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REVIEW 2645
Development 140, 2645-2655 (2013) doi:10.1242/dev.087668
© 2013. Published by The Company of Biologists Ltd
Lineage-dependent circuit assembly in the neocortex
Peng Gao1,2,*, Khadeejah T. Sultan1,2,*, Xin-Jun Zhang1 and Song-Hai Shi1,2,‡
The neocortex plays a key role in higher-order brain functions,
such as perception, language and decision-making. Since the
groundbreaking work of Ramón y Cajal over a century ago,
defining the neural circuits underlying brain functions has been
a field of intense study. Here, we review recent findings on the
formation of neocortical circuits, which have taken advantage of
improvements to mouse genetics and circuit-mapping tools.
These findings are beginning to reveal how individual
components of circuits are generated and assembled during
development, and how early developmental processes, such as
neurogenesis and neuronal migration, guide precise circuit
assembly.
Key words: Lineage, Neuronal circuits, Neocortex
Introduction
The mammalian cerebral cortex is composed of the archicortex
(hippocampal region), the paleocortex (olfactory cortex) and the
neocortex, with the last being the evolutionarily youngest region.
The neocortex is composed of two major classes of neurons:
glutamatergic projection neurons (see Glossary, Box 1), which elicit
excitation in postsynaptic neurons and generate circuit output; and
GABA (γ-aminobutyric acid)-ergic interneurons (see Glossary, Box
1), which typically trigger inhibition in postsynaptic neurons and
are essential for shaping circuit output. It is generally accepted that
two defining structural and functional features of the neocortex are
lamination and radial columns (Douglas and Martin, 2004).
Together, these features provide the basic framework on which
neocortical circuits are built. Interestingly, both of these features are
tightly linked to early developmental events, including
neurogenesis and neuronal migration. In this Review, we discuss
recent findings on the generation, migration and organization of
excitatory and inhibitory neurons in the neocortex, with a focus on
how the lineage history of neurons influences the assembly of
functional circuits.
Lamination: a hallmark of the neocortex
The neocortex is a continuous six-layered structure. All
components of neocortical circuits, including afferents, excitatory
cells, inhibitory cells and efferents, are organized with respect to
the laminae (Douglas and Martin, 2004). Cortical lamination is
generated as a result of radial migration of newborn excitatory
neurons during development (Hatten, 1999; Rakic, 1971; Rakic,
1972). Glutamatergic excitatory neurons are produced from
progenitor cells (Fig. 1A) that reside in the proliferative zone of the
1
Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, 1275
York Avenue, New York, NY 10065, USA. 2Graduate Program in Neuroscience, Weill
Cornell Medical College, 1300 York Avenue, New York, NY 10065, USA.
*These authors contributed equally to this work
‡
Author for correspondence ([email protected])
dorsal telencephalon (see Glossary, Box 1). In the earliest stages,
the neural tube is composed of a single layer of neuroepithelial
(NE) cells that proliferate rapidly (Breunig et al., 2011). A small
fraction of NE cells undergoes asymmetric division to generate the
first wave of postmitotic neurons, which migrate out radially and
form a transient structure called the preplate (see Glossary, Box 1)
(Del Río et al., 2000; Marin-Padilla, 1970; Marin-Padilla, 1971;
Marin-Padilla, 1978). As development proceeds, NE cells
transform into a more fate-restricted progenitor type: radial glial
cells (RGCs, see Glossary, Box 1), a major population of neuronal
progenitors in the dorsal telencephalon (Anthony et al., 2004;
Fishell and Kriegstein, 2003; Malatesta et al., 2000; Malatesta et
al., 2003; Miyata et al., 2001; Noctor et al., 2001; Noctor et al.,
2004). Residing in the ventricular zone (VZ), RGCs display a
characteristic bipolar morphology with a short apical process (the
ventricular endfoot) that reaches the luminal surface of the VZ and
an elongated process (the radial glial fiber) that extends basally to
the surface of the pia (see Glossary, Box 1). It is generally believed
that RGCs undergo symmetric division to expand the progenitor
pool, and then switch to asymmetric division where they self-renew
Box 1. Glossary
Cortical plate. A progressively thickening layer in the dorsal
telencephalon that harbors newly born post-mitotic neurons and
eventually develops into the future cortex.
Hebbian learning rule. ‘Cells that fire together, wire together’: a
theory introduced by Donald O. Hebb (Hebb, 1949) for the
mechanism of synaptic plasticity whereby repeated and persistent
stimulation of the postsynaptic cell by a presynaptic cell increases
synaptic efficacy.
Interneurons. Inhibitory neurons with short axons in the cortex
that typically participate in only local circuits.
Marginal zone. A superficial layer that develops as the preplate is
split during early corticogenesis; it eventually becomes layer 1 of
the mature cortex.
Pia (or pia mater). Innermost layer of the meninges that surrounds
the brain and spinal cord.
Preplate. Located between the pia and the ventricular zone, it
contains the earliest born neurons and represents the beginning of
corticogenesis prior to the emergence of the cortical plate.
Projection neurons. Excitatory neurons in the cortex that send
long-range projections to different brain regions.
Radial glial cells. A major population of neural stem cells
transiently existing in the developing brain that are crucial for
generating neurons and glia.
Striatum. A subcortical structure derived from ventral regions of
the developing telecephalon that receives input from the cortex.
Subplate. A transient zone comprising of some of the earliest
generated neurons in the cortex; it is crucial for both structural and
functional development of the cortex.
Subventricular zone. A region situated above the ventricular zone
that harbors intermediate progenitor cells and migrating neurons.
Telencephalon. The anteriormost region of the developing CNS
that gives rise to the mature cerebrum.
DEVELOPMENT
Summary
Development 140 (13)
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A Excitatory neurons
B Inhibitory neurons
CP
(future
cortex)
VZ
CGE
LGE
MGE
Striatum
Striatum
PoA
Key
Pax6
Migrating excitatory neurons
Nkx2.1
Early migrating interneurons (<E12)
N kx6.2
Late migrating interneurons (>E13)
Intracortical radial migration of interneurons
C Layer formation
L1(MZ)
MZ
L2/3
MZ
CP
CP
PP
VZ
L4
SP
SP
SVZ/
IZ
SVZ/
IZ
L5
VZ
VZ
L6b(SP)
L6a
WM
Key
E12-E13
E13-E18
Mature cortex
Marginal zone cells
Intermediate progenitor cells
Callosal projection neurons
Subplate cells
Earlier-born excitatory neurons
Stellate cells
Neuroepithelial cells
Later-born excitatory neurons
Subcerebral projection neurons
Radial glia cells
Subcortical projection neurons
Fig. 1. Generation and migration of neocortical excitatory and inhibitory neurons. (A,B) Excitatory and inhibitory neurons originate from different
germinal zones of the embryonic telencephalon. (A) Cortical excitatory neurons are generated from progenitor cells (Pax6+, orange) residing in the
ventricular zone (VZ) of the dorsal telencephalon. Newborn excitatory neurons undergo radial glial fiber-guided radial migration (orange arrows) and
settle into the developing cortical plate (CP, light green). (B) Cortical inhibitory interneurons are predominantly generated from progenitor cells located
in the proliferative zone of the ventral telencephalon, mainly within the medial ganglionic eminence (MGE; contains Nkx2.1+ cells, dark green) and the
caudal ganglionic eminence (CGE). A small population of cortical inhibitory interneurons is produced from the preoptic area (PoA). Newborn inhibitory
interneurons follow two tangentially oriented migratory streams to enter the cortex: a superficially migrating early cohort (pale-blue arrows) migrates
through the marginal zone, and a deeply migrating second and more prominent cohort (dark-blue arrows) migrates through the lower intermediate
zone and subventricular zone. Upon reaching the cortex, they switch to radial migration (pink double-headed arrows) and settle into their final laminar
position in the CP. (C) Inside-out fashion of cortical layer (L) formation. In early developmental stages (E10-E11), the neural tube is composed of a single
layer of neuroepithelial cells. A small fraction of these undergo asymmetric division to generate the first wave of postmitotic neurons that migrate out
radially and form the preplate (PP). As development proceeds (E12-E13), newborn excitatory neurons split the PP into a superficial marginal zone (MZ)
and a deeper subplate (SP). Successive waves of newly generated excitatory neurons migrate past the existing neurons to occupy a more superficial
region in the CP (E13-E18), creating the mature six-layered cortex. Excitatory neurons in the mature cortex are heterogeneous. IZ/SVZ, intermediate
zone/subventricular zone; WM, white matter.
DEVELOPMENT
E10-E11
and simultaneously generate daughter cells that are either
postmitotic neurons or intermediate progenitor cells (IPCs). IPCs
then undergo additional rounds of symmetric division in the
subventricular zone (SVZ, see Glossary, Box 1)to produce neurons
(Kowalczyk et al., 2009; Noctor et al., 2004). Newborn neurons
undertake radial glial fiber-guided radial migration, splitting the
existing preplate into a superficial marginal zone (MZ, see
Glossary, Box 1) and a deeper subplate (SP, see Glossary, Box 1),
and reside in the middle region, leading to the formation of the
cortical plate (CP, see Glossary, Box 1) – the future cortex.
Successive waves of newly generated neurons migrate past the
existing early-born neurons and occupy more superficial layers in
the CP, creating cortical layers (L) 2-6. Thus, cortical lamination
occurs in an ‘inside-out’ fashion (Angevine and Sidman, 1961)
(Fig. 1C).
It is becoming increasingly clear that the progenitor cells for
excitatory neurons are not homogeneous, but rather diverse. In
addition to RGCs and IPCs, two new types of neuronal progenitor
cells were recently discovered in the developing neocortex: short
neural precursors (SNPs) and outer subventricular zone (OSVZ)
radial glial progenitors. SNPs maintain their ventricular end-feet
but their basal processes are of variable length (Gal et al., 2006)
and, unlike RGCs, they generate neurons directly instead of going
through an IPC stage (Stancik et al., 2010). OSVZ progenitors, by
contrast, maintain the basal processes but lack the apical processes,
and are capable of undergoing asymmetric division in the OSVZ.
They were initially discovered in humans and later found in
primates, ferrets, mice and other species (Fietz et al., 2010; Hansen
et al., 2010; Kelava et al., 2012; Shitamukai et al., 2011; Wang et
al., 2011). Notably, the abundance of the OSVZ progenitor
population and their increased proliferative potential has been
suggested to underlie the evolutionary expansion of the cortex from
mouse to human (Lui et al., 2011). To add to the progenitor
heterogeneity, a recent study indicated that a subset of RGCs
expressing the homeobox protein cut-like 2 (Cux2) is pre-specified
to give rise to upper-layer neurons (L2-4). The Cux2-expressing
RGCs proliferate early in development when lower-layer neurons
(L5-6) are generated, and only start to produce neurons at later
stages (Franco et al., 2012). This is at odds with the prevailing
model of neocortical neurogenesis through progressive fate
restriction (Desai and McConnell, 2000; Frantz and McConnell,
1996; Luskin et al., 1988; McConnell and Kaznowski, 1991; Price
and Thurlow, 1988; Shen et al., 2006; Tan et al., 1998; Walsh and
Cepko, 1988); additional studies, such as systematic and precise
clonal/lineage analysis of individual progenitor cells (e.g. Cux2
expressing versus non-Cux2 expressing), are required to resolve
this discrepancy and to better understand the progenitor
heterogeneity with regards to the generation of diverse neuron
types in the neocortex.
In the mature neocortex, L1 mainly contains distal tufts of
pyramidal cell apical dendrites, axon terminations, Cajal-Retzius
cells and some GABAergic cells, but lacks excitatory neurons.
L2/3 predominantly consists of callosal projection neurons, which
project their axon collaterals across the corpus callosum and
mediate the communication between the two cerebral hemispheres,
in addition to participating in local circuits. In primary sensory
areas, L4 contains spiny stellate cells, which form an important
population for thalamic innervation. L5/6 contains largely
corticofugal projection neurons that provide major cortical output
to the thalamus, midbrain, spinal cord and other brain regions, as
well as a small population of callosal projection neurons
(Molyneaux et al., 2007; Fame et al., 2011). Importantly, the
REVIEW 2647
corticofugal projection neurons in L5 are morphologically and
physiologically heterogeneous, depending on their long-range
projection targets (Hattox and Nelson, 2007). In fact, the projection
identity of L5 neurons is regulated by a network of transcription
factors (Srinivasan et al., 2012). L6 neurons are also diverse, with
at least two broad categories based on their morphology and
physiological properties (Thomson and Lamy, 2007) (Fig. 1C,
right). Interneurons are present in all layers and mainly contribute
to local circuitry (Markram et al., 2004).
In 1989, in trying to understand the rules that govern the
synaptic connections between different neuronal types in different
layers of the neocortex, Douglas and Martin developed the model
of a ‘canonical cortical microcircuit’ based on electrophysiological
and modeling studies in the cat visual cortex. Their model contains
three groups of neurons: superficial pyramidal cells, deep
pyramidal cells and a common pool of inhibitory cells. All three
groups are interconnected, while thalamic input mainly targets
superficial pyramidal cells and inhibitory cells. These connections
allow the circuit to amplify transient thalamic input while
maintaining the balance of excitation and inhibition (Douglas and
Martin, 1991; Douglas et al., 1989). Subsequent studies
demonstrated that the most frequently connected cells were located
in the same layer, whereas interlaminar connections are dominated
by feedforward connections from L4 to L3 and from L3 to L5
(Thomson et al., 2002; reviewed by Bastos et al., 2012). Based on
substantial studies, we now know that in the canonical microcircuit
of the neocortex, thalamic relay cells provide input into the cortex
and mainly target L4, although they also form synapses with
neurons in other layers. This input is relatively weak, and is
amplified by recurrent excitation of L4 excitatory neurons.
Recurrent excitation can be potentially detrimental in leading to
hyper-excitation of the circuit; inhibition is therefore required to
modulate this excitation. Within all layers, excitatory and inhibitory
neurons form recurrent connections. Between cortical layers,
information flow has a strong directional tendency: from L4 up to
L2/3 and then down to L5/6. There is also a weaker projection
from L4 directly down to L5/6. The principles of the canonical
microcircuit can be applied to other cortical areas, such as the
motor cortex, suggesting that they may reflect the underlying
organization of the entire neocortex (Douglas and Martin, 2007).
This model has greatly advanced our understanding of the wiring
principle for cortical circuits. Nonetheless, recent studies also
suggest that there may be some variations in circuit organization in
certain cortical areas, e.g. the rodent somatosenstory cortex (Bruno
and Sakmann, 2006; Meyer et al., 2010; Oberlaender et al., 2012;
Wimmer et al., 2010). In summary, substantial work has
demonstrated a precise orchestration of neuronal production and
migration leads to the formation of distinct cortical lamina, each of
which contains unique populations of neurons poised for the
assembly of highly organized circuits.
The neocortical column
The second fundamental feature of the neocortex is the functional
column. The concept of the ‘neocortical functional column’ was first
introduced by Mountcastle in 1957 and has proven invaluable in
understanding the functional organization of the neocortex. When
recording the somatosensory cortex of cats and monkeys,
Mountcastle and colleagues discovered that neurons sharing
common functional properties, including corresponding peripheral
receptors, receptive fields and firing latencies, were located in a
radial column extending from pial surface to white matter
(Mountcastle, 1957; Powell and Mountcastle, 1959). The diameter
DEVELOPMENT
Development 140 (13)
of columns is of approximately same size in both cats and monkeys.
The functional properties of neurons are similar within a column, but
significantly differ between adjacent columns (Mountcastle, 1997).
Seminal work by Hubel and Wiesel in the 1960s and 1970s then
triggered tremendous interest in studying the neocortical column.
Echoing Mountcastle’s observation in the somatosensory cortex,
they found that, in the visual cortex of cats, neurons with a similar
orientation selectivity were located in a single radial penetration
from pial surface to white matter (termed ‘orientation columns’)
(Hubel and Wiesel, 1962; Hubel and Wiesel, 1963). Later, they
found that the two eyes differentially activated cortical neurons:
neurons with similar eye preference were also grouped into
columns (termed ‘ocular dominance columns’), and left and right
eye-dominated columns alternated across the cortex (Wiesel and
Hubel, 1963). The relationship between orientation columns and
ocular dominance columns was summarized in their classic icecube diagram, in which thin orientation slabs cut the coarser ocular
dominance columns at right angles (Hubel and Wiesel, 1977).
Similar functional columns were also discovered in the cat
primary auditory cortex (Abeles and Goldstein, 1970) and in many
other cortical areas (Mountcastle, 1997). These observations
prompted a deep thought that ‘the cells behave as though they
shared certain connections among themselves, but not with cells of
neighboring columns, and in this sense a single group of cells is
looked upon as a more or less autonomous functional unit’ (Hubel
and Wiesel, 1974). Importantly, however, columns are not isolated;
in fact, extensive studies have demonstrated horizontal connections
between columns, especially between those with similar functional
properties (Bosking et al., 1997; Gilbert and Wiesel, 1983; Gilbert
and Wiesel, 1989; Katz et al., 1989; McGuire et al., 1991; Ts’o et
al., 1986).
Despite the long history of successful identification of neocortical
columns with electrophysiological recordings, especially in
mammals such as cats and monkeys, the anatomical basis of these
columns has remained elusive. Minicolumns have been proposed to
be the basic unit of the neocortex, which are composed of chains of
neurons (typically ~80-120 in primates) spanning cortical layers
whose cell bodies are vertically aligned within a diameter of ~40-50
μm; about ~50-80 minicolumns link together to form the structural
basis of functional columns (Mountcastle, 2003). Another candidate
is a related structure referred to as ‘bundles’, which mainly comprise
closely associated apical dendrites of pyramidal cells whose cell
bodies are located in different layers (Peters and Kara, 1987; Peters
and Sethares, 1996; Peters and Walsh, 1972; Peters et al., 1997).
However, both views have met ample criticism (Rockland and
Ichinohe, 2004; da Costa and Martin, 2010). Whether there is a
structural correlate of the functional columns remains controversial.
One obvious challenge is that functional columns are defined based
on the functional properties of neurons, which may not be simply
reflected anatomically. A more effective search for the structural
correlate of functional columns requires a precise characterization of
the functional properties of individual neurons. Recent advances in
the field of in vivo Ca2+ imaging provide a powerful route to reveal
the functional properties of large ensembles of neurons (Ohki et al.,
2005; Bock et al., 2011; Chen et al., 2011; Ko et al., 2011),
effectively bridging of the gap between structure and function (Li et
al., 2012).
Lineage-dependent circuit assembly of neocortical
excitatory neurons
In the rodent visual cortex, the equivalent of the functional columns
observed in higher mammals has proven difficult to find. This may
Development 140 (13)
be largely attributed to the fact that, in the horizontal dimension
(i.e. within the same cortical layers), neurons with different
orientation preferences are intermingled spatially in a ‘salt-andpepper’ fashion (Ohki and Reid, 2007; Ohki et al., 2005). Similar
fine-scale heterogeneity in the functional properties of neurons has
been observed in the somatosensory and auditory cortices
(Rothschild et al., 2010; Sato et al., 2007). These findings imply
that if functional columns exist in rodents, they may be built at a
single-cell resolution. Interestingly, by combining in vivo twophoton Ca2+ imaging and ex vivo patch-clamp recording
techniques, Ko et al. recently demonstrated that, in L2/3 of mouse
visual cortex, neurons that share orientation preference response
properties are more likely to be synaptically connected,
highlighting the presence of fine-scale subnetworks dedicated to
processing related sensory information (Ko et al., 2011). A
remaining mystery is how these highly connected subnetworks are
constructed. One possibility is that neurons with similar functional
properties fire at the same stimuli repeatedly and therefore
gradually develop strong specific connections, as suggested by the
Hebbian learning rule (see Glossary, Box 1). Alternatively, it is
possible that there are other rules that govern their connectivity
even before their functional properties fully emerge.
How do functional columns emerge in the developing
neocortex? In 1988, Rakic proposed the ‘radial unit hypothesis’
(Rakic, 1988). According to this hypothesis, neurons derived from
the same proliferative unit in the VZ migrate along the radial glial
fiber(s) and form ‘ontogenetic/embryonic’ columns, which are the
building blocks for the cerebral cortex. Based on the similarity of
a vertical organization of neurons, it was postulated that
ontogenetic columns might relate to functional columns. However,
this hypothesis has only recently been tested experimentally. Yu et
al. injected EGFP-expressing retroviruses intraventricularly into
developing mouse embryos at embryonic days E12-E13 to label
individual asymmetrically dividing RGCs, which give rise to
ontogenetic columns composed of four to six vertically aligned
sister excitatory neurons spanning different cortical layers.
Multiple-electrode whole-cell patch clamp recordings at postnatal
stages (P10-P21) revealed that sister neurons are preferentially
connected by chemical synapses when compared with nearby nonsister neurons. Interestingly, the direction of interlaminar
connectivity among sister neurons in an ontogenetic column
resembles that observed in the mature cortex, suggesting that these
ontogenetic columns could lead to the formation of functional
columns in the cortex (Yu et al., 2009). Tracing this back to even
earlier in development, sister neurons preferentially form transient
electrical synapses with each other (peaking at ~P1-P2, largely
disappearing after P6), which allow for selective electrical
communication and promote action potential generation/
synchronous firing between sister neurons (Yu et al., 2012).
Although these gap junctions largely disappear before functional
chemical synapses can be detected, they are necessary for the
formation of specific chemical synapses between sister neurons.
Blockade of electrical communication impaired the subsequent
assembly of lineage-related sister excitatory neurons into specific
microcircuits (Yu et al., 2012). This line of studies not only
demonstrates a new principle of circuit assembly that depends on
the lineage relationship of neurons (i.e. on their specific
developmental history), but also suggests that ontogenetic columns
may contribute to the emergence of the functional columns in the
neocortex (Fig. 2A).
To test this directly, Li et al. used the same retrovirus-labeling
technique to label sister excitatory neurons derived from the same
DEVELOPMENT
2648 REVIEW
Development 140 (13)
REVIEW 2649
A Synaptic connectivity
L2/3
L4
L5/6
Embryonic
P1-P6
(ontogenetic column)
Key
Gap junction
P10-P21
Chemical synapse
B Functional similarity (in L2/3 of visual cortex)
Sister neurons
Fig. 2. Lineage-dependent circuit assembly of
neocortical excitatory neurons. (A) Sister
neurons (dark green) derived from the same RGCs
during embryonic development migrate along the
radial glial fiber (light green) and form ontogenetic
columns. Sister neurons are preferentially coupled
through electrical synapses (gap junctions, purple)
in the first postnatal week. In the second postnatal
week, sister neurons develop preferential chemical
synapses (orange) with each other, and the
direction of connectivity resembles that in the
mature circuits. (B) In layer (L)2/3 of the mouse
visual cortex, lineage-related neurons have similar
orientation tuning response properties (colored
bars). Vertically aligned sister neurons (top) labeled
by retrovirus at E15-E17 have similar orientation
tuning response properties, unlike those of their
non-sisters. Remote lineage-related clones of
neurons (bottom), labeled by a sporadically
expressing Cre driver line, still have slightly more
similar orientation tuning response properties
compared with those of non-related neurons.
Remote lineage-related neurons
Preferred orientation
RGCs at E15-E17 in the mouse visual cortex, and performed in
vivo two-photon Ca2+ imaging to assess their orientation tuning
response properties at P12-P17 (Li et al., 2012). They found that
sister neurons have similar orientation preferences compared with
those of nearby non-sister neurons (Fig. 2B). Interestingly, in line
with the findings of Yu et al., blockade of electrical coupling
between sister neurons abolished the functional similarity between
sister neurons, highlighting the significance of early gap junctionmediated electrical communication in establishing specific
connections between sister neurons and their shared functional
properties (Li et al., 2012).
How far does the lineage relationship go in shaping neocortical
circuitry? In another recent study, Ohtsuki et al. used a different
approach to label lineage-related neurons (Ohtsuki et al., 2012).
They used a transgenic mouse line in which Cre recombinase is
expressed sparsely in progenitor cells early in forebrain
development, generating individual clones containing 600-800
fluorescently labeled neurons derived from the same progenitors.
They then used in vivo two-photon Ca2+ imaging to examine the
orientation tuning response properties of clonally related neurons
and nearby non-clonally related neurons. Interestingly, even in
such a large population of neurons, the lineage relationship of
which is much further away compared with that of the sister
neurons labeled by Li et al., orientation preferences among
clonally related neurons were still more similar than those among
unrelated neurons (Fig. 2B). However, there was considerable
diversity within the large clones, such that nearly one half of all
neuronal pairs had preferred orientations with a difference greater
than 30°, and one quarter of them exhibited a difference greater
than 60° (Ohtsuki et al., 2012). One plausible explanation is that
remote lineage relationship, although still influential, is not as
strong as close lineage relationship (i.e. neurons derived from
asymmetrically dividing RGCs) in predicting shared functional
similarities among neurons. However, there might be other
factors that contribute to the observed diversity. Ohtsuki et al.
performed the experiments in relatively mature (P49-P62) mice
whose visual system was well developed, whereas Li et al.
conducted the experiments in young mice (P12-P17), close to the
time of eye opening. As it is well established that neuronal
activity as well as visual experience exert tremendous influence
DEVELOPMENT
Key
Development 140 (13)
2650 REVIEW
on circuit development (Cang et al., 2005; Caporale and Dan,
2008; Hubel and Wiesel, 1965; Katz and Crowley, 2002; Katz
and Shatz, 1996), it is possible that lineage relationship instructs
the formation of the initial neocortical circuit, which is then
further modified by experience. In this regard, it will be
interesting to test whether remote lineage-related neurons behave
more similarly when tested in younger animals or, vice versa,
whether the shared functional similarities between closely related
‘sister neurons’ persist into adulthood.
Together, these studies strongly suggest that, in the mouse,
lineage plays a crucial role in organizing neocortical excitatory
neuron circuits. Ontogenetic columns formed by clonally related
neurons could be the basic structural and functional unit that
constitutes the neocortex. One important issue is whether these
lineage-related specific circuits also exist in other mammalian
species, especially higher mammals such as cats and monkeys. The
tremendous interspecies difference in the organization of
orientation preference maps from rodents to higher mammals could
be due to the differences in patterns of neurogenesis and the layout
of ontogenetic columns (Fig. 3). It has been proposed that the
extensive proliferation capacity of progenitor cells in the SVZ
Rodents
Higher mammals
Embryonic
Pia
CP
SVZ
Adult
VZ
Key
underlies cortical expansion from rodents to higher mammals,
including ferrets, cats and primates (Kriegstein et al., 2006), which
presumably would give rise to ontogenetic columns that are much
larger in size and with many more horizontal features. Recent
discoveries of OSVZ progenitors with increased amplification
capability support this hypothesis (Lui et al., 2011). Interestingly,
computational modeling based on the ‘wire length minimization
principle’ predicts that a strong horizontal connection pattern would
lead to smooth varying maps, such as those discovered in cats and
monkeys. By comparison, the proliferation potential of IPCs in the
SVZ of rodents is much more limited, and lack of specific
horizontal connections is predicted to produce an apparent salt-andpepper organization of maps (Koulakov and Chklovskii, 2001). It
will be interesting to test whether ontogenetic columns are the
long-awaited structural basis of functional columns in higher
mammals. In addition, two recent studies demonstrated that
neurons with certain molecular identities are arranged in a periodic
manner in L5 of mouse and human neocortex (Kwan et al., 2012;
Maruoka et al., 2011). It will be interesting to understand the
cellular events responsible for the formation of these ‘molecular
minicolumns’ and how they relate to functional columns. It is also
important to note that the cellular organization of the thalamus that
relays information to the neocortex appears different between
rodents and higher mammals; for example, the lateral geniculate
complex is distinctly laminated in cats, monkeys and humans, but
not in mice and rats, and this difference may also fundamentally
influence the functional organization of the cortex.
Radial glia cells
Migrating neuron
Neurons with different
orientation preference
Intermediate progenitor cells
Lineage-related production and organization of
inhibitory neurons
Neocortical inhibitory neurons exhibit an incredibly rich diversity
of subtypes and are distributed throughout the neocortex in a
stereotypical manner. Extensive studies have suggested that, as for
excitatory neurons, lineage and/or the developmental history (i.e.
place and time of birth) of cortical interneurons underlies their
subtype specification and distribution in the mature neocortex,
thereby contributing to their proper circuit assembly and function.
It is important to note that, unlike excitatory neurons, very little is
known about the lineage of interneurons at the single progenitor
level, and most previous work has focused on interneuron lineage
at the level of populations of progenitors. Nonetheless, the advent
of optogenetic tools, in combination with mouse genetics, allows
researchers to dissect the functional output of different classes of
interneurons within cortical circuits in vivo (Cardin et al., 2009;
Lee et al., 2012; Sohal et al., 2009; Wilson et al., 2012), and offers
an unprecedented opportunity to understand how early
developmental events and distinct lineages of interneurons
contribute to the assembly of precise circuits.
OSVZ progenitor
Unlike dorsally derived excitatory neurons, GABAergic inhibitory
neurons are born in transient ventral telencephalic regions known
as the ganglionic eminences (GEs) (Anderson et al., 1997;
Anderson et al., 2002; Butt et al., 2005; Gelman and Marín, 2010;
Valcanis and Tan, 2003; Wichterle et al., 1999; Wichterle et al.,
2001; Xu et al., 2004; Xu et al., 2006; Xu et al., 2008) (Fig. 1B).
The GE is further subdivided into three distinct domains, namely
the lateral, medial and caudal GEs (LGE, MGE and CGE,
respectively). Numerous fate-mapping studies have demonstrated
that the MGE and the CGE are the predominant sources of cortical
interneurons (Fogarty et al., 2007; Nery et al., 2002; Xu et al.,
2008). More specifically, MGE progenitor cells produce ~70% of
DEVELOPMENT
Fig. 3. Patterns of neocortical neurogenesis may influence the
organization of functional maps. In the visual cortex of rodents (left),
functional columns are thought to exist at single-cell resolution, and
individual embryonic/ontogenetic columns (dotted red lines) composed
of a few sister excitatory neurons may lead to this organization in adults.
In higher mammals (right), by contrast, functional columns with clusters
of neurons sharing similar properties are observed; the expansion of the
subventricular zone (SVZ) through its greater proliferative potential may
significantly increase the number of neurons in individual embryonic/
ontogenetic columns and contribute to the development of these
functional columns in adults. CP, cortical plate; VZ, ventricular zone.
Cortical inhibitory neuron development
Development 140 (13)
Lineage and subtype specification
One of the most striking features of interneurons in the adult
neocortex is the incredibly rich diversity they display in their
morphology, biochemical marker expression, electrophysiological
properties and synaptic connectivity patterns. Axons of inhibitory
neurons are highly selective in the postsynaptic neuronal
compartment (i.e. soma, dendritic tree or axon initial segment) that
they target. The distinct subcellular targeting and firing patterns of
each subtype allows populations of interneurons to exert their
inhibitory influence on surrounding neurons in numerous ways,
thereby shaping circuit output dynamically and allowing for a wide
range of neuronal computations. For example, perisomatic
inhibition controls the output of the postsynaptic neuron, and is
primarily mediated by parvalbumin (PV)-containing basket cells.
Dendritic inhibition, by contrast, sculpts the local input of the
postsynaptic neuron, and is mainly mediated by somatostatin
(SST)-expressing interneurons, which are mostly Martinotti cells
(McGarry et al., 2010). PV-positive chandelier (also referred to as
axo-axonic) cells exclusively target the axon initial segment of
pyramidal cells and play an enigmatic role in the cortical circuit as
they can be inhibitory or excitatory, depending on the membrane
potential of the postsynaptic neuron and the overall activity state
of the network (Pouille et al., 2009; Szabadics et al., 2006;
Taniguchi et al., 2013).
Two important determinants of subtype specification of
neocortical interneurons are the place of birth and the time of birth.
The first level of spatial segregation of progenitors is seen when
comparing the MGE and CGE, as they give rise to largely nonoverlapping subtypes of cortical interneurons. The MGE generates
the majority of cortical interneurons that mostly comprise PV-
positive, fast-spiking basket and chandelier cells, as well as SSTpositive, burst-spiking cells that include Martinotti cells. The CGE,
by contrast, gives rise to a more heterogeneous population of
cortical interneurons, which includes reelin-positive multipolar
cells, vasointestinal peptide (VIP)-positive/calretinin (CR)-positive,
bitufted, irregular spiking cells, as well as VIP-positive/CRnegative biopolar cells that display a fast-adapting firing pattern
(Lee et al., 2010; Miyoshi et al., 2010; Nery et al., 2002). Within
the MGE, there seems to be additional spatial bias in the
specification of SST-positive and PV-positive interneurons (Flames
et al., 2007; Fogarty et al., 2007; Wonders et al., 2008). A
comprehensive analysis of expression patterns of several
transcription factors in the VZ of the developing mouse GE by
Flames et al. revealed that expression of Nkx-6.2 in the dorsal
MGE underlies specification of SST-positive interneurons, whereas
PV-positive interneurons are derived from Nkx-2.1-expressing
progenitors located more ventrally within the MGE, suggesting that
anatomically defined subpallial regions can be further divided into
subdomains that give rise to functionally distinct interneuron
subtypes (Flames et al., 2007) and that lineage plays an important
role in generating diverse interneuron populations that are
characteristic of the mature neocortex.
In addition to the presence of spatially distinct progenitor
domains, a temporal bias in neurogenesis is thought to contribute
to interneuron subtype specification. Fate mapping of MGEderived interneurons showed that these progenitors undergo
temporal changes in fate such that they progress from generating
mainly SST-expressing neurons to making mainly PV-positive
interneurons (Miyoshi et al., 2007). Recent transplantation and
lineage-tracing experiments elegantly demonstrated that chandelier
cells in the mouse neocortex are selectively born in the MGE at late
stages of embryonic development (Inan et al., 2012; Taniguchi et
al., 2013).
Although the spatiotemporal dynamics of neurogenesis
evidently contribute to diversification of neocortical interneurons,
it remains unclear whether interneuron subtype specification
occurs at the population or single progenitor level. Using mouse
genetics in combination with in utero retroviral labeling, Brown
et al. were the first to conduct a clonal analysis of the MGE at the
single progenitor level to show that individual RGCs within the
MGE are able to generate clones of cortical interneurons that
share the same neurochemical markers, as well as clones that
contain interneurons expressing different neurochemical markers
(Brown et al., 2011). More extensive characterization of
interneuron subtypes within clonal clusters using morphological
and physiological analysis will help elucidate how many subtypes
a single progenitor can generate and in what combinations, as
well as the early developmental principles that generate
interneuron diversity.
Lineage and spatial distribution
Similar to excitatory neurons, interneurons are distributed
throughout the cortex in a laminar fashion. Classic birthdating
studies and transplantation experiments have demonstrated that
interneurons born at different times in the MGE populate specific
layers of the neocortex in an inside-out order (Nery et al., 2002;
Valcanis and Tan, 2003). This is also apparent in the case of CGEderived interneurons that are born relatively late during embryonic
neurogenesis and tend to occupy more superficial layers of the
cortex in comparison with most MGE-derived interneurons
(Miyoshi et al., 2010). Interestingly, cortical interneurons and
projection neurons born at roughly the same time tend to occupy
DEVELOPMENT
neocortical interneurons (Fogarty et al., 2007; Lavdas et al., 1999;
Xu et al., 2008) and CGE progenitor cells give rise to the
remaining 30% (Butt et al., 2005; Miyoshi et al., 2010; Nery et al.,
2002). In addition, a small subpopulation (fewer than 3%) of
cortical interneurons is derived from the embryonic preoptic area,
which is situated in the telencephalic stalk (Gelman et al., 2009).
MGE progenitors also give rise to interneurons of the striatum (see
Glossary, Box 1) and are characterized by the expression of a
transcription factor, the homeobox protein Nkx-2.1 (Marin et al.,
2000; Sussel et al., 1999). Notably, it has been suggested that, in
humans as well as non-human primates, besides the GE of the
ventral telencephalon, the VZ and/or SVZ of the dorsal
telencephalon also produce a substantial population of cortical
GABAergic neurons (Fertuzinhos et al., 2009; Jakovcevski et al.,
2011; Letinic et al., 2002; Petanjek et al., 2009). However,
additional studies are needed to explore this further (Hansen et al.,
2010).
In rodents, interneurons destined for the cortex must undergo
a long and tortuous journey from their subpallial origins to reach
the cortex. In order to avoid the developing striatum, interneurons
migrate superficially or deep relative to the striatal mantle (Marín
et al., 2001). Two main migratory streams of interneurons follow
tangentially oriented paths to enter the cortex: a superficially
migrating early cohort migrates through the MZ of the cortex
(Lavdas et al., 1999); a deeply migrating second and more
prominent cohort migrates predominantly through the lower
intermediate zone and SVZ (Wichterle et al., 2001). Upon
reaching the cortex, interneurons adopt a radial trajectory to settle
into their final laminar position within the CP (Ang et al., 2003;
Hevner et al., 2004; Polleux et al., 2002; Tanaka et al., 2003)
(Fig. 1B).
REVIEW 2651
the same cortical layer (Valcanis and Tan, 2003). In attempting to
understand mechanisms that direct interneurons to position
themselves precisely within specific cortical layers, Lodato et al.
replaced subcerebral projection neurons with collosal projection
neurons and found that this led to abnormal lamination of
interneurons. In addition, artificial introduction of corticofugal or
callosal projection neurons below the cortex was sufficient to
recruit cortical interneurons to these ectopic locations. This study
demonstrated that different populations of projection neurons can
influence the laminar fate of interneurons (Lodato et al., 2011).
Therefore, although the temporal dynamics of neurogenesis
correlate with the laminar fate of both projection neurons and
interneurons, there may be additional rules that govern their
positioning within the neocortex.
Interestingly, Brown et al. showed that neocortical interneurons
are produced as spatially organized clonal units in the MGE; in the
adult neocortex, these clonally related interneurons are organized
into spatially isolated clusters (Brown et al., 2011). Lineage, or
clonal relationship, therefore, plays a pivotal role in the production
and spatial organization of neocortical interneurons. So how far do
lineage/clonal relationships go in establishing functional
interneuron microcircuitry? Although some interneurons form and
receive non-specific synaptic connections (Fino and Yuste, 2011;
Hofer et al., 2011; Packer and Yuste, 2011), several studies have
shown that inhibitory interneurons in the neocortex exhibit highly
specific synaptic connections within functional circuits (Jiang et al.,
2013; Otsuka and Kawaguchi, 2009; Thomson and Lamy, 2007;
Yoshimura and Callaway, 2005). Moreover, the synaptic
connectivity between local interneurons and excitatory neurons
also shows a stereotypic spatial pattern across different regions of
the neocortex (Kätzel et al., 2011), suggesting a high degree of
specificity in the functional organization of neocortical
interneurons. Given the ventral origin and long tangential migration
of neocortical interneurons, how stereotypic inhibitory circuits
form in the neocortex is an unresolved issue. The spatial
organization of clonally related sister inhibitory interneurons raises
an intriguing possibility of a lineage-dependent functional
organization (electrical- and/or chemical synapse-based) of
interneurons that may contribute to specific inhibitory circuits in
the mammalian neocortex.
Conclusions
Here, we have reviewed recent findings on how early developmental
processes, such as neurogenesis and neuronal migration, instruct
circuit assembly for both excitatory and inhibitory neurons in the
neocortex. One emerging theme is that, lineage, or the developmental
history of a neuron, strongly influences its connectivity. For
excitatory neurons, sister neurons derived from the same progenitors
preferentially form synaptic connections with each other and process
related sensory information. In the case of inhibitory interneurons,
lineage appears to play a crucial role in their production and
organization. With the recent surge of tools that enable labeling and
manipulation of circuit components, we are optimistic that many new
insights will be revealed along this line in the near future. For
example, does lineage-related circuit assembly only apply to the
neocortex, or does it also play a role in circuit formation in other
brain regions? How is lineage-related circuitry regulated by
experience? How does this basic structural and functional unit evolve
from mouse to human? Is it affected in neurological diseases?
Answers to these questions would greatly advance our knowledge
about the fundamental principles that nature uses to construct
functional brain circuits.
Development 140 (13)
Acknowledgements
We apologize to the authors whose work we could not cite owing to space
limitations. We thank Ryan Insolera for critical reading of the manuscript and
anonymous reviewers for insightful comments that significantly improved the
paper.
Funding
Our research was supported by grants from the National Institutes of Health,
the McKnight Foundation and the March of Dimes Foundation (to S.-H.S).
Deposited in PMC for release after 12 months.
Competing interests statement
The authors declare no competing financial interests.
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