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Sweeping visions
NEURAL DEVELOPMENT
HOLLIS T. CLINE
Sweeping visions Waves of action potential activity in embryonic retina may have an instructional role in the development of the part of the brain that will later respond to retinal stimuli. It has long been recognized that the development of the amrdian visual system involves a two-step process [ 11. $e lirst step is characterized by the development of a diffusely organized projection from the retinal ganglion cells to their direct central targets in the brain - including the lateral geniculate nucleus (IGN) of the thalamus - and to their indirect central targets, including the primary visual cortex. At a later point in development, the diiksely organized projection is relined in two respects. One is that the retinal axon arbors from the two eyes segregate from one another into eye-specik termination zones in the IGN and visual cortex. The second type of refinement occurs in the spatial distribution of the tierent terminals from each eye, so that the positions of the axon terminals convey to the central visual areas of the brain a precise point to point representation of the two-dimensional array of retinal ganglion cell bodies. This representation is known as a topographic map. These rehnements of the visual projections require neural activity in the retinal ganglion cells [ 231. One popular model for this developmental process is based on observations of neighboring retinal ganglion cells that display correlated patterns of electrical activity, in both mature and developing retina. The correlatd activity patterns in the retinal axon terminals, which arise from neighboring retinal ganglion cell bodies, would facilitate the formation and maintenance of synapses on common target neurons [ 41.
Fig. 1. The ganglion cell layer of the retina of an 18-day-old ferret, stained with to&dine blue and placed on the electrode array. The ekactrodes appear as black spots just out of the focal plane.Bar, 58 pm. (Photograph courtesy M Meister, reproduced with permission from Science 191.)
It is the timing of this activity-dependent refinement of the retinal projections with respect to the maturation of the
khrne
1
Number 5
1991
--L-L--IIL-L-..LIII’ A.--L-LII)I -.-II I-II L-L-L-II L--L-l-III I-III /-III i-l--L--l-l--l-I 0
Time
(seconds)
Fig. 2 Rhythmic bursts of action potentials neighbouring neurons in a s-day-old ferret riod. (Adapted from 191.1
1200
recorded from over a 28-minute
ten pe-
retina that has presented developmental neuroscientists with a dilemma The retinal projection to the LGN dlsplays the activity-dependent refinement long before the retina can receive and process visual inputs. In the kitten, eye opening and the iirst light responses occur about 10 days after birth. But the activity-dependent reorganization of the retinogeniculate axon arbors begins in utero at about embryonic day 47 and continues until embryonic day 60 [ 51. In the ferret, the developmental timetable parallels that of the kitten, but the ferret is born at a relatively immature state. Reorganization of the ferret retinogeniculate projection occurs 3-20 days after birth, whereas visual responses start at day 35 [6]. How can correlated patterns of retinal ganglion cell activity be responsible for the organization of the retinogeniculate projection at developmental stages prior to the maturation of retinal circuitry? Three years ago, Galli and Maffei [7] recorded intracellularly from retinal ganglion cells in fetal rat retinae at embryonic stages corresponding to the period of retlnogeniculate reorganization. They reported that the ganglion cells spontaneously Rre rhythmic bursts of action
275
Fig. 3. The progression of one burst of action potentials as it sweeps across the retinal tissue in a wave. Recordings from the hexagonal multi-electrode array cover a d-second period, Each dot represents the approximate location of a neuron in the electrode array. The area of the dots is proportional to the average firing rate of the neuron during the OS-second interval recorded. (Adapted from [91.)
potentials in the absence of synaptic inputs. Furthermore, recordings from neighboring ganglion cells showed correlated patterns of bursting activity [ 81. These important studies suggested that endogenous ganglion cell activity might provide the afferent coactivity required for normal visual system development. The existence of correlated bursts of action potentials in neighboring ganglion cells has now been elegantly demonstrated in a recent paper by Meister et al [ 91. Using a hexagonal multi-electrode array, the authors were able to record spatial and temporal associations of extracellular action potential activity in flat-mounted bits of retinae from fetal and adult cats and ferrets (Fig. 1). Each electrode can record from several ganglion cells, but activity in individual cells can be distinguished from others recorded by the same electrode on the basis of spike amplitude, waveform, refractory period and estimated location of the cell within the array. Cells in embryonic retina 6re bursts of action potentials that are correlated with bursts recorded from neighboring cells. The bursts usually last 2-4 seconds with an interburst interval of about 40-100 seconds. Recordings of activity from several neighboring neurons show a remarkable synchrony in the bursting (Fig. 2). Not only are the bursts temporally correlated with those in neighboring neurons, but the multi-electrode array clearly demonstrates the dynamic spatial relationship of the bursts within the retinal tissue. Waves of bursts seem to sweep radially across the retina.at about 100 dsecond (Fig. 3). Meister and his colleagues suggest that the radial propagation indicates that excited ganglion cells stimulate their circle of neighbors to fire action potentials and that those excited cells then stimulate their neighbors. The wave action would be due to an apparent refractory period in the ganglion cells which prevents their continued activity. After the refractory period, the neurons would again be susceptible to excitation by neighboring neurons. It is not yet clear what the source of the bursting activity is, or what synchronizes the bursts; Related to the question of synchronization, is the issue of the regulation of the refractory period. It is not clear whether the ganglion cells are endogenously active or whether they are driven by other cells within the retina, such as the amacrine cells. The rate of progression of the waves is too slow for classical synaptic transmission, or transmission thtough gap junctions of the sort previously studied in developing or mature tissue. ‘However, it is in the correct velocity range for diffusion of small molecules through the
276
extracellular space over the distance between ganglion cell bodies. Therefore, the stimulus could be an increase in extracellular potassium ions or a transmitter-like substance acting extrasynaptically. The synchronization of the burst and the refractory period may also be influenced by intercellular communication. The lengths of the burst and of the refractory period can be shortened in low-calcium saline, consistent with the modulation of these parameters by inhibitov transmitter substances. Therefore, it seems that the waves of activity in the retina are due to discrete excitatory and inhibitory factors acting independently of synaptic connections. A critical point of this paper is that the activity patterns observed in the embryonic retina are optimal in terms of their ability to provide patterns of correlated activity in the retinogeniculate tierent terminals. Such patterns would permit the segregation of the axon terminals into eye-specific laminae and the refinement of the topographic order of the terminals driven by each eye within the laminae. In addition, the bursts are completely wiped out by the Na + channel blocker, tetrodotoxin (‘ITX). When injected into the eye, this drug also prevents the normal development of the visual projections [2,3]. Therefore, the TIX-sensitivity of the bursts is consistent with the suggestion that these waves of bursts might provide the correlated activity that organizes the retinogeniculate projection. The creative use of a multielectrode array for recording neural activity in relatively large pieces of intact retina has thus provided some fascinating information on the spatio-temporal pattern of action potential activity in developing retina, and has extended data gathered previously by recording from limited mumbers of ganglion cells. That a pattern exists at all is big news and addresses a critical issue in the development of visual projections. Namely, the temporal mismatch between retinal maturation and the activity-dependent segregation of retinal projections in the thalamus. As with many provocative fmlings, this study raises further questions for future research into the early events in retinal maturation. References 1. SHAFZCJ: Impulse activity and the patterning of connections during CNS development Neuron 1990, 5:74S-756. 2.
MP, Hmus WA: Biocular impulse blockade prevents the formation of ocular dominance columns in cat visual cortex / Neurazi 1986, 6:2117-2133.
STRYKER
@
1991
Current
Biology
3.
4.
SHAH CJ, SIRYKJ% Mp: Prenatal infusion of tetfodototi blocks segegadon of retioogeni~ alTerems. .scierw WEa, 242:87+X CONSTANTINE-PATON M, CIINIZHT, DEBSKIE: Pattcmed activity, synaptic conveqpce and the NMDA receptor in developing visual paWvays. Ann Rev Neumci 1990, 13:12%154.
5.
SHKYZCJ: The prenatal development of the cat’s retinogenicdate pathway. J Neumci 1983, 3~482-499.
6.
CUCCHIAROJ, GUIIU~Y RW: The de-velopment of the retinogeniculate pathways in normal and albino ferrets. Proc Roy Sot 1984, 223:141-164.
7.
GAIN L, MAFFEIL Spontaneous impulse activity of rat retinal ganglion cells in prenatal life. Science 1988, 2429B-91.
8.
MAFFEIL, GNU-RESTAL Cordation in the discharges of ne-ighboring rat retinal ganglion cells during prenatal life. Boc Nut1 Auzd Sci (ISA 1990, 87:2861-2864. MEISTERM, WONG ROI, BAYLORDA, SH&?Z CJ: Synchronous bursts of action potentials in gaoglion cells of the developing mammalian retina. Scheme 1991, 252:93%943.
9.
Hollis T. Cline, Dept of Physiology and Biophysics, 51 Newton Street, University of Iowa Medical School, Iowa City, Iowa 52242, USA,
NEURAL DFWJXQPMENT IN CURRENT. OPINION IN NEUROBIOLOGY Corey Goodman and Thomas Jessell will be editing the following reviews in the February 1992 issue: Retinotectal specificity by S Fraser Repellant cues in axon guidance by R Keynes Detection of gradients by M Tessier-Iavigne Development of cortical connections by C Shatz Pruning of collateral projections in developing brain by D O’Leary Motor axon pa-ding by M Westerfield Axon pathfinding in Zebrafish by J Kuwada Genetics of axonal projections in C e&guns by E Hedgecock Genetics of axonal growth in DtwmpMu by G Grenningloh Mesodermal control of neural cell identity in vertebrates by J Dodd Control of photoreceptor differentiation by L Lillien Innervation-dependent control of post-synaptic differentiation by H Steller Molecules that organize the neuro-muscular synapse by R Scheller Control of transmitter phenotype by the CNTF, LtF, IL.6 family by P Patterson Determination of neuronal identity in Zebrafish by S Easter and S Wilson Neurotrophic factor receptors by L Parada Control of neuronal identity in cerebral cortex by S MCCOMefl Axonal glycoproteins by J Bixby Guidepost cells by J Palka
Volume 1
Number 5
1991
277
HOLLIS T. CLINE
Sweeping visions Waves of action potential activity in embryonic retina may have an instructional role in the development of the part of the brain that will later respond to retinal stimuli. It has long been recognized that the development of the amrdian visual system involves a two-step process [ 11. $e lirst step is characterized by the development of a diffusely organized projection from the retinal ganglion cells to their direct central targets in the brain - including the lateral geniculate nucleus (IGN) of the thalamus - and to their indirect central targets, including the primary visual cortex. At a later point in development, the diiksely organized projection is relined in two respects. One is that the retinal axon arbors from the two eyes segregate from one another into eye-specik termination zones in the IGN and visual cortex. The second type of refinement occurs in the spatial distribution of the tierent terminals from each eye, so that the positions of the axon terminals convey to the central visual areas of the brain a precise point to point representation of the two-dimensional array of retinal ganglion cell bodies. This representation is known as a topographic map. These rehnements of the visual projections require neural activity in the retinal ganglion cells [ 231. One popular model for this developmental process is based on observations of neighboring retinal ganglion cells that display correlated patterns of electrical activity, in both mature and developing retina. The correlatd activity patterns in the retinal axon terminals, which arise from neighboring retinal ganglion cell bodies, would facilitate the formation and maintenance of synapses on common target neurons [ 41.
Fig. 1. The ganglion cell layer of the retina of an 18-day-old ferret, stained with to&dine blue and placed on the electrode array. The ekactrodes appear as black spots just out of the focal plane.Bar, 58 pm. (Photograph courtesy M Meister, reproduced with permission from Science 191.)
It is the timing of this activity-dependent refinement of the retinal projections with respect to the maturation of the
khrne
1
Number 5
1991
--L-L--IIL-L-..LIII’ A.--L-LII)I -.-II I-II L-L-L-II L--L-l-III I-III /-III i-l--L--l-l--l-I 0
Time
(seconds)
Fig. 2 Rhythmic bursts of action potentials neighbouring neurons in a s-day-old ferret riod. (Adapted from 191.1
1200
recorded from over a 28-minute
ten pe-
retina that has presented developmental neuroscientists with a dilemma The retinal projection to the LGN dlsplays the activity-dependent refinement long before the retina can receive and process visual inputs. In the kitten, eye opening and the iirst light responses occur about 10 days after birth. But the activity-dependent reorganization of the retinogeniculate axon arbors begins in utero at about embryonic day 47 and continues until embryonic day 60 [ 51. In the ferret, the developmental timetable parallels that of the kitten, but the ferret is born at a relatively immature state. Reorganization of the ferret retinogeniculate projection occurs 3-20 days after birth, whereas visual responses start at day 35 [6]. How can correlated patterns of retinal ganglion cell activity be responsible for the organization of the retinogeniculate projection at developmental stages prior to the maturation of retinal circuitry? Three years ago, Galli and Maffei [7] recorded intracellularly from retinal ganglion cells in fetal rat retinae at embryonic stages corresponding to the period of retlnogeniculate reorganization. They reported that the ganglion cells spontaneously Rre rhythmic bursts of action
275
Fig. 3. The progression of one burst of action potentials as it sweeps across the retinal tissue in a wave. Recordings from the hexagonal multi-electrode array cover a d-second period, Each dot represents the approximate location of a neuron in the electrode array. The area of the dots is proportional to the average firing rate of the neuron during the OS-second interval recorded. (Adapted from [91.)
potentials in the absence of synaptic inputs. Furthermore, recordings from neighboring ganglion cells showed correlated patterns of bursting activity [ 81. These important studies suggested that endogenous ganglion cell activity might provide the afferent coactivity required for normal visual system development. The existence of correlated bursts of action potentials in neighboring ganglion cells has now been elegantly demonstrated in a recent paper by Meister et al [ 91. Using a hexagonal multi-electrode array, the authors were able to record spatial and temporal associations of extracellular action potential activity in flat-mounted bits of retinae from fetal and adult cats and ferrets (Fig. 1). Each electrode can record from several ganglion cells, but activity in individual cells can be distinguished from others recorded by the same electrode on the basis of spike amplitude, waveform, refractory period and estimated location of the cell within the array. Cells in embryonic retina 6re bursts of action potentials that are correlated with bursts recorded from neighboring cells. The bursts usually last 2-4 seconds with an interburst interval of about 40-100 seconds. Recordings of activity from several neighboring neurons show a remarkable synchrony in the bursting (Fig. 2). Not only are the bursts temporally correlated with those in neighboring neurons, but the multi-electrode array clearly demonstrates the dynamic spatial relationship of the bursts within the retinal tissue. Waves of bursts seem to sweep radially across the retina.at about 100 dsecond (Fig. 3). Meister and his colleagues suggest that the radial propagation indicates that excited ganglion cells stimulate their circle of neighbors to fire action potentials and that those excited cells then stimulate their neighbors. The wave action would be due to an apparent refractory period in the ganglion cells which prevents their continued activity. After the refractory period, the neurons would again be susceptible to excitation by neighboring neurons. It is not yet clear what the source of the bursting activity is, or what synchronizes the bursts; Related to the question of synchronization, is the issue of the regulation of the refractory period. It is not clear whether the ganglion cells are endogenously active or whether they are driven by other cells within the retina, such as the amacrine cells. The rate of progression of the waves is too slow for classical synaptic transmission, or transmission thtough gap junctions of the sort previously studied in developing or mature tissue. ‘However, it is in the correct velocity range for diffusion of small molecules through the
276
extracellular space over the distance between ganglion cell bodies. Therefore, the stimulus could be an increase in extracellular potassium ions or a transmitter-like substance acting extrasynaptically. The synchronization of the burst and the refractory period may also be influenced by intercellular communication. The lengths of the burst and of the refractory period can be shortened in low-calcium saline, consistent with the modulation of these parameters by inhibitov transmitter substances. Therefore, it seems that the waves of activity in the retina are due to discrete excitatory and inhibitory factors acting independently of synaptic connections. A critical point of this paper is that the activity patterns observed in the embryonic retina are optimal in terms of their ability to provide patterns of correlated activity in the retinogeniculate tierent terminals. Such patterns would permit the segregation of the axon terminals into eye-specific laminae and the refinement of the topographic order of the terminals driven by each eye within the laminae. In addition, the bursts are completely wiped out by the Na + channel blocker, tetrodotoxin (‘ITX). When injected into the eye, this drug also prevents the normal development of the visual projections [2,3]. Therefore, the TIX-sensitivity of the bursts is consistent with the suggestion that these waves of bursts might provide the correlated activity that organizes the retinogeniculate projection. The creative use of a multielectrode array for recording neural activity in relatively large pieces of intact retina has thus provided some fascinating information on the spatio-temporal pattern of action potential activity in developing retina, and has extended data gathered previously by recording from limited mumbers of ganglion cells. That a pattern exists at all is big news and addresses a critical issue in the development of visual projections. Namely, the temporal mismatch between retinal maturation and the activity-dependent segregation of retinal projections in the thalamus. As with many provocative fmlings, this study raises further questions for future research into the early events in retinal maturation. References 1. SHAFZCJ: Impulse activity and the patterning of connections during CNS development Neuron 1990, 5:74S-756. 2.
MP, Hmus WA: Biocular impulse blockade prevents the formation of ocular dominance columns in cat visual cortex / Neurazi 1986, 6:2117-2133.
STRYKER
@
1991
Current
Biology
3.
4.
SHAH CJ, SIRYKJ% Mp: Prenatal infusion of tetfodototi blocks segegadon of retioogeni~ alTerems. .scierw WEa, 242:87+X CONSTANTINE-PATON M, CIINIZHT, DEBSKIE: Pattcmed activity, synaptic conveqpce and the NMDA receptor in developing visual paWvays. Ann Rev Neumci 1990, 13:12%154.
5.
SHKYZCJ: The prenatal development of the cat’s retinogenicdate pathway. J Neumci 1983, 3~482-499.
6.
CUCCHIAROJ, GUIIU~Y RW: The de-velopment of the retinogeniculate pathways in normal and albino ferrets. Proc Roy Sot 1984, 223:141-164.
7.
GAIN L, MAFFEIL Spontaneous impulse activity of rat retinal ganglion cells in prenatal life. Science 1988, 2429B-91.
8.
MAFFEIL, GNU-RESTAL Cordation in the discharges of ne-ighboring rat retinal ganglion cells during prenatal life. Boc Nut1 Auzd Sci (ISA 1990, 87:2861-2864. MEISTERM, WONG ROI, BAYLORDA, SH&?Z CJ: Synchronous bursts of action potentials in gaoglion cells of the developing mammalian retina. Scheme 1991, 252:93%943.
9.
Hollis T. Cline, Dept of Physiology and Biophysics, 51 Newton Street, University of Iowa Medical School, Iowa City, Iowa 52242, USA,
NEURAL DFWJXQPMENT IN CURRENT. OPINION IN NEUROBIOLOGY Corey Goodman and Thomas Jessell will be editing the following reviews in the February 1992 issue: Retinotectal specificity by S Fraser Repellant cues in axon guidance by R Keynes Detection of gradients by M Tessier-Iavigne Development of cortical connections by C Shatz Pruning of collateral projections in developing brain by D O’Leary Motor axon pa-ding by M Westerfield Axon pathfinding in Zebrafish by J Kuwada Genetics of axonal projections in C e&guns by E Hedgecock Genetics of axonal growth in DtwmpMu by G Grenningloh Mesodermal control of neural cell identity in vertebrates by J Dodd Control of photoreceptor differentiation by L Lillien Innervation-dependent control of post-synaptic differentiation by H Steller Molecules that organize the neuro-muscular synapse by R Scheller Control of transmitter phenotype by the CNTF, LtF, IL.6 family by P Patterson Determination of neuronal identity in Zebrafish by S Easter and S Wilson Neurotrophic factor receptors by L Parada Control of neuronal identity in cerebral cortex by S MCCOMefl Axonal glycoproteins by J Bixby Guidepost cells by J Palka
Volume 1
Number 5
1991
277