The subplate is a unique layer in the mammalian neocortex. It consists of the earliest-born
neurons in the neocortex and undergoes a massive reduction in the number of neurons
during postnatal development. The subplate is also characterized by its heterogeneity
in cell morphology, incomparable gene expression pattern, and an early functional
maturation. This diversity in form and function is evident in its role in circuit
formation processes between the cortex and thalamus and also within a local cortical
area above it. Disruptions of the subplate can lead to neurodevelopmental deficits
such as autism spectrum disorder.
Postmitotic neurons born in the ventricular zone first form the preplate together
with Cajal-Retzius cells, which originate from three distinct regions of the dorsal
telencephalon (reviewed in Barber and Pierani, 2016). The preplate is then split,
by later-born neurons coming in between to form the cortical plate, into the marginal
zone at the surface (containing Cajal-Retzius cells) and the subplate at the base
of the cortical plate. Although most of the subplate neurons are early born preplate
neurons in rodents, the vast majority of subplate neurons are generated during mid-gestation
in primates (Duque et al., 2016). While many subplate neurons are lost during postnatal
development, not all of them disappear. Recent morphological and gene expression studies
have provided evidence that layer 6b in the adult (or juvenile) cortex contains remnant
subplate neurons (Hoerder-Suabedissen et al., 2013; Marx et al., 2017). Subplate neurons
exhibit morphological heterogeneity in the somatodendritic structure. In addition
to typical pyramidal neurons found in layers 2-6a; horizontal cells, multipolar cells,
inverted pyramidal cells, fusiform cells, and polymorphous cells are among those reported
in the subplate (Mrzljak et al., 1988; Hanganu et al., 2002). These cell types are
maintained between the early postnatal subplate and juvenile layer 6b despite a decrease
in their abundance (Marx et al., 2017). The subplate is more than a transient embryonic
structure. In primates, the subplate is much thicker, and subplate neurons remain
as “interstitial cells” in the white matter (Kostovic and Rakic, 1990), suggesting
prominent roles of subplate neurons in primates. As pyramidal neurons increase in
abundance in layer 6b, it is suggested that layer 6b consists of remnant subplate
neurons and cortical pyramidal neurons. Interestingly, intermediate progenitor cells
expressing Tbr2 contribute to projection neurons in all layers, including preplate
Cajal-Retzius neurons and the subplate (Vasistha et al., 2015; Mihalas et al., 2016),
suggesting that pyramidal neurons that increase in juveniles might derive from Tbr2-expressing
progenitors.
Transcriptomic analyses of cortical neurons and those focused on subplate neurons,
identified genes specifically expressed in subplate/layer 6b with a differential time
course (Bernard et al., 2012; Oeschger et al., 2012; Hoerder-Suabedissen et al., 2013;
Tasic et al., 2016). A cell clustering analysis based on single cell RNAseq data classified
layer 6b cells into two cell types (Tasic et al., 2016). Molecular markers for subplate/layer
6b neurons, however, have been shown to be expressed in overlapping populations (Hoerder-Suabedissen
and Molnár, 2013; Tiong et al.), making it difficult to correlate gene expression
profiles with cellular morphology, neuronal connection patterns, and electrophysiological
properties.
During the embryonic stage, the subplate serves as a critical interface between cortical
neurons and incoming thalamocortical axons. Thalamocortical axons transiently connect
with subplate neurons before they enter the cortical plate and finally reach layer
4 (Kostovic and Goldman-Rakic, 1983; Kageyama and Robertson, 1993; Herrmann et al.,
1994). This transient connection is functional, as thalamic stimulations in the thalamocortical
slices from rat embryos induce responses in subplate neurons (Higashi et al., 2002;
Molnár et al., 2003), indicating the early maturation of subplate neurons. Furthermore,
subplate neurons contain positional cues for thalamic axons to target appropriate
cortical areas. When the areal identity is disorganized by mis-expressing cortical
patterning molecule FGF8, in the subplate as well as in cortical plate, thalamic axons
run longer in the subplate before they turn into the cortical plate (Shimogori and
Grove, 2005). On the other hand, projection to the thalamus by subplate neurons was
thought to pioneer the cortico-thalamic projections by neurons in layers 5 and 6.
At least in ferrets, however, axons of layer 5 neurons arrive at the thalamic nuclei
earlier than those of subplate and layer 6 neurons (Clascá et al., 1995), arguing
against the pioneering function of subplate axons. Additionally, the subplate (layer
6b) also shapes corticofugal pathways (Grant et al., 2012) and callosal connections
(deAzevedo et al., 1997). For example, retinal inputs regulate layer 6b neuronal projections,
which may in turn influence the projection of layer 5 neurons (Grant et al., 2016).
Subplate neurons are also indispensable for local network formation, especially in
the primary sensory areas. For example, ablation of the subplate in the visual cortex
affects ocular dominance column formation by affecting the maturation of thalamocortical
connections to layer 4 (Ghosh and Shatz, 1992; Kanold and Shatz, 2006).
In addition to the foundational studies described above, recent work has revealed
new aspects of the subplate function and form, such as modulation of radial migration
of later-born neurons (Ohtaka-Maruyama et al., 2018), extra-cortical origins (Pedraza
et al., 2014), and fate selection of later-born neurons (Ozair et al., 2018). This
Research Topic entitled The Earliest-Born Cortical Neurons as Multi-Tasking Pioneers:
Expanding Roles for Subplate Neurons in Cerebral Cortex Organization and Function,
consists of a collection of three Review articles that provide up-to-date overviews
on multiple functions of the subplate in cortical development and two Original Research
articles that report novel findings in the development and function of the subplate.
Luhmann et al. summarize the electrophysiology of subplate neurons including intrinsic
membrane properties and firing patterns, and input/output connection patterns of subplate
neurons, discussing possible roles in cortical spindle burst and gamma oscillation.
A review by Kanold et al. explains sensory-evoked plasticity of neuronal circuits
of subplate neurons during development and in pathological conditions, focusing on
the silent synapses formed onto them.
In addition to the two Review articles above, a Mini Review by Ohtaka-Maruyama features
a novel function of the subplate in the regulation of the migration of cortical plate
neurons. This finding revealed another mechanism for mode switching of neuronal migration
from slow multipolar migration to rapid locomotion, guided by radial fibers.
Yu et al. use conditional mouse knockouts to define new functions of a well-established
subplate marker gene, Ctgf, in regulating the number and dendritic complexity of subplate
neurons, and maturation of oligodendrocytes in the white matter beneath the primary
somatosensory cortex.
Finally, an article by Tiong et al. identified a novel marker gene for the mouse embryonic
subplate and shows that it is expressed in 80% of layer 6b neurons in the primary
somatosensory cortex that project axons to the primary motor cortex. This marker should
be a useful tool to study functions of subplate neurons at early stages of cortical
development.
The aim of this Research Topic is to highlight the versatility of the subplate in
cortical development and to attract readers to this unique layer in the mammalian
neocortex. We would like to thank all the contributors and readers and hope future
work will elucidate developmental mechanisms and circuit functions of the subplate,
which is important both scientifically and clinically.
Author Contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of Interest
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.