Feature Article: Cajal–Retzius Cell Physiology: Just in Time to Bridge the 20th Century

Jean-Marc Mienville

The Psychiatric Institute, Department of Psychiatry, The University of Illinois at Chicago, Chicago, IL 60612, USA

Address correspondence to J.-M. Mienville, The Psychiatric Institute, Department of Psychiatry; m/c 912, The University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA. Email: jmm{at}psych.uic.edu.


    Abstract
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
Cajal–Retzius (CR) cells were discovered at the end of the 19th century but, surprisingly, the exploration of their physiological properties is only now beginning, as we near the end of the 20th century. A few papers addressing these properties have appeared recently, but incomplete data generally give the arguably misleading impression that CR cells are similar to other neocortical neurons, and therefore may perform analogous functions. It is one of the motives of this review to dispel such conceptions. Although CR cells display features of ‘regular’ neurons, including excitability and responsiveness to neurotransmitters, their function is probably limited to the primary implementation of cortical circuits. A strong indication in support of this idea is the fact that CR cells appear at the onset of neocorticogenesis and disappear at the end of neuronal migration.


    Introduction
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
The physiology of neocortical neurons has been characterized extensively over the past 15 years, in terms of both intrinsic membrane properties and synaptic activity. An important step was made with the assignment of specific firing properties to distinct neuronal phenotypes (McCormick et al., 1985Go), which essentially distinguished between ‘regular-spiking’ or ‘bursting’ pyramidal cells, and ‘fast-spiking’ GABAergic interneurons. Like many others, this study addressed neurons in layers II–VI, and it was soon recognized that further work was needed to examine layer I neurons (Connors and Gutnick, 1990Go). One problem is that the scarcity of layer I neurons (Marín-Padilla, 1984Go) [this remark applies only to mature stages of development. Perinatal Cajal–Retzius cell densities can be substantial (Derer and Derer, 1992Go), though they do not reach values observed in other zones of the developing cortex (Bayer and Altman, 1991Go)] tends to discourage their study, especially when one uses ‘blind’ techniques to record from brain slices (Budde and White, 1998Go). The advent of the in situ patch-clamp technique (Edwards et al., 1989Go) brought an answer to these difficulties, but somehow may have added to the confusion already existing around layer I. One aspect of this technique is that it requires using relatively young tissue, which has little extracellular matrix, in order to be able to seal the electrode tip to the cellular membrane. Then, because the cell composition of layer I changes with development, one may expect a fair amount of variability in the physiological properties expressed by different cells at different times. Using in situ patch-clamp techniques in brain slices from postnatal day (P) 14 to 21 rats, Zhou and Hablitz performed the first detailed study of cortical layer I neurons and classified them as fast-spiking interneurons (Zhou and Hablitz, 1996bGo,cGo), consistent with the high proportion of GABA-immunoreactive cells in that layer (Gabbott and Somogyi, 1986Go).

Cajal–Retzius (CR) cells represent a major component of layer I in its immature stage. In rodents, they are present in the marginal zone at the earliest stages of neocorticogenesis (Bayer and Altman, 1991Go), and show time-dependent changes in a number of membrane properties (Fig. 2Go) (Zhou and Hablitz, 1996aGo; Mienville and Barker, 1997Go; Mienville, 1998Go; Mienville and Pesold, 1999Go; Mienville et al., 1999aGo) before disappearing around the end of the second postnatal week (Derer and Derer, 1990Go, 1992Go; Del Río et al., 1995Go, 1996Go; Mienville and Pesold, 1999Go).



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Figure 2.  Voltage- and ligand-gated conductances in developing Cajal–Retzius cells recorded in slices from rat neocortex (adapted from Mienville, 1998; Mienville and Pesold, 1999; Mienville et al., 1999a). (A,B) Conductance densities of inactivating (A) and delayed rectifier (B) K currents at different postnatal days (P). (C,D) Densities of NMDA (C) and GABA (D) currents at different embryonic (E) or postnatal days. In (D) the original data (Mienville, 1998Go) were divided by the corresponding average cell capacitance measured at E18 or P11. Data (mean ± SEM) are fitted with a Boltzman (A,B) or Michaelis–Menten (C,D) equation.

 

    Some Anatomical and Technical Considerations
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
CR cells were discovered at the end of the 19th century almost simultaneously by Ramón y Cajal and Retzius (Ramón y Cajal, 1891Go; Retzius, 1893Go) [for historical details see Huntley and Jones (Huntley and Jones, 1990Go) and Jacobson (Jacobson, 1991Go)]. These cells are generated at the onset of neocorticogenesis [embryonic day (E) 12 in the rat] and are therefore considered as pioneer neurons, but their period of production may extend up to E15 (König and Marty, 1981Go; Bayer and Altman, 1991Go) [see also Meyer et al. for a radically different theory on CR cell genesis (Meyer et al., 1998Go)]. CR cells settle in the marginal zone where they morphologically differentiate by growing one or two major processes in a tangential direction. These two parameters (location and orientation), combined with a distinctive ovoid or fusiform somatic morphology, readily allow identification of CR cells in a slice preparation under Nomarski optics (Fig. 1AGo) (Zhou and Hablitz, 1996aGo; Schwartz et al., 1998Go), or after dye loading (Fig. 1BGo) (Kim et al., 1995Go; Hestrin and Armstrong, 1996Go; Mienville and Barker, 1997Go). During the postnatal period, the morphology of non-primate CR cells does not seem to change (Marín-Padilla, 1984Go) and their maximal neuritic growth is achieved by E18 (Derer and Derer, 1990Go), which is consistent with the lack of change in CR cell capacitance from E18 to P11–13 (Mienville, 1998Go). It should be noted, however, that morphopathological changes have been observed in postnatal CR cells in relation to ongoing degenerative processes (Derer and Derer, 1990Go, 1992Go; Del Río et al., 1995Go, 1996Go). The postnatal disappearance of these cells is the subject of controversy, being attributed either to ‘dilution’ in a rapidly expanding cortex, transformation into another cell type, or necrotic death [reviewed by Marín-Padilla (Marín-Padilla, 1998Go)]. The degenerative alterations just mentioned provide strong support for the latter alternative.



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Figure 1.  Digital images of Cajal–Retzius cells in slices of postnatal day 11 rat neocortex. (A) Infrared differential interference contrast image. (B) Lucifer Yellow fill with electrode still attached to the cell. Pial border is on the left. Bar = 20 µm.

 
The above considerations emphasize that CR cells should be easy to recognize for the electrophysiologist. Marín-Padilla proposes distinguishing between only two types of layer I neurons: the CR cells and a class of small neurons with somewhat variable arborizations (Marín-Padilla, 1984Go). This simple dichotomy between CR and non-CR cells has been used in recent functional studies of layer I neurons (Zhou and Hablitz, 1996aGo; Schwartz et al., 1998Go). It should be noted that work on rodents is facilitated by the fact that their CR cells do not display the complex — and variable — morphologies of primate CR cells (Marín-Padilla, 1984Go; Huntley and Jones, 1990Go; Meyer et al., 1998Go). The identity of layer I non-CR cells is less clear. The putatively GABAergic interneurons recorded by Zhou and Hablitz (Zhou and Hablitz, 1996bGo,cGo) may comprise a heterogeneous population that includes neurogliaform cells as well as other cell types (Marín-Padilla, 1984Go; Hestrin and Armstrong, 1996Go). In my experience, non-CR cells indeed exhibit small, roundish somata, but paradoxically display lower input resistances than CR cells recorded in the same slice (Mienville, 1998Go), which, unless electrical coupling is involved, would be consistent with the neurogliaform type because of its extensive arborization (Hestrin and Armstrong, 1996Go). Contrary to this finding, Zhou and Hablitz measured similar input resistances for CR and non-CR cells of a given age (Zhou and Hablitz, 1996aGo). Together, these results lend support to the presence of more than two cell types in layer I.

A morphogenetic role linked to a secretory function has long been suspected for CR cells (Derer and Nakanishi, 1983Go), but it is not until recently that this role was demonstrated and clearly defined (D'Arcangelo et al., 1995Go; Ogawa et al., 1995Go) [reviewed by Rakic and Caviness (Rakic and Caviness, 1995Go)]. CR cells synthesize and secrete a novel type of extracellular matrix protein necessary for normal lamination of the neocortex. Because the genetic mutation that prevents its expression is responsible for the Reeler phenotype, this protein has been named Reelin. The development of specific antibodies against Reelin (Ogawa et al., 1995Go; De Bergeyck et al., 1997Go) now provides a further means of identifying CR cells, confirming a posteriori the validity of former criteria based on morphology (Schwartz et al., 1998Go; Mienville and Pesold, 1999Go).


    Intrinsic Properties of CR Cells
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
Firing Properties

Zhou and Hablitz (1996a) were the first to give a substantial electrophysiological account of neocortical CR cells (Zhou and Hablitz, 1996aGo). [Note, however, that the patch-clamp recordings performed by von Haebler et al. (von Haebler et al., 1993Go) in hippocampal horizontal cells, which it seems reasonable to consider as CR cells (Del Río et al., 1996Go), may constitute the first account of CR cell physiology.] Their contribution made two important points: (i) the fact that CR cells can fire action potentials (APs) confirmed their neuronal nature [although most glial cells have sodium and potassium voltage-dependent channels, the density ratio of these ion channels is, except for rare cases (Bordey and Sontheimer, 1998Go), unfavorable to AP generation (Sontheimer et al., 1996Go)] as initially intimated by their selective expression of specific markers (König and Schachner, 1981Go); and (ii) in contrast to their early morphological differentiation, CR cells undergo a profound postnatal maturation of their biophysical properties. This second point disproved the common belief that CR cells achieve maturity before birth (Jacobson, 1991Go).

The ability to fire APs evokes the possibility of a participation of CR cells in cortical network function. Indirectly supporting this idea, Zhou and Hablitz did not detect any major difference in membrane properties between CR cells and non-CR cells of layer I (Zhou and Hablitz, 1996aGo). Similarly, Budde and White observed homogeneous properties among CR and non-CR cells acutely dissociated from layer I to record voltage-dependent conductances (Budde and White, 1998Go). In this study, however, the actual presence of CR cells may be questioned because the tissue was obtained from rats 3–6 weeks old, a time when most CR cells have disappeared. At variance with these observations, Hestrin and Armstrong emphasized the longer AP duration and spike train dampening of CR cells compared with other layer I neurons of rat neocortex (Hestrin and Armstrong, 1996Go). Likewise, Mienville et al. confirmed the postnatal maturation of CR cell excitability, but underlined the fact that neither AP waveform nor maximal firing frequency appeared compatible with a role in cortical network function (Mienville et al., 1999aGo). Such a role is indeed highly unlikely from the simple fact that CR cells disappear before full maturation of the cortex. Finally, a third argument concerns the elusive synaptic connectivity of CR cells. This point along with a possible role for CR cell firing are discussed below.

Another finding was the fact that CR cells display a relatively low resting potential (RP) throughout their life, compared to both other layer I neurons (Mienville, 1998Go) and layer II/III pyramidal cells (Mienville and Pesold, 1999Go). In these studies, ‘instantaneous' RP was measured upon cell break-in, presumably reflecting true RP before whole-cell dialysis. The low RP of CR cells was apparently due to suboptimal activation of the Na/K pump since after 10 min with ATP in the patch electrode RP was restored to a high value (Mienville and Pesold, 1999Go). At this point, the mechanisms underlying this low activation may be only speculative; they may pertain either to energy depletion due to various factors, including Reelin synthesis, or to an immature expression of the pump (Haglund et al., 1985Go; von Haebler et al., 1993Go). Interestingly, a low RP was also found in hippocampal CR cells along with other properties such as low-amplitude, long-duration APs and lack of synaptic input (von Haebler et al., 1993Go) that appear characteristic of neocortical CR cells. Regardless, this low RP seems to be determining in the fate of CR cells, as explained below.

Voltage-dependent Conductances

A complete account of voltage-dependent currents in CR cells is not yet available. Nevertheless, the few current-clamp and voltage-clamp experiments that have been performed so far indicate developmental changes, from the late embryonic stage (E18) up to P13, in all the conductances studied. For example, Mienville and Barker did not detect any inward rectifying conductance (IIR) in embryonic CR cells (Mienville and Barker, 1997Go), whereas current-clamp experiments on early postnatal CR cells revealed hyperpolarization-induced depolarizing sags (Zhou and Hablitz, 1996aGo), which is a token of IIR expression. In contrast, from E18 to E21 the proportion of inactivating K current (IA) expressed by CR cells increases (Mienville and Barker, 1997Go); however, this trend is reversed in postnatal cells as expression of Kv1.4, the presumed molecular substrate of CR cell IA, and the functional expression of the underlying current both decrease from P1 to P13 (Fig. 2AGo), whereas the delayed rectifier K current remains stable (Fig. 2BGo) (Mienville et al., 1999aGo). It therefore would appear that in these cells IA displays a transient expression that peaks perinatally. The possible relevance of IA's virtual disappearance to CR cell function is discussed later.

No voltage-clamp data are available on sodium or calcium currents in CR cells. Since, however, their APs are blocked by 0.5–1 µM tetrodotoxin (Zhou and Hablitz, 1996aGo; Mienville et al., 1999aGo), implying sodium channel involvement, one may safely assume that the robust changes observed, from P1 to P13, in various AP parameters (threshold, amplitude, rate of rise, etc.) reflect a commensurate increase in sodium channel density (Zhou and Hablitz, 1996aGo; Mienville et al., 1999aGo).


    Neurotransmitter Receptors of CR Cells
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
Glutamate Receptors

The first electrophysiological recording of a neocortical CR cell seems to be attributable to Kim et al. (Kim et al., 1995Go) [but see above regarding von Haebler's work (von Haebler et al., 1993Go)]. Their work suggested that CR cells express receptors for excitatory amino acids of both the NMDA and non-NMDA type. Although expression of the former has been confirmed thoroughly (Fig. 2CGo), responses to AMPA or kainate have been more elusive (Schwartz et al., 1998Go; Mienville and Pesold, 1999Go). In the central nervous system (CNS), the expression of NMDA receptor subunits is subject to spatiotemporal regulation (Monyer et al., 1994Go). In cortex, NR2B subunits are expressed prenatally, whereas NR2A subunits are expressed only postnatally (Sheng et al., 1994Go). Our results (Mienville and Pesold, 1999Go) suggest that while layer II/III pyramidal neurons may follow this scheme, both embryonic and late postnatal CR cells seem to express a large proportion of NR2B subunits, as if the switch to NR2A expression failed to occur.

Postnatal CR cells incur a dramatic increase in their NMDA receptor density, which ultimately may trigger their death. Thus, a likely scenario is that the low RP of CR cells relieves an increasing density of NMDA channels from magnesium block, leading to overactivation by ambient glutamate (LoTurco et al.,1991Go; Rakic and Komuro, 1994), calcium overload and subsequent necrosis. This intimates that what takes place is a physiological version of excitotoxicity, which so far has been considered only in a pathological context (McDonald and Johnston, 1990Go). The fact that in vivo pharmacological blockade of NMDA receptors curtails the disappearance of CR cells (Mienville and Pesold, 1999Go) strongly supports such a hypothesis. Although CR cell RP is intrinsically low, in the sense that in vitro exposure to GABA or NMDA antagonists fails to restore a high RP (Mienville and Pesold, 1999Go), it is tempting to speculate that CR cell death results from a cascade that ‘adds insult to injury’. That is, in vivo exposure to ambient glutamate (or GABA) probably increases the intrinsic depolarization, there- by providing further relief of NMDA channels from magnesium block. The ensuing calcium overload may then further burden the existing energetic deficit by mobilizing the Na/Ca ATPase, especially if CR cells downregulate their expression of certain calcium-binding proteins (Huntley and Jones, 1990Go).

GABAA Receptors

The first demonstration of the presence of GABAA receptors in CR cells should be credited to Schwartz et al. who used a calcium-imaging strategy to simultaneously record a large number of cells in a slice preparation (Schwartz et al., 1998Go). Their observation that the GABAA agonist muscimol was able to increase intracellular calcium is consistent with the GABAA receptor-mediated depolarization of CR cells (Mienville, 1998Go). In the CNS, the developmental switch from a depolarizing to a hyperpolarizing action of GABA has been shown recently to be due to the action of a K+/Cl cotransporter, KCC2, whose expression closely follows patterns of both ontogenetic and phylogenetic maturation (Rivera et al., 1999Go). Cells such as dorsal root ganglion neurons, in which the hyperpolarizing switch does not occur, do not express KCC2. As CR cells also fail to activate this switch (Mienville, 1998Go), it would be interesting to see if they express KCC2.

Other Receptors

Limited proportions of CR cells have glycine, muscarinic and adrenergic receptors (Schwartz et al., 1998Go). Non-synaptic, depolarizing glycine receptors (of the strychnine-sensitive type) have been shown to be transiently expressed in perinatal cortex (Flint et al., 1998Go), whereas in adult glycine receptors are preferentially expressed in lower brain structures (Cooper et al., 1991Go), which may have relevance to CR cell lineage (see below). The responsiveness of CR cells to norepinephrine is interesting in view of the early afferentation of layer I by catecholaminergic fibers (Marín-Padilla, 1998Go). Finally, CR cells lack GABAB (Mienville, 1998Go) and nicotinic receptors (Schwartz et al., 1998Go) (see also J.-M. Mienville, unpublished observations on nicotinic receptors).


    Synaptic Inputs
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
No studies are presently available that give a clear sense of the nature, extent or origin of synaptic inputs to CR cells. Data obtained at the ultrastructural level prompt the provisional conclusion that few postnatal CR cells bear synapses, and that in those rare cells synaptic density is extremely low. For instance, König and Marty found somatic and dendritic synapses on embryonic CR cells, but their ‘extensive surveys' revealed that these transitory synapses disappear completely from postnatal CR cells (König and Marty, 1981Go). Somewhat echoing these findings, Derer and Derer were able to find P1 mouse CR cells bearing as few as one or two synapses (Derer and Derer, 1990Go, 1992Go)! Consistent with these observations, spontaneous synaptic activity is never observed in CR cells, in striking contrast with the robust activity recorded in neighboring layer II/III neurons (J.-M. Mienville, unpublished observations). Given the high density of transmitter receptors on CR cells (Fig. 2C,DGo) (Mienville, 1998Go; Mienville and Pesold, 1999Go), the lack of spontaneous postsynaptic currents (PSC) is consistent with a low density of synaptic input, and suggests that these receptors are mainly extrajunctional. On the other hand, PSCs can be recorded upon stimulation of the cortical plate (Kim et al., 1995Go) or of layer I (A. Kriegstein, personal communication), suggesting that the few synapses present on CR cells may be functional. These synapses may have various neurochemical components (some of which may be undetectable electrophysiologically) since orthodromically activated calcium transients can be partially blocked by antagonists of glutamate, GABA and norepinephrine receptors (Schwartz et al., 1998Go).


    Several Signaling Roles for CR Cells?
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
In recent years, a growing list of extracellular matrix proteins have been shown to exert signaling roles in various developmental processes such as cell migration. Reelin is one of the latest additions to the list, although its mechanism of action is still unknown. Because CR cells are excitable, it initially was tempting to postulate (Mienville, 1998Go) that Reelin is released according to a classical stimulus–secretion coupling involving activity-driven secretion (Penner and Neher, 1988Go). This hypothesis is not supported by recent data (Mienville et al., 1999aGo) showing that spontaneous spiking activity starts to occur in postnatal CR cells and becomes substantial at P12–13, when neuronal migration is practically achieved. Such a schedule is contrary to that expected if the release of Reelin, whose mRNA displays high expression in embryonic CR cells (Schiffmann et al., 1997Go), was coupled to spiking activity. Instead, since the secretion of extracellular matrix proteins is constitutive (Alberts et al., 1994Go), it is likely that this is also the case for Reelin. Ongoing antisense experiments performed in our laboratory support this view by indicating that Reelin is secreted as soon as it is synthesized (Lacor et al., 1999Go). These considerations do not rule out the possibility that Reelin synthesis could be regulated through activation of transmitter receptors expressed by CR cells, possibly via calcium-dependent signaling pathways (Owens et al., 1996Go; Schwartz et al., 1998Go).

What, then, could be the purpose of the spontaneous firing of CR cells? No direct answer is presently available, but an exciting and testable hypothesis can be proposed. The formation of neuronal circuits proceeds in three major phases: an initial mapping that relies on chemotactic cues; a structural refinement that depends on spontaneous activity; and a functional refinement that uses sensory experience (Goodman and Shatz, 1993Go). The differentiation of cortical pyramidal cells includes the elaboration of an apical dendritic arborization anchored in layer I and destined to receive contacts from multiple afferents. CR cells could constitute a temporary interface between these cells and their future afferents (Meyer and González-Hernández, 1993Go), for instance by assuring that the formation of active synapses with the apical dendrites of pyramidal neurons allows their vertical elongation (Marín-Padilla, 1998Go). Such a role would be reminiscent of that played by subplate neurons in the establishment of thalamocortical projections (Goodman and Shatz, 1993Go), with the exception that subplate neurons provide a target for the latter, whereas CR cells would provide an input to pyramids. From this viewpoint, CR cells would be more akin to retinal ganglion cells, whose spontaneously active input to central neurons serves to refine retinofugal connections (Goodman and Shatz, 1993Go). The similarity between ganglion cell and CR cell firing frequencies (Galli and Maffei, 1988Go; Mienville et al., 1999aGo) is compatible with this hypothesis. Ultrastructurally, the latter is also consistent with the finding that CR cell axons make synaptic contacts with pyramidal cell dendrites (Marín-Padilla, 1984Go; Del Río et al., 1995Go). It is worthwhile noting here the postnatal increase in spontaneous activity and concomitant decline of IA expression in CR cells (Mienville et al., 1999aGo). Our computer simulations indicate that both the increase in INa and decrease in IA densities are responsible (and necessary) for repetitive and spontaneous firing to occur, as observed in late CR cells (Mienville et al., 1999bGo). A comparable phenomenon was observed in Ascidian embryos, in which the emergence of spontaneous firing is temporally correlated with the disappearance of an inward rectifier potassium current and appearance of a high-threshold calcium current. These two examples thus illustrate possible mechanisms for regulating spontaneous firing as an important developmental function (Moody, 1998Go).

There is disagreement as to whether the neurotransmitter synthesized by CR cells is glutamate (Del Río et al., 1995Go) or GABA (Imamoto et al., 1994Go). This would be a relatively trivial issue if depolarization were the only important parameter since both transmitters are depolarizing in immature cortex (Owens et al., 1996Go). However, the fact that NMDA receptors, which are abundant in young pyramidal cells (Mienville and Pesold, 1999Go), might be involved in activity-dependent circuit maturation (Goodman and Shatz, 1993Go) warrants further work to resolve this question. If the above hypothesis was verified, this would imply that CR cells handle two crucial phases of corticogenesis: an early, Reelin-dependent phase concerned with cell placement and perhaps primitive arborization, and a later, activity- dependent phase involving adequate synaptogenesis. [Recently, Borrell et al. also have linked mouse hippocampal CR cells to synaptogenesis, but they implicated Reelin in the underlying mechanism (Borrell et al., 1999Go)].


    On the Nature of CR Cells
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
When considering several aspects of CR cell physiology, one can only agree with a comment made by Derer and Derer concerning ‘a state of persisting immaturity’ (Derer and Derer, 1992Go). Their remark referred to the observation that long after neurite elongation has ceased, growth cones are still present at the end of CR cell processes. The physiological properties described above add to this impression of immaturity, by suggesting that several developmental switches are not activated in CR cells. A first example is the low RP of CR cells. This feature is expected in immature neurons, but neurons usually become more hyperpolarized as they mature (Kim et al., 1995Go), which does not seem to happen for CR cells. Second, the AP and repetitive firing properties of CR cells appear largely immature compared to those of other cortical neurons. A third example is the hyperpolarizing switch in the reversal potential for GABA-mediated currents (Owens et al., 1996Go), which also fails to occur in CR cells. A fourth ‘miss' may be the postnatal expression of the NR2A subunit of the NMDA receptor, but this will have to be confirmed by immunocytochemistry. In contrast to these properties, a well-developed endoplasmic reticulum and Golgi complex, along with a sometimes intricate morphology, have led many authors to emphasize the highly differentiated status of CR cells.

This brings us to the question as to whether these cells are immature forms of neocortical neurons, or whether they could belong to a special class of neurons that happen to settle in the cortex. Marín-Padilla's theory on the dual origin of the mammalian neocortex (Marín-Padilla, 1998Go) suggests some answers by proposing that layer I phylogenetically and ontogenetically originates from a primitive, pre-mammalian cortex. Being part of layer I, CR cells may thus represent primitive neuronal elements. Interestingly, CR cells seem capable of phylogenetic evolution since they further differentiate into three different subtypes in human cortex (Marín-Padilla, 1984Go; Meyer and González- Hernández, 1993Go; Meyer et al., 1998Go). It would therefore be insightful to investigate whether CR cells recorded from human tissue exhibit distinctive physiological properties, both among themselves and in comparison with those of lower species. A salient feature of CR cells is their limited electrical excitability (Mienville et al., 1999aGo), which is probably due to a low sodium channel density; their AP waveform pattern closely resembles that of, for example, astrocytoma (Bordey and Sontheimer, 1998Go) or subplate cells (Friauf et al., 1990Go). As it turns out, the latter would also be part of the primitive cortex according to the dual-origin theory (Marín-Padilla, 1998Go). It is therefore possible that neocortical evolution in mammals endowed layer II–VI cells, along with late-migrating layer I interneurons, with ‘improved’ ion channel sets that allow ultrafast signaling. As a corollary, CR cells may represent electrically active units in the neuronal circuits of primitive cortices in which lamination is rudimentary (reptiles) or absent (amphibians). This would be consistent with the fact that, contrary to the mammalian case, CR cells persist in large numbers in adult reptilian cortex (Blanton et al., 1987Go).


    Concluding Remarks
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
Subsequent to their discovery at the turn of the century, CR cells have inspired a large amount of anatomical work, which has by no means been matched by functional studies; it is, for instance, significant that the first electrical recording from CR cells was not performed until a hundred years later. Although this may be related in part to technical considerations, such a limited interest is surprising because owing to their ready identification and relatively short lifespan, CR cells represent an ideal mammalian system for the developmental neurobiologist. Moreover, a detailed understanding of CR cell physiology may help unravel the phylogenetic and ontogenetic mechanisms leading to the ultimate elaboration of the adult human neocortex. At the present stage, the available functional data on CR cells may have raised more questions than answers. One may hope that the picture will be clearer well before the end of the 21st century.


    Acknowledgments
 
I thank Drs Hector Caruncho, Arnold Kriegstein and Erminio Costa for reviewing the manuscript.


    Footnotes
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
* Most of the data and descriptionsprovided in this paper are from rodents. Care should be taken when extrapolating to or from primate CR cells, whose morphology, physiology and fate may be widely different (Marín-padilla, 1984Go; Meyer et al., 1998Go).


    References
 Top
 Abstract
 Introduction
 Footnotes
 Some Anatomical and Technical...
 Intrinsic Properties of CR...
 Neurotransmitter Receptors of CR...
 Synaptic Inputs
 Several Signaling Roles for...
 On the Nature of...
 Concluding Remarks
 References
 
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