The group I mGluR agonist DHPG increased theamplitude of the EPSP evoked by the second actionpotential without affecting the first EPSP. This was coun-

21teracted by ryanodine, indicating an involvement of Carelease from internal stores. The presynaptic group ImGluRs are suggested to facilitate synaptic transmission

21by increasing the basal Ca concentration, which is added21to the Ca influx during action potentials, thus leading to

an enhanced transmitter release. Repetitive stimulation isthought to be required to activate the presynaptic group ImGluRs since the antagonist CPCCOEt at a high con-centration (500mM) reduced the amplitude of the EPSPswithin a stimulus train [12]. This finding needs to be

Fig. 3. mGluR1 interacts with NMDA receptors in spinal neurons. DHPG confirmed using a lower concentration of the antagonistincreases the plateau duration and changes the frequency of the NMDA-CPCCOEt (|100mM) at which it specifically blocks groupinduced oscillations. These effects are blocked by the mGluR1 antagonist

I mGluRs. Schwartz and Alford [51] also suggested that aCPCCOEt.presynaptic facilitation of transmission by group I mGluRsoccurs at the vestibulospinal–reticulospinal synapse in

brane potential oscillations induced by NMDA [54] that larval lampreys.play a role in the generation of the locomotor rhythm [60]. There is, however, no evidence to suggest that group IDHPG increases the duration of the plateau depolarization mGluRs also act presynaptically in adult lampreys.and decreased the duration of the hyperpolarization phase Ryanodine, which blocks the presynaptic facilitation in-of the NMDA-induced TTX-resistant oscillations (Fig. 3). duced by DHPG in larval lampreys, failed to affect groupThis is counteracted by the mGluR1 antagonist CPCCOEt I-mediated modulation of network neurons and locomotor(Fig. 3). activity in adult lampreys [35] (see below).

In addition to potentiating NMDA receptors, activationof group I mGluRs on its own can induce oscillations in

21 21the intracellular Ca concentration ([Ca ] ) in disso- 7 . Presynaptic group III mGluRs modulate the bursti

ciated lamprey spinal cord neurons (Fig. 7). These oscilla- frequency and synaptic transmission from networktions were blocked by the mGluR5 antagonist (MPEP) neurons[18], but not by the mGluR1 antagonist (CPCCOEt) [28].

21The mGluR5-induced [Ca ] oscillations were due to The effect of the different mGluR subtypes on thei21release of Ca from internal stores through PLC- and locomotor burst frequency was analyzed during fictive

21Ca -dependent mechanisms, presumably by acting on locomotion induced by NMDA in the isolated spinal cord21IP -gated intracellular Ca stores (Fig. 7) [28]. These in vitro. Activation of group III mGluRs causes a reduction3

results together with those of the potentiation of NMDA of the frequency of the locomotor rhythm (by|5%) that is,receptors show that mGluR1 and mGluR5 thus produce at least partially, mediated by a depression of synapticdifferent cellular effects, which can be specifically blocked transmission from network interneurons. The degree ofby their respective antagonists (Fig. 7). modulation of synaptic transmission was determined in

experiments in which the recording chamber was split intotwo pools by a Vaseline barrier (Fig. 4A). Fictive locomo-

6 . Group I mGluRs may facilitate synaptic tion was induced by application of NMDA only in the pooltransmission in larval lampreys containing the rostral part of the spinal cord, while the

resulting excitatory synaptic drive (from the descendingIn larval lampreys, group I mGluRs have been suggested propriospinal interneurons) was recorded intracellularly

to act presynaptically on reticulospinal axons and facilitate from neurons in the caudal spinal cord, which was21synaptic transmission by releasing Ca from internal perfused with strychnine to block inhibitory transmission

21stores via activation of ryanodine receptors [12]. Ca (Fig. 4A). The amplitude of the excitatory synaptic driveimaging experiments showed that group I mGluR activa- was depressed (by|20%) by application of the group III

21tion increased the presynaptic Ca transient elicited in agonistL-AP4 to the caudal spinal cord (Fig. 4B, C) [33].

14 A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18

Fig. 4. Group III mGluRs mediate presynaptic inhibition of synaptic transmission from propriospinal interneurons. (A) The experimental set-up used tostudy the effect of mGluR activation on intraspinal synaptic transmission. Fictive locomotion is induced by bath application of NMDA in the rostral pool,which is separated from the caudal pool by a Vaseline barrier. Intracellular recordings are made from a neuron (intracell.) in the caudal pool perfused withstrychnine and from an ipsilateral ventral root (i-vr ) in the rostral pool. (B) Activation of group III mGluRs byL-AP4 decreases the amplitude ofR

locomotor-driven oscillations. (C)L-AP4 reversibly decreased the amplitude of locomotor-driven oscillations (n512).

The decrease in the locomotor burst frequency was more action potentials [33]. These effects are blocked bysurprisingly small in relation to the substantial decrease in the mGluR1 antagonist CPCCOEt (Fig. 5A, B). Endoge-excitatory synaptic transmission by group III mGluRs. nously released glutamate during locomotor activity fromThis difference could be due either to a saturation of these excitatory network interneurons activate this receptorreceptors by the endogenously released glutamate or to a subtype as its blockade decreases the frequency of thecombined effect on both excitatory and inhibitory synaptic locomotor bursts (Fig. 6A, B). It may therefore betransmission within the locomotor network. It would thus concluded that in the lamprey locomotor network gluta-be important to test the effect of specific group III mGluR mate not only acts as a transmitter to activate ionotropicantagonists on the locomotor frequency to determine the receptors to generate the locomotor rhythm, but also actsinvolvement of these receptors in the intrinsic modulation as an intrinsic neuromodulator through its action onof the spinal locomotor network. mGluR1, which contributes to the regulation of the basal

locomotor frequency. mGluR1 mediates its modulatoryeffects on the locomotor network activity by interactingwith NMDA receptors postsynaptically [35]. The DHPG-

8 . Endogenous activation of mGluR1 during induced potentiation of NMDA receptors (Fig. 7), modula-locomotor activity tion of NMDA-induced TTX-resistant oscillations (Fig. 3),

and increase in the locomotor frequency (Fig. 5) are allActivation of group I mGluRs by DHPG increases the blocked by antagonizing mGluR1. Simulation of the

frequency of ventral root bursts (Fig. 5A, B). This is potentiation of NMDA receptors by mGluR1, using aaccompanied by an increase in the excitability of computer model of the lamprey locomotor network [20],motoneurons and interneurons, which depolarize and fire reproduces the potentiation of NMDA current and the

A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18 15

Fig. 5. Activation of mGluR1 increases the frequency of the locomotor rhythm. (A) The group I agonist DHPG increases the frequency of the locomotorburst. The mGluR1 antagonist CPCCOEt counteracts the DHPG-induced modulation of the locomotor frequency. (B) Percentage increase in the locomotorburst frequency induced by DHPG before, during and after washout of CPCCOEt.

modulation of NMDA-induced TTX-resistant oscillations 9 . Presynaptic facilitation does not contribute to the[35]. The computational model also reproduces the in- modulation of the locomotor rhythm by mGluR1crease in the locomotor burst frequency when the NMDAreceptors are potentiated in all network neurons [35]. The Can the increase in the locomotor frequency by mGluR1results of the computer simulations provide further support be mediated by a presynaptic facilitation similar to thatthat the interaction between mGluR1 and NMDA receptors reported in lampreys at the early larval stage [12]? Asis sufficient to account for this modulation of the mentioned above, mGluR1 has been suggested to facilitatelocomotor network in the lamprey. reticulospinal transmission via a ryanodine-sensitive in-

Fig. 6. Endogenous activation of mGluR1 during fictive locomotion. (A) Blockade of mGluR1 by CPCCOEt reduces the frequency of the locomotorrhythm induced by NMDA, indicating that these receptors are activated by the endogenously released glutamate. (B) The time-course of theCPCCOEt-induced decrease in the locomotor burst frequency.

16 A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18

Fig. 7. Mechanisms underlying modulation of the locomotor network activity by mGluR1 and mGluR5. mGluR1 interacts with NMDA receptors to21increase their current and Ca responses via activation of G-proteins. This results in an increase in the locomotor frequency. mGluR1 is endogenously

21 21activated and its blockade decreases the burst frequency. mGluR5 induces [Ca ] oscillations, which are dependent on PLC and Ca influx throughi

L-type channels. mGluR5 is activated during fictive locomotion and its blockade increases the burst frequency.

21crease in presynaptic Ca . If a similar mechanism occurs (Fig. 7). The mechanisms by which mGluR5 decreases thein network interneurons, it may lead to an increase in the frequency are not yet fully determined. However, since

21locomotor frequency. The increase and the decrease in the [Ca ] oscillations are the only cellular response inducedi

locomotor frequency induced by mGluR1 activation and by mGluR5 activation in lamprey spinal cord neurons, theyblockade, respectively, are however not affected by might in turn regulate the frequency of the locomotorryanodine [35]. Therefore, the modulation of the locomotor rhythm by activating intracellular messenger pathways.rhythm by mGluR1 does not involve presynaptic facilita- The two subtypes of group I mGluRs are both activated

21tion of synaptic transmission via Ca release from by endogenously released glutamate during locomotion,internal stores. In addition, ryanodine alone had no signifi- but they produce opposite effects on the locomotor rhythmcant effect on the locomotor rhythm. Thus, ryanodine- (Fig. 7). It is possible that they are selectively recruited tosensitive presynaptic facilitation is neither involved in the modulate the activity of the locomotor network in aunderlying basal activity in the locomotor network, nor context-dependent manner. It is not known if mGluR1 anddoes it underlie the mGluR1-mediated regulation of mGluR5 are present in all network neurons or where theylocomotor activity. are located in relation to the synaptic sites. This in-

formation is critical for understanding the conditions underwhich these receptors are activated during locomotion.

1 0. Endogenous activation of mGluR5 produceseffects opposite to mGluR1 on the locomotor rhythm

1 1. Concluding remarksThe role of mGluR5 on the locomotor network activity

was examined by applying the specific antagonist MPEP In this review, we have summarized the modulatoryduring NMDA-induced fictive locomotion [28]. Blockade effects of mGluRs on neuronal excitability, synapticof mGluR5 increases the locomotor burst frequency, transmission and locomotor network activity in the lam-showing that these receptors are activated by endogenously prey. Group II and III mGluRs act only at presynapticreleased glutamate (Fig. 7). Although mGluR1 and axons to limit synaptic transmission. The two group ImGluR5 are both coupled to the activation of PLC, they do mGluR subtypes (mGluR1 and mGluR5) are locatednot serve similar roles in the lamprey locomotor network postsynaptically and induce different cellular responses

A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18 17

[4] R. Anwyl, Metabotropic glutamate receptors: electrophysiologicalleading to opposing modulation of the locomotor rhythm.properties and role in plasticity, Brain Res. Rev. 29 (1999) 83–120.Group I mGluRs are endogenously activated and may be

[5] Y.I. Arshavsky, G.N. Orlovsky, Y.V. Panchin, A. Roberts, S.R. Soffe,an integral part of the glutamatergic transmission in the Neuronal control of swimming locomotion: analysis of the pteropodlocomotor network, whereas the presynaptic action of mollusc Clione and embryos of the amphibianXenopus, Trends

Neurosci. 16 (1993) 227–233.group II and III mGluRs may regulate glutamate release[6] F. Asztely, G. Erdemli, D.M. Kullmann, Extrasynaptic glutamatethrough autoinhibition. How activation of the different

spillover in the hippocampus: dependence on temperature and themGluR subtypes is regulated relative to each other and role of active glutamate uptake, Neuron 18 (1997) 281–293.relative to ionotropic glutamate receptors remains to be [7] C.I. Bargmann, Neurobiology of theCaenorhabditis elegans

genome, Science 282 (1998) 2028–2033.elucidated. The mGluR subtypes may have different[8] Z.A. Bortolotto, S.M. Fitzjohn, G.L. Collingridge, Roles of metabot-affinities for endogenously released glutamate, and/or be

ropic glutamate receptors in LTP and LTD in the hippocampus,differentially distributed in relation to the release sites.Curr. Opin. Neurobiol. 9 (1999) 299–304.

This could account for their relative activation and contri- [9] J.T. Buchanan, Contributions of identifiable neurons and neuronbution in modulating the operation of the locomotor classes to lamprey vertebrate neurobiology, Prog. Neurobiol. 63

(2001) 441–466.network. The variety of mGluRs, their cellular distribution[10] G. Casabona, T. Knopfel, R. Kuhn, F. Gasparini, P. Baumann, M.A.and various transduction pathways provide an intricate

Sortino, A. Copani, F. Nicoletti, Expression and coupling tomechanism by which glutamate will act as an intrinsic polyphosphoinositide hydrolysis of group I metabotropic glutamatemodulator to alter locomotor pattern generation. receptors in early postnatal and adult rat brain, Eur. J. Neurosci. 9

(1997) 12–17.In mammals, the effects of mGluRs on locomotor[11] J.R. Cazalets, S. Bertrand, Ubiquity of motor networks in the spinalbehavior have been examined in intact animals using

cord of vertebrates, Brain Res. Bull. 53 (2000) 627–634.injections of agonists and antagonists in different brain [12] A.J. Cochilla, S. Alford, Metabotropic glutamate receptor-mediatedregions [58] or by using transgenic animals [1,14,24]. control of neurotransmitter release, Neuron 20 (1998) 1007–1016.

[13] P.J. Conn, J.P. Pin, Pharmacology and functions of metabotropicThese approaches do not, however, allow establishing howglutamate receptors, Annu. Rev. Pharmacol. Toxicol. 37 (1997)the operation of the neural networks generating behavior is205–237.altered by the pharmacological or genetic manipulations.

[14] F. Conquet, Z.I. Bashir, C.H. Davies, H. Daniel, F. Ferraguti, F.The knowledge available on the lamprey locomotor net- Bordi, K. Franz-Bacon, A. Reggiani, V. Matarese, F. Conde et al.,work organization and its experimental accessibility al- Motor deficit and impairment of synaptic plasticity in mice lacking

mGluR1, Nature 372 (1994) 237–243.lowed us to carry out a detailed analysis of the mecha-[15] N. Dale, F.M. Kuenzi, Ion channels and the control of swimming innisms underlying the modulation of locomotor pattern

the Xenopus embryo, Prog. Neurobiol. 53 (1997) 729–756.generation (Fig. 7). This may allow a bridge from actions ´[16] A. El Manira, P. Wallen, Mechanisms of modulation of a neuralof the different mGluRs at the cellular and molecular network, News Physiol. Sci. 15 (2000) 186–191.levels to the regulation and shaping of activity at the [17] A. El Manira, M.A. Pombal, S. Grillner, Diencephalic projection to

reticulospinal neurons involved in the initiation of locomotion innetwork and behavioral levels.adult lampreysLampetra fluviatilis, J. Comp. Neurol. 389 (1997)603–616.

[18] F. Gasparini, K. Lingenhohl, N. Stoehr, P.J. Flor, M. Heinrich, I.Vranesic, M. Biollaz, H. Allgeier, R. Heckendorn, S. Urwyler, M.A.A cknowledgementsVarney, E.C. Johnson, S.D. Hess, S.P. Rao, A.I. Sacaan, E.M.Santori, G. Velicelebi, R. Kuhn, 2-Methyl-6-(phenylethynyl)-

This work was supported by the Swedish Research pyridine (MPEP), a potent, selective and systemically active mGlu5Council (project 11562), the Swedish Foundation for receptor antagonist, Neuropharmacology 38 (1999) 1493–1503.

˚ [19] G.B. Awatramani, M.M. Slaughter, Intensity-dependent, rapid acti-Strategic Research, A. Eriksson Foundation, A. Wibergvation of presynaptic metabotropic glutamate receptors at a centralFoundation, the Knut and Alice Wallenbergs Foundation,synapse, J. Neurosci. 21 (2001) 741–749.the Swedish Society for Medicine, and Karolinska In-

´[20] S. Grillner, P. Wallen, Cellular bases of a vertebrate locomoterstitutet funds. system–steering, inter-segmental and segmental co-ordination and

sensory control, This issue.[21] S. Grillner, P. Wallen, R. Hill, L. Cangiano, A. El Manira, Ion

channels of importance for the locomotor pattern generation in theR eferences lamprey brainstem-spinal cord, J. Physiol. 533 (2001) 23–30.

[22] R.M. Harris-Warrick, E. Marder, Modulation of neural networks forbehavior, Annu. Rev. Neurosci. 14 (1991) 39–57.[1] A. Aiba, M. Kano, C. Chen, M.E. Stanton, G.D. Fox, K. Herrup,

[23] J. Hounsgaard, J.F. Perrier, This volume.T.A. Zwingman, S. Tonegawa, Deficient cerebellar long-term de-[24] T. Ichise, M. Kano, K. Hashimoto, D. Yanagihara, K. Nakao, R.pression and impaired motor learning in mGluR1 mutant mice, Cell

Shigemoto, M. Katsuki, A. Aiba, mGluR1 in cerebellar Purkinje79 (1994) 377–388.cells essential for long-term depression, synapse elimination, and[2] S. Alford, R. Dubuc, Glutamate metabotropic receptor mediatedmotor coordination, Science 288 (2000) 1832–1835.depression of synaptic inputs to lamprey reticulospinal neurones,

[25] L.M. Jordan, R.M. Brownstone, B.R. Noga, Control of functionalBrain Res. 605 (1993) 175–179.systems in the brainstem and spinal cord, Curr. Opin. Neurobiol. 2[3] H. Annoura, A. Fukunaga, M. Uesugi, T. Tatsuoka, Y. Horikawa, A(1992) 794–801.novel class of antagonists for metabotropic glutamate receptors,

[26] L.M. Jordan, Initiation of locomotion in mammals, Ann. N.Y. Acad.7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates, Bioorg.Sci. 860 (1998) 83–93.Med. Chem. Lett. 6 (1996) 763–766.

18 A. El Manira et al. / Brain Research Reviews 40 (2002) 9–18

[27] O. Kiehn, P.S. Katz, Making circuits dance: modulation of motor The roles of co-transmission in neural network modulation, Trendspattern generation, in: P.S Katz (Ed.), Beyond Neurotransmission. Neurosci. 24 (2001) 146–154.Neuromodulation and its Importance for Information Processing, [44] Y. Ohta, S. Grillner, Monosynaptic excitatory amino acid transmis-Oxford University Press, Oxford, 1999, pp. 275–317. sion from the posterior rhombencephalic reticular nucleus to spinal

[28] P. Kettunen, P. Krieger, D. Hess, A. El Manira, Signaling mecha- neurons involved in the control of locomotion in lamprey, J.nisms of mGluR5 subtype and its endogenous role in a locomotor Neurophysiol. 62 (1989) 1079–1089.network, J. Neurosci. 22 (2002) 1868–1873. [45] M.L. Parmentier, J.P. Pin, J. Bockaert, Y. Grau, Cloning and

[29] O. Kiehn, J. Hounsgaard, K.T. Sillar, Basic buildings blocks of functional expression of a Drosophila metabotropic glutamatevertebrate central pattern generators, in: P.S.G. Stein, S. Grillner, A. receptor expressed in the embryonic CNS, J. Neurosci. 16 (1996)Selverston, D.G. Stuart (Eds.), Neurons, Networks and Motor 6687–6694.Behavior, MIT Press, Cambridge, USA, 1997, pp. 47–59. [46] J.P. Pin, R. Duvoisin, The metabotropic glutamate receptors: struc-

[30] O. Kiehn, O. Kjaerulff, M.C. Tresch, R.M. Harris-Warrick, Contri- ture and functions, Neuropharmacology 34 (1995) 1–26.butions of intrinsic motor neuron properties to the production of [47] A. Roberts, S.R. Soffe, E.S. Wolf, M. Yoshida, F.Y. Zhao, Centralrhythmic motor output in the mammalian spinal cord, Brain Res. circuits controlling locomotion in young frog tadpoles, Ann. N.Y.Bull. 53 (2000) 649–659. Acad. Sci. 860 (1998) 19–34.

[31] P. Krieger, A. El Manira, Group III mGluR-mediated depression of [48] C.M. Rovainen, Synaptic interactions of reticulospinal neurons andsensory synaptic transmission, Brain Res. 937 (2002) 41–44. nerve cells in the spinal cord of the sea lamprey, J. Comp. Neurol.

[32] P. Krieger, A. El Manira, S. Grillner, Activation of pharmacological- 154 (1974) 207–223.ly distinct metabotropic glutamate receptors depresses reticulos- [49] M. Scanziani, P.A. Salin, K.E. Vogt, R.C. Malenka, R.A. Nicoll,pinal-evoked EPSPs in the lamprey spinal cord, J. Neurophysiol. 76 Use-dependent increases in glutamate concentration activate pre-(1996) 3834–3841. synaptic metabotropic glutamate receptors, Nature 385 (1997) 630–

[33] P. Krieger, S. Grillner, A. El Manira, Endogenous activation of 634.metabotropic glutamate receptors contributes to burst frequency [50] B.J. Schmidt, L.M. Jordan, The role of serotonin in reflex modula-regulation in the lamprey locomotor network, Eur. J. Neurosci. 10 tion and locomotor rhythm production in the mammalian spinal(1998) 3333–3342. cord, Brain Res. Bull. 53 (2000) 689–710.

¨[34] P. Krieger, A. Buschges, A. El Manira, Calcium channels involved [51] N.E. Schwartz, S. Alford, Physiological activation of presynapticin synaptic transmission from reticulospinal axons in lamprey, J. metabotropic glutamate receptors increases intracellular calcium andNeurophysiol. 81 (1999) 1699–1705. glutamate release, J. Neurophysiol. 84 (2000) 415–427.

[35] P. Krieger, J. Hellgren-Kotaleski, P. Kettunen, A. El Manira, [52] M.L. Shik, G.N. Orlovsky, Neurophysiology of locomotor automat-Interaction between metabotropic and ionotropic glutamate receptors ism, Physiol. Rev. 56 (1976) 465–501.regulates neuronal network activity, J. Neurosci. 20 (2000) 5382– [53] O. Shupliakov, L. Brodin, S. Cullheim, O.P. Ottersen, J. Storm-5391. Mathisen, Immunogold quantification of glutamate in two types of

[36] P. Krieger, On the role of metabotropic glutamate receptors in motor excitatory synapse with different firing patterns, J. Neurosci. 12control—Analysis of synaptic, cellular and network properties. (1992) 3789–3803.

´Ph.D. thesis, Karolinska Institutet (2000). [54] K.A. Sigvardt, S. Grillner, P. Wallen, P.A.Van Dongen, Activation of[37] K. Kubokawa, T. Miyashita, H. Nagasawa, Y. Kubo, Cloning and NMDA receptors elicits fictive locomotion and bistable membrane

characterization of a bifunctional metabotropic receptor activated by properties in the lamprey spinal cord, Brain Res. 336 (1985)both extracellular calcium and glutamate, FEBS Lett. 392 (1996) 390–395.71–76. [55] K.T. Sillar, C.A. Reith, J.R. McDearmid, Development and aminer-

[38] D.M. Kullmann, Spillover and synaptic cross talk mediated by gic neuromodulation of a spinal locomotor network controllingglutamate and GABA in the mammalian brain, Prog. Brain Res. 125 swimming inXenopus larvae, Ann. N.Y. Acad. Sci. 860 (1998)(2000) 339–351. 318–332.

[39] S. Litschig, F. Gasparini, D. Rueegg, N. Stoehr, P.J. Flor, I.Vranesic, [56] K.T. Sillar, D.L. McLean, H. Fischer, S.D. Merrywest, Fast inhib-L. Prezeau, J.P. Pin, C. Thomsen, R. Kuhn, CPCCOEt, a noncom- itory synapses: targets for neuromodulation and development ofpetitive metabotropic glutamate receptor 1 antagonist, inhibits vertebrate motor behaviour, 2002, This issue.receptor signaling without affecting glutamate binding, Mol. Phar- [57] M.G. Sirota, G.V. Di Prisco, R. Dubuc, Stimulation of the mesence-macol. 55 (1999) 453–461. phalic locomotor region elicits controlled swimming in semi-intact

[40] A.D. McClellan, S. Grillner, Initiation and sensory gating of ‘fictive’ lampreys, Eur. J. Neurosci. 12 (2000) 4081–4092.swimming and withdrawal responses in an in vitro preparation of the [58] P. Vezina, J.H. Kim, Metabotropic glutamate receptors and thelamprey spinal cord, Brain Res. 269 (1983) 237–250. generation of locomotor activity: interactions with midbrain dopa-

[41] A.D. McClellan, In vitro CNS preparations: unique approaches to mine, Neurosci. Biobehav. Rev. 23 (1999) 577–589.the study of command and pattern generation systems in motor [59] H. von Gersdorff, R. Schneggenburger, S. Weis, E. Neher, Presynap-control, J. Neurosci. Methods 21 (1987) 251–264. tic depression at a calyx synapse: the small contribution of metabot-

[42] D.L. McLean, S.D. Merrywest, K.T. Sillar, The development of ropic glutamate receptors, J. Neurosci. 17 (1997) 8137–8146.´neuromodulatory systems and the maturation of motor patterns in [60] P. Wallen, S. Grillner,N-methyl-D-aspartate receptor-induced, inher-

amphibian tadpoles, Brain Res. Bull. 53 (2000) 595–603. ent oscillatory activity in neurons active during fictive locomotion in[43] M.P. Nusbaum, D.M. Blitz, A.M. Swensen, D. Wood, E. Marder, the lamprey, J. Neurosci. 7 (1987) 2745–2755.