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Introduction: Spontaneous activity in the developing central nervous system
seminars in
CELL & DEVELOPMENTAL BIOLOGY, Vol 8, 1997: pp 1–4
Introduction: Spontaneous activity in the developing central nervous system Rafael Yuste
retinal activity with injections of the sodium-channel blocker tetrodotoxin (TTX) prevents the segregation of retinogeniculate afferents and ocular dominance columns,10,12 and, as Stryker and Strickland reported, imposing synchronized activity patterns on a TTXtreated animal can rescue the refinement of ocular dominance columns.13 These TTX experiments have put the spotlight on the spontaneous activity by demonstrating that it is a necessary and sufficient condition for the normal segregation of the retinogeniculate and geniculocortical pathways. This issue of Seminars in Cell & Developmental Biology concentrates on understanding the patterns of intrinsic, spontaneous activity present in the developing mammalian CNS and the cellular mechanisms behind them. Here, we present a small number of studies where optical and electrical multicellular recording techniques have allowed investigators to characterize the spontaneous activity patterns in developing retina, spinal cord, locus coeruleus, hippocampus and neocortex. As it will be argued below, these studies are revealing many similarities between different brain regions in the patterns of correlated spontaneous activity and in their underlying mechanisms.
IN 1963, Wiesel and Hubel published a series of electrophysiological recordings reporting that, after raising kittens under monocular deprivation, neurons in the primary visual cortex became unresponsive to stimulation by the deprived eye.1 Although it was known that sensory deprivation during development had profound effects on the adult behavior,2-4 these results showed for the first time at the cellular level that neuronal activity during a ‘critical period’ of early development was necessary for the normal function of the adult visual cortex. Two years later, in follow-up studies, they reported that, while binocularly deprived animals had surprisingly normal ocular dominance responses, animals raised under artificial squint conditions had no binocular cells in their visual cortices.5,6 This implied that the important factor was not the absolute level of activity, but instead the relative level of activity in one eye versus that of the other. These experiments thus suggested a scenario where inputs from both eyes compete for cortical territory, using correlated activity to identify each other.7 These findings, of central importance in the nature/nurture debate, opened the door to the field of activitydependent development, i.e. the branch of neurobiology that studies the effects of neuronal activity in determining the pattern of connectivity in the brain.8,9 Since these initial studies, it has become increasingly clear that the types of activity influencing the development of the visual system are not limited to sensory stimulation, but can also be spontaneous activity patterns present during early development. For instance, in cats, ocular dominance columns form normally when animals are binocularly deprived5 or raised in the dark.10 In monkeys, ocular dominance columns are already formed before birth, and therefore, before eye opening.11 Also, activity-dependent remodeling of the retino-geniculate projection takes place before photoreceptors are even born (see Wong, this issue). Finally, blocking all spontaneous
What are the spontaneous activity patterns in the developing brain? Three major spatio-temporal patterns of activity have been described so far in the developing central nervous system: waves, domains and oscillations, and it is likely that each brain region displays a combination of them. Waves were first discovered in developing retina as synchronous bursts of action potentials that spontaneously sweep through the entire retina.14 Their existence has been well documented in vitro using multielectrode arrays and calcium imaging (Wong, this issue) and there are signs of their possible existence in vivo.15 Because of the high fidelity of synaptic transmission with correlated firing patterns in the visual system,16 waves could reverberate
From the Department of Biological Sciences, Columbia University, New York, NY 10027, USA ©1997 Academic Press Ltd/sr960114
1
Introduction this issue). In fact, a recurring theme throughout the developing CNS is the excitatory role of GABA, mediated by a depolarization due to increased intracellular chloride concentration. In the developing hippocampus, GABA-induced depolarizations and calcium accumulations are ubiquitous21-23 and may play an essential role in the formation of new synapses (Hanse et al, this issue). In the developing spinal cord, depolarizing GABA modulates the behavior of the network (refs 24, 25; O’Donovan and Chub, this issue), Finally, in the developing neocortex, GABA also produces major calcium influxes into neurons.26,27 An alternative mechanism underlying spontaneous activity during development is gap-junctional communication. In the retina, extensive networks of coupled neurons — presumably linked through gap-junctions — appear after intracellular tracer injections.28 Although these gap-junctional networks seem ideally suited to mediate circuit activation, their participation in the waves is controversial (Wong, this issue). In the developing neocortex, however, gap-junctional communication is necessary for neuronal domains to occur (Kandler, this issue): while TTX or synaptic blockers do not prevent the appearance of domains, gap-junction antagonists reversibly block them.29 Also, tracer injections show extensive networks of coupled neurons forming columnar structures.30-33 Finally, significant coupling between developing cortical neurons can be revealed electrophysiologically.29 Interestingly, coupling in neocortex and retina is specific for particular cell types, strongly indicating that it is not artifactual.28,33 Neuronal coupling, presumably mediated by gap junctions, has also been described in the developing spinal cord,34-36 genioglossal nucleus,37 locus coeruleus (ref 38, Christie, this issue) striatum,39 and hippocampus.40 Gap-junctional communication thus appears as a general feature throughout the developing CNS. The existence of gap-junctional coupling does not necessarily imply that neurons use them to activate each other electrically. The historical bias to consider gap-junctions as merely electrical connections is now changing because of techniques that allow imaging of intracellular ions and second messengers. Because gap-junctions also couple neurons biochemically, important developmental signals like calcium, IP3, cAMP, or even mRNA and DNA, could be easily transmitted from cell to cell. In fact, the homophilic nature of many connexons could restrict the sharing of instructive developmental signals to cells members of the same class. Indeed, the activity
through the lateral geniculate nucleus (LGN) and into the cortex. Domains were first described with calcium imaging as groups of five to 50 neurons that increased their calcium concentration in synchrony.17 The term ‘domain’, originally suggested by Scott Fraser, was used to define the territory encompassed by a given neuronal coactivation. In developing neocortex these groups of spontaneously coactive neurons form a modular architecture of columns which cover the cortex with little overlap.17 In the retina, waves advance by sequentially recruiting neuronal domains which also lack substantial overlap of territories on a short time scale.18 Domain-like coactivations have been found in the hippocampus, cerebellum, thalamus and superior colliculus (Yuste and Katz, unpublished; Wong, personal communication; Sejnowski, personal communication; Konnerth, personal communication). In developing spinal cord in vivo neuronal coactivations also occur, but coactive neurons are not necessarily next to each other (Spitzer and Gu, this issue). Finally, a third type of spontaneous activity in the developing CNS consists of synchronous oscillations of the electrical activity of an area. These oscillations can recruit an entire region, like in the locus coeruleus (Christie, this issue) or the hippocampus (Konnerth et al, in preparation), or particular cells within a region, like in the spinal cord (O’Donovan and Chub, this issue). These phenomena possibly represent an early stage of oscillatory behaviors ubiquitous in the adult CNS.19
What are the mechanisms underlying spontaneous activity patterns? Our understanding of the mechanisms responsible for the spontaneous activity patterns in the developing CNS is still incomplete. Most circuit activations could be carried out by conventional synaptic transmission and, indeed, waves in the retina appear to be mediated synaptically because they can be blocked by TTX20 and by cholinergic antagonists.18 Synaptic transmission also appears to mediate the bulk of the circuit activation in the spinal cord (O’Donovan and Chub, this issue), although not in developing neocortex and locus coeruleus (Kandler, this issue; Christie, this issue). In the hippocampus, ‘silent’ synapses, composed of NMDA receptors, only become active during strong depolarizations mediated by a paradoxical excitatory effect of GABA (Hanse et al, 2
Introduction frequency, code would improve substantially the specificity and precision of activity-dependent rules of circuit rearrangements.
responsible for a neuronal domain appears to be a second messenger wave mediated by IP3, rather than conventional electrical activity (Kandler, this issue). Why gap junctional coupling? In developing cortex and locus coeruleus, coupling is most extensive at a time when synaptic connections are scarce (Kandler, this issue; Christie, this issue). In fact, in developing neocortex, electrophysiological recordings consistently show a paucity of electrical activity.41-43 As suggested by Katz, gap-junctional coupling could amplify weak synaptic inputs, by carrying their effects, translated into a strong second messenger signal, throughout the network of coupled neurons.44 A similar amplification of activity could occur in the retina, spinal cord and locus coeruleus. Finally, in locus coeruleus, gap-junctions may synchronize the oscillations (Christie, this issue).
Future directions of research In spite of all this exciting progress, the basic patterns of spontaneous activity in vivo still have not been explored appropriately, and it is possible that new types of activity patterns might be discovered. Also, the causal link between waves, domains, or oscillations and circuit modifications remains to be demonstrated. Current studies have shown a temporal correlation between spontaneous activity patterns and synaptic remodeling, but in order to prove causality experiments analogous to the Stryker and Strickland approach, of blocking and inducing waves, domains or oscillations to produce circuit alterations will be needed. A better knowledge of the cellular mechanisms underlying the spontaneous activity patterns will make possible more specific pharmacological or genetic approaches designed to prevent them. Also, novel imaging47 or photostimulation techniques48 provide new ways of recording or altering spontaneous activity in vivo which may be very useful for these types of experiments.
What is the function of spontaneous activity during development? The main hypothesis being investigated is the possibility that the spontaneous activity patterns in the developing CNS are regulating the refinement of the circuitry. For instance, in the neocortex, columnar domains could be the precursors of adult functional columns.17 In the hippocampus, synaptogenesis might be controlled by the interplay between NMDA synapse activation and GABA-mediated depolarization (Hanse et al, this issue). In the retina, waves trigger correlated epochs of synchronous firing which can produce long-lasting synaptic enhancement in the LGN, and therefore stabilize appropriate synapses.45 In locus coeruleus, oscillations could enhance the effect of adrenergic innervation in target regions (Christie, this issue). Finally, in the spinal cord, two different types of calcium accumulations, ‘waves’ and ‘spikes’, appear to specifically regulate neurite extension and channel differentiation (Spitzer and Gu, this issue). In this delicate interplay between neuronal activity and circuit remodeling, developing neurons could be using a temporal code to distinguish appropriate from inappropriate targets. Hints that this may be happening are the results from developing retina showing that different cell types produce different temporal patterns of activity (Wong, this issue), or the finding from developing spinal cord that the differentiation depends on the frequency of the calcium transients (ref 46; Spizter and Gu, this issue). By allowing many different types of correlated activity, a temporal, or
References 1. Wiesel TN, Hubel DH (1963) Single-cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophys 26:1003-1017 2. Hebb DO (1949) The Organization of Behaviour. Wiley, New York 3. Spitz RA (1945) Hospitalism: Inquiry into the genesis of psychiatric conditions in early childhood. Psychoanal Study Child 1:53-74 4. Harlow HF, Dodsworth RO, Harlow MK (1965) Total social isolation in monkeys. Proc Natl Acad Sci USA 54:90-97 5. Wiesel TN, Hubel DH (1965) Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. J Neurophys 28:1029-1040 6. Hubel DH, Wiesel TN (1965) Binocular interaction in striate cortex of kittens reared with artificial squint. J Neurophys 28:1041-1059 7. Wiesel TN (1982) Postnatal development of the visual cortex and the influence of the environment. Nature 299:583-592 8. Goodman CS, Shatz CJ (1993) Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell 72:77-98 9. Shatz CJ (1990) Impulse activity and the patterning of connections during CNS development. Neuron 5:745-756 10. Stryker MP, Harris WA (1986) Binocular impulse blockade prevents the formation of ocular dominance columns in cat visual cortex. J Neurosci 6:2117-2133
3
Introduction 11. Raki¸c P (1977) Prenatal development of the visual system in the developing nervous system. Phil Trans R Soc Lond (B) 278:245-260 12. Shatz CJ, Stryker MP (1988) Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents. Science 242:87-89 13. Stryker MP, Strickland SL (1984) Physiological segregation of ocular dominance columns depends on the pattern of afferent electrical activity. Invest Ophthalmol Vis Sci 25 (suppl.):278 14. Meister M, et al (1991) Synchronous bursts of action potentials in ganglion cells of the developing mammalian retina. Science 252:939-943 15. Maffei L, Galli-Resta L (1990) Correlation in the discharges of neighboring rat retinal ganglion cells during prenatal life. Proc Natl Acad Sci USA 87:2861-2864 16. Alonso J-M, Usrey WM, Reid RC (1996) Precisely correlated firing in cells of the lateral geniculate nucleus. Nature, in press 17. Yuste R, Peinado A, Katz LC (1992) Neuronal domains in developing neocortex. Science 257:665-669 18. Feller MB, et al (1996) Requirement for cholinergic synaptic transmission in the propagation of spontaneous retinal waves. Science 272:1182-1187 19. Basar E, Bullock TH (eds) (1992) Induced Rhythms In The Brain. Birkhaeuser Boston, Cambridge, Basel 20. Wong ROL (1993) The role of spatio-temporal firing patterns in neuronal development of sensory systems. Curr Opin Neurobiol 3:595-601 21. Mueller AL, Taube JS, Schwartzkroin PA (1984) Development of hyperpolarizing inhibitory postsynaptic potentials and hyperpolarizing responses to gamma-amino butyric acid in rabbit hippocampus studied in vitro. J Neurosci 4:860-867 22. Ben-Ari Y, et al (1989) Giant synaptic potentials in immature rat CA3 hippocampal neurons. J Physiol (Lond.) 416:303-325 23. Ben Ari Y, et al (1994) Gamma-aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life. Prog Brain Res 102:261-273 24. Bixby JL, Spitzer NC (1982) The appearance and development of chemosensitivity in Rohon-Beard neurones of the Xenopus spinal cord. J Physiol 330:513-536 25. Rohrbough J, Spitzer NC (1996) Regulation of intracellular Cl levels by Na-dependent Cl cotransport distinguished depolarizing from hyperpolarizing GABA-a receptor-mediated responses in spinal cords. J Neurosci 16:82-91 26. Yuste R, Katz LC (1991) Control of postsynaptic Ca2 + influx in developing neocortex by excitatory and inhibitory neurotransmitters. Neuron 6:333-344 27. LoTurco JJ, et al (1995) GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15:1287-1298 28. Penn A, Wong R, Shatz C (1994) Neuronal coupling in the developing mammalian retina. J Neurosci 14:3805-3815 29. Yuste R, et al (1995) Neuronal domains in developing neocortex: mechanisms of coactivation. Neuron 14:7-17
30. Gutnick MJ, Prince DA (1981) Dye coupling and possible electrotonic coupling in the guinea pig neocortical slice. Science 211:67-70 31. Connors BW, Bernardo LS, Prince DA (1983) Coupling between neurons of the developing rat neocortex. J Neurosci 3:773-782 32. Lo Turco JJ, Kriegstein AR (1991) Clusters of coupled neuroblasts in embryonic neocortex. Science 252:563-566 33. Peinado A, Yuste R, Katz LC (1993) Extensive dye coupling between rat neocortical neurons during the period of circuit formation. Neuron 10:103-114 34. Fulton BP, Miledi R, Takahashi T (1980) Electrical synapses between motoneurons in the spinal cord of the newborn rat. Proc R Soc Lond B Biol Sci 208:115-120 35. Spitzer NC (1982) Voltage- and stage-dependent uncoupling of Rhodon-Beard neurones during embryonic development of Xenopus tadpoles. J Physiol 330:145-162 36. Walton K, Navarrete R (1991) Postnatal changes in motorneurone electrotonic coupling studied in the in vivo rat lumbar spinal cord. J Physiol (Lond.) 433:283-305 37. Mazza E, et al (1992) Anatomical and electrotonic coupling in developing genioglossal motorneurons of the rat. Brain Res 598:127-137 38. Christie MJ, Williams JT, North RA (1989) Electrical coupling synchronizes subthreshold activity in locus coeruleus neurons in vitro from neonatal rats. J Neurosci 9:3584-3589 39. Walsh JP, et al (1989) Dye-coupling in the neostriatum of the rat: II. Decreased coupling between neurons during development. Synapse 4:238-247 40. MacVicar BA, Dudek FE (1981) Electronic coupling between pyramidal cells: a direct demonstration in rat hippocampal slices. Science 213:782-785 41. Hubel DH, Wiesel TN (1963) Receptive fields of cells in striate cortex of very young, visually inexperienced kittens. J Neurophysiol 26:994-1002 42. Armstrong-James M (1975) The functional status and columnar organization of single cells responding to cutaneous stimulation in neonatal rat somatosensory cortex S1. J Physiol 246:501-538 43. Armstrong-James M, Johnson R (1970) Quantitative studies of postnatal changes in synapses in rat superficial motor cortex. Z Zellforsch Mikrosk Anat 110:559-568 44. Katz LC (1993) Coordinate activity in retinal and cortical development. Curr Opin Neurobiol 3:93-99 45. Mooney R, Madison DV, Shatz CJ (1993) Synaptic enhancement of transmission at the developing retinogeniculate synapse. Neuron 10:815-825 46. Gu X, Spitzer NC (1995) Distinct aspects of neuronal differentiation encoded by frequency of spontaneous Ca + transients. Nature 375:784-787 47. Denk W, et al (1994) Anatomical and functional imaging of neurons using 2-photon laser scanning microscopy. J Neurosci Meth 54:151-162 48. Katz LC, Dalva MB (1994) Scanning laser photostimulation: a new approach for analysing brain circuits. J Neurosci Meth 54:205-218
4
CELL & DEVELOPMENTAL BIOLOGY, Vol 8, 1997: pp 1–4
Introduction: Spontaneous activity in the developing central nervous system Rafael Yuste
retinal activity with injections of the sodium-channel blocker tetrodotoxin (TTX) prevents the segregation of retinogeniculate afferents and ocular dominance columns,10,12 and, as Stryker and Strickland reported, imposing synchronized activity patterns on a TTXtreated animal can rescue the refinement of ocular dominance columns.13 These TTX experiments have put the spotlight on the spontaneous activity by demonstrating that it is a necessary and sufficient condition for the normal segregation of the retinogeniculate and geniculocortical pathways. This issue of Seminars in Cell & Developmental Biology concentrates on understanding the patterns of intrinsic, spontaneous activity present in the developing mammalian CNS and the cellular mechanisms behind them. Here, we present a small number of studies where optical and electrical multicellular recording techniques have allowed investigators to characterize the spontaneous activity patterns in developing retina, spinal cord, locus coeruleus, hippocampus and neocortex. As it will be argued below, these studies are revealing many similarities between different brain regions in the patterns of correlated spontaneous activity and in their underlying mechanisms.
IN 1963, Wiesel and Hubel published a series of electrophysiological recordings reporting that, after raising kittens under monocular deprivation, neurons in the primary visual cortex became unresponsive to stimulation by the deprived eye.1 Although it was known that sensory deprivation during development had profound effects on the adult behavior,2-4 these results showed for the first time at the cellular level that neuronal activity during a ‘critical period’ of early development was necessary for the normal function of the adult visual cortex. Two years later, in follow-up studies, they reported that, while binocularly deprived animals had surprisingly normal ocular dominance responses, animals raised under artificial squint conditions had no binocular cells in their visual cortices.5,6 This implied that the important factor was not the absolute level of activity, but instead the relative level of activity in one eye versus that of the other. These experiments thus suggested a scenario where inputs from both eyes compete for cortical territory, using correlated activity to identify each other.7 These findings, of central importance in the nature/nurture debate, opened the door to the field of activitydependent development, i.e. the branch of neurobiology that studies the effects of neuronal activity in determining the pattern of connectivity in the brain.8,9 Since these initial studies, it has become increasingly clear that the types of activity influencing the development of the visual system are not limited to sensory stimulation, but can also be spontaneous activity patterns present during early development. For instance, in cats, ocular dominance columns form normally when animals are binocularly deprived5 or raised in the dark.10 In monkeys, ocular dominance columns are already formed before birth, and therefore, before eye opening.11 Also, activity-dependent remodeling of the retino-geniculate projection takes place before photoreceptors are even born (see Wong, this issue). Finally, blocking all spontaneous
What are the spontaneous activity patterns in the developing brain? Three major spatio-temporal patterns of activity have been described so far in the developing central nervous system: waves, domains and oscillations, and it is likely that each brain region displays a combination of them. Waves were first discovered in developing retina as synchronous bursts of action potentials that spontaneously sweep through the entire retina.14 Their existence has been well documented in vitro using multielectrode arrays and calcium imaging (Wong, this issue) and there are signs of their possible existence in vivo.15 Because of the high fidelity of synaptic transmission with correlated firing patterns in the visual system,16 waves could reverberate
From the Department of Biological Sciences, Columbia University, New York, NY 10027, USA ©1997 Academic Press Ltd/sr960114
1
Introduction this issue). In fact, a recurring theme throughout the developing CNS is the excitatory role of GABA, mediated by a depolarization due to increased intracellular chloride concentration. In the developing hippocampus, GABA-induced depolarizations and calcium accumulations are ubiquitous21-23 and may play an essential role in the formation of new synapses (Hanse et al, this issue). In the developing spinal cord, depolarizing GABA modulates the behavior of the network (refs 24, 25; O’Donovan and Chub, this issue), Finally, in the developing neocortex, GABA also produces major calcium influxes into neurons.26,27 An alternative mechanism underlying spontaneous activity during development is gap-junctional communication. In the retina, extensive networks of coupled neurons — presumably linked through gap-junctions — appear after intracellular tracer injections.28 Although these gap-junctional networks seem ideally suited to mediate circuit activation, their participation in the waves is controversial (Wong, this issue). In the developing neocortex, however, gap-junctional communication is necessary for neuronal domains to occur (Kandler, this issue): while TTX or synaptic blockers do not prevent the appearance of domains, gap-junction antagonists reversibly block them.29 Also, tracer injections show extensive networks of coupled neurons forming columnar structures.30-33 Finally, significant coupling between developing cortical neurons can be revealed electrophysiologically.29 Interestingly, coupling in neocortex and retina is specific for particular cell types, strongly indicating that it is not artifactual.28,33 Neuronal coupling, presumably mediated by gap junctions, has also been described in the developing spinal cord,34-36 genioglossal nucleus,37 locus coeruleus (ref 38, Christie, this issue) striatum,39 and hippocampus.40 Gap-junctional communication thus appears as a general feature throughout the developing CNS. The existence of gap-junctional coupling does not necessarily imply that neurons use them to activate each other electrically. The historical bias to consider gap-junctions as merely electrical connections is now changing because of techniques that allow imaging of intracellular ions and second messengers. Because gap-junctions also couple neurons biochemically, important developmental signals like calcium, IP3, cAMP, or even mRNA and DNA, could be easily transmitted from cell to cell. In fact, the homophilic nature of many connexons could restrict the sharing of instructive developmental signals to cells members of the same class. Indeed, the activity
through the lateral geniculate nucleus (LGN) and into the cortex. Domains were first described with calcium imaging as groups of five to 50 neurons that increased their calcium concentration in synchrony.17 The term ‘domain’, originally suggested by Scott Fraser, was used to define the territory encompassed by a given neuronal coactivation. In developing neocortex these groups of spontaneously coactive neurons form a modular architecture of columns which cover the cortex with little overlap.17 In the retina, waves advance by sequentially recruiting neuronal domains which also lack substantial overlap of territories on a short time scale.18 Domain-like coactivations have been found in the hippocampus, cerebellum, thalamus and superior colliculus (Yuste and Katz, unpublished; Wong, personal communication; Sejnowski, personal communication; Konnerth, personal communication). In developing spinal cord in vivo neuronal coactivations also occur, but coactive neurons are not necessarily next to each other (Spitzer and Gu, this issue). Finally, a third type of spontaneous activity in the developing CNS consists of synchronous oscillations of the electrical activity of an area. These oscillations can recruit an entire region, like in the locus coeruleus (Christie, this issue) or the hippocampus (Konnerth et al, in preparation), or particular cells within a region, like in the spinal cord (O’Donovan and Chub, this issue). These phenomena possibly represent an early stage of oscillatory behaviors ubiquitous in the adult CNS.19
What are the mechanisms underlying spontaneous activity patterns? Our understanding of the mechanisms responsible for the spontaneous activity patterns in the developing CNS is still incomplete. Most circuit activations could be carried out by conventional synaptic transmission and, indeed, waves in the retina appear to be mediated synaptically because they can be blocked by TTX20 and by cholinergic antagonists.18 Synaptic transmission also appears to mediate the bulk of the circuit activation in the spinal cord (O’Donovan and Chub, this issue), although not in developing neocortex and locus coeruleus (Kandler, this issue; Christie, this issue). In the hippocampus, ‘silent’ synapses, composed of NMDA receptors, only become active during strong depolarizations mediated by a paradoxical excitatory effect of GABA (Hanse et al, 2
Introduction frequency, code would improve substantially the specificity and precision of activity-dependent rules of circuit rearrangements.
responsible for a neuronal domain appears to be a second messenger wave mediated by IP3, rather than conventional electrical activity (Kandler, this issue). Why gap junctional coupling? In developing cortex and locus coeruleus, coupling is most extensive at a time when synaptic connections are scarce (Kandler, this issue; Christie, this issue). In fact, in developing neocortex, electrophysiological recordings consistently show a paucity of electrical activity.41-43 As suggested by Katz, gap-junctional coupling could amplify weak synaptic inputs, by carrying their effects, translated into a strong second messenger signal, throughout the network of coupled neurons.44 A similar amplification of activity could occur in the retina, spinal cord and locus coeruleus. Finally, in locus coeruleus, gap-junctions may synchronize the oscillations (Christie, this issue).
Future directions of research In spite of all this exciting progress, the basic patterns of spontaneous activity in vivo still have not been explored appropriately, and it is possible that new types of activity patterns might be discovered. Also, the causal link between waves, domains, or oscillations and circuit modifications remains to be demonstrated. Current studies have shown a temporal correlation between spontaneous activity patterns and synaptic remodeling, but in order to prove causality experiments analogous to the Stryker and Strickland approach, of blocking and inducing waves, domains or oscillations to produce circuit alterations will be needed. A better knowledge of the cellular mechanisms underlying the spontaneous activity patterns will make possible more specific pharmacological or genetic approaches designed to prevent them. Also, novel imaging47 or photostimulation techniques48 provide new ways of recording or altering spontaneous activity in vivo which may be very useful for these types of experiments.
What is the function of spontaneous activity during development? The main hypothesis being investigated is the possibility that the spontaneous activity patterns in the developing CNS are regulating the refinement of the circuitry. For instance, in the neocortex, columnar domains could be the precursors of adult functional columns.17 In the hippocampus, synaptogenesis might be controlled by the interplay between NMDA synapse activation and GABA-mediated depolarization (Hanse et al, this issue). In the retina, waves trigger correlated epochs of synchronous firing which can produce long-lasting synaptic enhancement in the LGN, and therefore stabilize appropriate synapses.45 In locus coeruleus, oscillations could enhance the effect of adrenergic innervation in target regions (Christie, this issue). Finally, in the spinal cord, two different types of calcium accumulations, ‘waves’ and ‘spikes’, appear to specifically regulate neurite extension and channel differentiation (Spitzer and Gu, this issue). In this delicate interplay between neuronal activity and circuit remodeling, developing neurons could be using a temporal code to distinguish appropriate from inappropriate targets. Hints that this may be happening are the results from developing retina showing that different cell types produce different temporal patterns of activity (Wong, this issue), or the finding from developing spinal cord that the differentiation depends on the frequency of the calcium transients (ref 46; Spizter and Gu, this issue). By allowing many different types of correlated activity, a temporal, or
References 1. Wiesel TN, Hubel DH (1963) Single-cell responses in striate cortex of kittens deprived of vision in one eye. J Neurophys 26:1003-1017 2. Hebb DO (1949) The Organization of Behaviour. Wiley, New York 3. Spitz RA (1945) Hospitalism: Inquiry into the genesis of psychiatric conditions in early childhood. Psychoanal Study Child 1:53-74 4. Harlow HF, Dodsworth RO, Harlow MK (1965) Total social isolation in monkeys. Proc Natl Acad Sci USA 54:90-97 5. Wiesel TN, Hubel DH (1965) Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. J Neurophys 28:1029-1040 6. Hubel DH, Wiesel TN (1965) Binocular interaction in striate cortex of kittens reared with artificial squint. J Neurophys 28:1041-1059 7. Wiesel TN (1982) Postnatal development of the visual cortex and the influence of the environment. Nature 299:583-592 8. Goodman CS, Shatz CJ (1993) Developmental mechanisms that generate precise patterns of neuronal connectivity. Cell 72:77-98 9. Shatz CJ (1990) Impulse activity and the patterning of connections during CNS development. Neuron 5:745-756 10. Stryker MP, Harris WA (1986) Binocular impulse blockade prevents the formation of ocular dominance columns in cat visual cortex. J Neurosci 6:2117-2133
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Introduction 11. Raki¸c P (1977) Prenatal development of the visual system in the developing nervous system. Phil Trans R Soc Lond (B) 278:245-260 12. Shatz CJ, Stryker MP (1988) Prenatal tetrodotoxin infusion blocks segregation of retinogeniculate afferents. Science 242:87-89 13. Stryker MP, Strickland SL (1984) Physiological segregation of ocular dominance columns depends on the pattern of afferent electrical activity. Invest Ophthalmol Vis Sci 25 (suppl.):278 14. Meister M, et al (1991) Synchronous bursts of action potentials in ganglion cells of the developing mammalian retina. Science 252:939-943 15. Maffei L, Galli-Resta L (1990) Correlation in the discharges of neighboring rat retinal ganglion cells during prenatal life. Proc Natl Acad Sci USA 87:2861-2864 16. Alonso J-M, Usrey WM, Reid RC (1996) Precisely correlated firing in cells of the lateral geniculate nucleus. Nature, in press 17. Yuste R, Peinado A, Katz LC (1992) Neuronal domains in developing neocortex. Science 257:665-669 18. Feller MB, et al (1996) Requirement for cholinergic synaptic transmission in the propagation of spontaneous retinal waves. Science 272:1182-1187 19. Basar E, Bullock TH (eds) (1992) Induced Rhythms In The Brain. Birkhaeuser Boston, Cambridge, Basel 20. Wong ROL (1993) The role of spatio-temporal firing patterns in neuronal development of sensory systems. Curr Opin Neurobiol 3:595-601 21. Mueller AL, Taube JS, Schwartzkroin PA (1984) Development of hyperpolarizing inhibitory postsynaptic potentials and hyperpolarizing responses to gamma-amino butyric acid in rabbit hippocampus studied in vitro. J Neurosci 4:860-867 22. Ben-Ari Y, et al (1989) Giant synaptic potentials in immature rat CA3 hippocampal neurons. J Physiol (Lond.) 416:303-325 23. Ben Ari Y, et al (1994) Gamma-aminobutyric acid (GABA): a fast excitatory transmitter which may regulate the development of hippocampal neurones in early postnatal life. Prog Brain Res 102:261-273 24. Bixby JL, Spitzer NC (1982) The appearance and development of chemosensitivity in Rohon-Beard neurones of the Xenopus spinal cord. J Physiol 330:513-536 25. Rohrbough J, Spitzer NC (1996) Regulation of intracellular Cl levels by Na-dependent Cl cotransport distinguished depolarizing from hyperpolarizing GABA-a receptor-mediated responses in spinal cords. J Neurosci 16:82-91 26. Yuste R, Katz LC (1991) Control of postsynaptic Ca2 + influx in developing neocortex by excitatory and inhibitory neurotransmitters. Neuron 6:333-344 27. LoTurco JJ, et al (1995) GABA and glutamate depolarize cortical progenitor cells and inhibit DNA synthesis. Neuron 15:1287-1298 28. Penn A, Wong R, Shatz C (1994) Neuronal coupling in the developing mammalian retina. J Neurosci 14:3805-3815 29. Yuste R, et al (1995) Neuronal domains in developing neocortex: mechanisms of coactivation. Neuron 14:7-17
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