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EDITORIAL FOCUS
Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts 02111
Proper function of the nervous system is critically dependent on precise synaptic connectivity among the constituent neurons. For the neuronal circuit mediating the simple stretch reflex, for example, sensory axons supplying stretch-sensitive spindles in skeletal muscles (Ia axons) make direct connections only with specific groups of motoneurons (MNs). Even after the initial pattern of synaptic connectivity is established, however, the strength of these connections is modulated postnatally. This modulation allows both for adjustment of inputs to changes in the size of the postsynaptic cell and for possible rearrangements of synaptic strength from different presynaptic inputs. In this issue (p. 2394–2404), Arvanian et al. (2004)
show that a critical period for the modulation of synaptic inputs to MNs is controlled by the expression of a particular subunit of the N-methyl-D-aspartate receptor (NMDAR).
Experiments over the last several years have shown that the trophic factor neurotrophin-3 (NT-3), produced by muscle spindles, modulates the strength of synaptic connections between Ia axons and MNs (Chen et al. 2003). Depriving Ia axons of NT-3, either by cutting a muscle nerve or by genetically blocking NT-3 production in spindles, causes a reduction in synaptic strength, and application of exogenous NT-3 restores this loss in both situations (Chen et al. 2002; Mendell et al. 1999). In older animals, these effects occur slowly (1–2 days). However, during the first postnatal week, bath application of NT-3 to isolated spinal cords potentiates Ia inputs to MNs within minutes, and the effect lasts at least several hours after NT-3 is removed (Arvanov et al. 2000). This rapid potentiation requires the synaptic activation of NMDARs on MNs, because injection of the NMDA blocker MK801 into an MN blocks the potentiation. During the first postnatal week, these NMDARs can be activated at normal Mg2+ concentrations. By the second week, however, they are blocked in normal saline, and NT-3 no longer potentiates synaptic transmission. At these later times, lowering the [Mg2+] in the bath restores the NMDAR-mediated component of the excitatory postsynaptic potential (EPSP) as well as the potentiating effect of NT-3 (Arvanian and Mendell 2001).
One way this change in Mg2+ sensitivity could be mediated is by a change in the subunit composition of NMDARs. In particular the subunits NR2C and NR2D confer the ability to respond to glutamate at relatively high levels of Mg2+ (Cull-Candy et al. 2001). In this study, Arvanian and coworkers show that the loss of potentiation by NT-3 in the second postnatal week is caused by down-regulation of the NR2D subunit of the NMDA receptor. Microarray analysis of lumbar spinal cord revealed that, within the NR2 family of subunits, only expression of NR2D mRNA drops significantly from P2 to P12. There is also a significant fall in NR2D protein levels in MNs. In a technical tour de force, Arvanian et al. proceed to show that infection of MNs at P2 with viral vectors carrying the NR2D gene results in increased expression of this subunit in MNs and extends to at least P12 the period of both Mg2+ insensitivity of NMDA-mediated synaptic input and potentiation by bath-applied NT-3.
An intriguing aspect of these results is that the critical period for potentiation of synaptic input from different classes of presynaptic axons onto the same MN occurs at different times in development. Synaptic inputs from descending axons in the ventrolateral funiculus (VLF) can be mediated by both NMDA and non-NMDA receptors during the first postnatal week, but the NMDAR-mediated components are only present in low [Mg2+]; in normal saline, they are already blocked at birth. Consistent with the mechanism for modulating inputs from Ia axons, VLF synaptic inputs are not potentiated by NT-3, even at birth (Arvanov et al. 2000). Following overexpression of NR2D, however, NT-3 modulation of these inputs is restored. Apparently, the NMDAR subunit composition at different synapses on the same MN can vary, allowing different classes of synaptic inputs to be modulated independently at different developmental times. The authors suggest that this probably requires an instructive signal from presynaptic terminals, either mediated via activity or by some trophic factor released from terminals and acting locally on their own postsynaptic sites.
The ability to extend a critical period for synaptic plasticity beyond its normal duration by viral infection of NMDAR subunits raises the possibility that similar approaches might be applicable to injured spinal cord in adults. If sensory-motor synapses can be induced to reform after spinal injuries, restoration of a period of plasticity for these connections might be important to allow for adjustments of synaptic strength to promote appropriate function. Moreover, it may be possible to deliver the viral constructs from the periphery. Retrograde transport from a muscle nerve of a viral vector carrying the NT-3 gene induces NT-3 expression in MNs, resulting in sprouting of axons into the ventral horn of injured spinal cord (Zhou et al. 2003). Perhaps retrograde transport of genes for both NR2D and NT3 could stimulate synaptogenesis by regenerating Ia axons as well as provide a conducive environment for appropriate modulation of the new synapses.
Address for reprint requests and other correspondence: E. Frank, (E-mail: eric.frank{at}tufts.edu).
REFERENCES
Arvanian VL, Bowers WJ, Petruska JC, Motin V, Manuzon H, Narrow WC, Federoff HJ, and Mendell LM. Viral delivery of NR2D subunits reduces Mg2+ block of NMDA receptors and restores NT-3-induced potentiation of AMPA-kainate responses in maturing rat motoneurons. J Neurophysiol 92: 2394–2404, 2004.
Arvanian VL and Mendell LM. Removal of NMDA receptor Mg(2+) block extends the action of NT-3 on synaptic transmission in neonatal rat motoneurons. J Neurophysiol 86: 123–129, 2001.
Arvanov VL, Seebach BS, and Mendell LM. NT-3 evokes an LTP-like facilitation of AMPA/kainate receptor-mediated synaptic transmission in the neonatal rat spinal cord. J Neurophysiol 84: 752–758, 2000.
Chen HH, Hippenmeyer S, Arber S, and Frank E. Development of the monosynaptic stretch reflex circuit. Curr Opin Neurobiol 13: 96–102, 2003.[CrossRef][ISI][Medline]
Chen HH, Tourtellotte WG, and Frank E. Muscle spindle-derived neurotrophin 3 regulates synaptic connectivity between muscle sensory and motor neurons. J Neurosci 22: 3512–3519, 2002.
Cull-Candy S, Brickley S, and Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol 11: 327–335, 2001.[CrossRef][ISI][Medline]
Mendell LM, Johnson RD, and Munson JB. Neurotrophin modulation of the monosynaptic reflex after peripheral nerve transection. J Neurosci 19: 3162–3170, 1999.
Zhou L, Baumgartner BJ, Hill-Felberg SJ, McGowen LR, and Shine HD. Neurotrophin-3 expressed in situ induces axonal plasticity in the adult injured spinal cord. J Neurosci 23: 1424–1431, 2003.
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