developmental processes including neurogenesis, neuronal migration, neurite outgrowth, and neurotransmitter signaling. Abnormal
neuronal morphology and cortical architecture are seen in human postmortem brain from patients with schizophrenia. However, the
point mutations (Q31L and L100P) and found a relative reduction in neuron number, decreased neurogenesis, and altered neuron
distribution compared to wild-type littermates. Frontal cortical neurons have shorter dendrites and decreased surface area and spine
Schizophrenia (SZ) is a common psychiatric disorder character-
ized by reduced hippocampal and cortical volume (Ross et al.,
2006), abnormal cytoarchitecture (Kovalenko et al., 2003), re-
duced neuronal density in superficial cortical layers (Akbarian et
dendritic arborization (Young et al., 1998) and dendritic spine
density (Garey et al., 1998). Many potential schizophrenia sus-
ceptibility genes have been identified (Wong and Van Tol,
2003; Ross etal.,2006),includingDisrupted-in-Schizophrenia1
(DISC1), first identified in a large Scottish family carrying a bal-
anced (1q42.1:11q14.3) translocation cosegregating with major
mental illnesses including SZ, bipolar disorder, and major de-
pression (Millar et al., 2000). The DISC1 locus shows genetic
linkage with SZ, and DISC1 variants show genetic association
with SZ (Nakata et al., 2009; Rastogi et al., 2009; Schumacher et
ing proteins that link DISC1 to important brain developmental
functions such as neurogenesis, neuron migration, neurite out-
margo et al., 2007; Brandon et al., 2009).
The cortical histology of transgenic mice expressing various
truncated mouse or human DISC1 fragments is similar to that
to express truncated DISC1 have morphological alterations in
medial prefrontal cortex and hippocampus (Kvajo et al., 2008).
Because the truncated DISC1 gene is unique to the original
translocation family and because common disease-associated
DISC1 variants are single-nucleotide polymorphisms (SNPs)
mice with Disc1 SNPs. Our group described previously two mu-
tant Disc1 mice, each with a different SNP: Q31L (127A/T) and
L100P (334T/C) (Clapcote et al., 2007). Both mutants have re-
duced brain volume, deficits in spatial working memory, and
decreased prepulse inhibition. In addition, the Q31L mutants
have abnormalities in social behavior and the forced swim test,
tical to human disease-associated variants, they may still provide
to the more drastic translocation mutations.
We undertook a comprehensive histological analysis of the
cerebral cortex of Disc1 Q31L and L100P mutant mice. Our mu-
tants have fewer neurons, decreased neuronal proliferation, and
altered cortical layer positioning compared to wild-type (WT)
littermates. Golgi staining showed shorter pyramidal neuron
dendrite length in frontal cortex and reduced spine density in
TheJournalofNeuroscience,March2,2011 • 31(9):3197–3206 • 3197
man studies of SZ and with transgenic
Disc1 mutant mouse models. Our results
provide evidence for the effects of DISC1
SNPs on neurodevelopment and cortical
ing DISC1 genetics in the general SZ pa-
tient population, and represent a starting
point for further investigations of molec-
ular disease mechanisms in SZ.
Mice. N-ethyl-N-nitrosurea-mutagenized Disc1
mutant mouse lines on a C57BL/6 background
(Q31L and L100P homozygous ?/?) were gen-
erated as described previously (Clapcote et al.,
2007), and additional mice were bred for histo-
logical analysis at the Toronto Centre for Phe-
nogenomics (TCP) (Toronto, Canada). WT
littermates from both Q31L and L100P groups
were combined and used as controls. All mouse
protocols were approved by the TCP Animal
Bromodeoxyuridine labeling. Timed pregnant
female mice were injected with bromodeoxyuri-
(E14) for proliferation experiments and at E12,
E15, or E18 for investigation of neuronal posi-
tioning. Embryonic brains were harvested 24 h
in 4% paraformaldehyde overnight, cryopro-
tected in 30% sucrose, and frozen at ?80°C be-
and frozen coronal sections of 5 and 10 ?m
thickness, respectively, were cut using a microtome cryostat system
ing solution (0.1 M PBS, 1% Triton X-100, 0.5% Tween 20, 2% skim
milk) or serum-free protein block (DakoCytomation) for 1 h at room
temperature to reduce nonspecific background and then incubated with
primary and secondary antibodies overnight at 4°C. The following pri-
mary antibodies were used: anti-NeuN (1:200; Millipore), anti-BrdU
Cux1 (1:200; Santa Cruz Biotechnology), and anti-Brn2 (1:200; Santa
Cruz Biotechnology). Fluorescent secondary antibodies conjugated to
Alexa 488 or Rhodamine Red-X (1:200; Invitrogen) or Cy3 (1:100; Jack-
son ImmunoResearch Laboratories) were used for detection of primary
Golgi–Cox staining. Golgi–Cox staining was performed as described
previously (Gibb and Kolb, 1998). In brief, adult mice (age 6–8 weeks)
were anesthetized with xylazene/ketamine (10 ml/kg) and intracardially
for 5 d. Sections of 200 ?m were sliced using a microtome (Leica
VT1000S) and placed on 2% gelatinized microscope slides. The slides
were stored in a humidified chamber for 3 d before further staining and
Analysis of immunohistochemistry: neuron number, distribution within
whole cortex were captured using a confocal microscope (Zeiss LSM510
converted to gray values and normalized to background staining. Sec-
tions chosen for analysis were anatomically matched along the rostral-
caudal axis for all samples. Regions of interest (ROIs) were positioned
over the cortex as sampling windows. A two-dimensional cell counting
approach of random sampling was used to provide accurate estimates of
counted using the ITCN plugin for ImageJ (http://rsb.info.nih.gov/ij/)
old, 1 pixel). Specific procedures for defining areas of analysis differed
slightly for each antibody, since each was chosen to address different
questions. These procedures are described in detail below.
NeuN antibody-labeled images were used to examine overall neuron
numbers in the cortex. Eight rectangular ROIs of fixed size (500 ?m
high ? 250 ?m wide), with the long axis perpendicular to the pial sur-
face, were outlined throughout the neocortex from medial to lateral (see
ber of neurons in the ROI was counted.
fluorescently labeled cells in the ventricular zone (VZ) and subventricu-
lar zone (SVZ) were counted in a fixed area ROI of 100 ? 120 ?m.
Similarly with P21 brains, BrdU-labeled cells in the frontal cortex were
counted in an ROI of fixed width (500 ?m) but of variable length, cor-
responding to the thickness of the cortex. Frontal cortical regions were
pendicular to the pia to assess the distribution of each wave of newly born
mally destined for the superficial cortical layers II and III would instead be
seen in deeper layers (IV-VI) in Disc1 mutant mice. In both Cux1- and
length spanning the thickness of the cortex were delineated. Each ROI was
subdivided into eight equal regions from the pia to the inner border of the
individual neurons, Golgi images at 40? magnification were captured
under brightfield illumination with a Nikon Eclipse E600 microscope.
3198 • J.Neurosci.,March2,2011 • 31(9):3197–3206Leeetal.•NeuronalDevelopmentinDisc1MutantMice
and V of the frontal cortex and CA1 area of the hippocampus, as shown
of different focal lengths for each individual neuron was generated to
ing tree in different planes. Acquisition parame-
ters were kept the same for all images. The
neurites of each neuron were traced, and the
length and surface area were estimated using
Neuromantic software (http://www.rdg.ac.uk/
neuromantic). All parameters were further nor-
Sholl analysis provides a quantitative mea-
we created 15 concentric and equidistant cir-
cles (8 ?m separation of each radius) centered
at the perikaryon and then counted the num-
ber of dendritic intersections at each circle of
increasing radius. The log of the number of
intersections per circle area versus the circle
The slope of the regression line (? ? Sholl re-
gression coefficient) is a measure of the decay
rate of the number of branches with distance
from the soma (Sholl, 1953). The Schoenen
ramification index (maximum number of in-
tersections/number of primary dendrites), a
measure of the ramification richness for each
neuron (Schoenen, 1982), and the number of
dendritic bifurcations provide important in-
Spine density was measured with Golgi-
stained images captured at 100? magnifica-
tion (Nikon Eclipse E600). Spines were
counted only on the apical dendrites of pyra-
midal neurons in layers III and V of frontal
dritic length (micrometer). All images for
quantification were blinded before analysis.
Statistical analysis. Statistical differences
among different mutant lines and across geno-
typic groups against various measured parame-
ters were determined using one-way or two-way
ANOVA (SPSS 13.0), followed by Bonferroni’s
correction for multiple testing. To further con-
firm significance, Student’s two-tailed t test was
performed in comparing two sets of data. Data
are expressed as mean ? SEM. A significance
Experimental evidence is accumulating
ation and neuronal migration (Kamiya et
al., 2005; Mao et al., 2009; Singh et al.,
2010). We therefore examined the num-
ber of neurons throughout the neocortex
along the medial-lateral axis. Neurons
were labeled with antibodies to NeuN, a
neuronal marker, and then counted in
though NeuN does not label some types of neuron such as Pur-
kinje cells, the high specificity and dense labeling of cortical
neurons and interneurons provide a suitable measure of neuro-
nal density (Wolf et al., 1996). We observed significantly fewer
NeuN-labeled neurons in both Q31L (7260 ? 863; p ? 0.001)
BrdU?/Ki67?cells was observed with the L100P mutants, but not the Q31L mutants, when compared to WT. All data are
Leeetal.•NeuronalDevelopmentinDisc1MutantMice J.Neurosci.,March2,2011 • 31(9):3197–3206 • 3199
0.001) across the neocortex when com-
pared with WT mice (8636 ? 522) (Fig.
1B). This observation of fewer NeuN-
labeled neurons in Q31L and L100P com-
pared to WT was also seen within each
individual ROI, spanning from medial to
lateral (Fig. 1C).
We next determined whether the differ-
ences in the number of NeuN-positive
neurons could be related to differences in
neurogenesis between WT, Q31L, and
L100P mice. First, BrdU was injected into
pregnant dams at E14 and embryonic
ral progenitor proliferation in SVZ/VZ of
tants had fewer BrdU?cells when com-
L100P: 66 ? 24 vs WT: 102 ? 33; p ?
0.001) (Fig. 2B, C). A similar pattern was
ther confirming a decrease in prolifera-
tion (Fig. 2D). As previous studies have
shown that DISC1 knockdown causes
premature neuronal differentiation (Mao
et al., 2009), we investigated whether our
tified cells that had left the cell cycle as
BrdU positive and Ki67 negative. The
percentage of BrdU?/Ki67?cells was
only slightly increased in L100P mutants
(96.75 ? 3.04%) compared to WT
(95.26 ? 3.00%) (Fig. 2E). These subtle
effects suggest that our Disc1 mutations
may not have strong effects on the timing
of neuronal differentiation.
To observe the numbers and eventual
location of neurons born at different
times during embryonic corticogenesis,
BrdU was injected at three different time
P21. Coimmunostaining with NeuN con-
firmed the neuronal identity of BrdU-
labeled cells (Fig. 3A). The average total
number of BrdU-positive cells was signif-
icantly lower in Q31L and L100P cortexes
compared to WT at E12 (Q31L: 61 ? 14
and L100P: 64 ? 14 vs WT: 149 ? 25; p ? 0.001) and at E15
(Q31L: 185 ? 21 and L100P: 199 ? 40 vs WT: 254 ? 31; p ?
7; p ? 0.05) but not in L100P mutants (42 ? 21) (Fig. 3B). Thus
are associated with decreased neuronal proliferation.
Because neurons destined for more superficial layers are
born later and because there is evidence that DISC1 may affect
neuronal migration (Marín and Rubenstein, 2003; Kamiya et
al., 2005; Young-Pearse et al., 2010), we next examined the
cortical distribution and position of BrdU-labeled cells for
each time point of BrdU injection. Confocal imaging and
quantification revealed that BrdU?cells were located in
deeper cortical layers for E12- and E15-injected Q31L and
L100P mice compared with WT (Fig. 3C). At E18, the distri-
bution of BrdU-labeled cells was similar in all cortical layers
and all groups, with a small number of BrdU?cells observed
in deeper layers of both Q31L and L100P lines but not in WT
(Fig. 3C). Together, these results suggest that point mutations
of neurons within the cortex.
BrdU-labeled cells was similar in all cortical layers between WT and mutants, with only a small number of BrdU-positive cells
3200 • J.Neurosci.,March2,2011 • 31(9):3197–3206Leeetal.•NeuronalDevelopmentinDisc1MutantMice
To further examine the relationship between DISC1 and neuro-
nal positioning, we performed IHC with two layer II/III-
specific protein markers, Cux1 and Brn2
(Molyneaux et al., 2007). When compared
to WT, both Cux1- and Brn2-labeled neu-
rons in Q31L and L100P animals were fur-
ther away from the pia (Fig. 4A). To
quantify the positions of Cux1- and Brn2-
over the neocortical region of fluorescent
staining, and each was divided into eight
equal octants (spanning superficial to deep
layers) (Fig. 4B). The percentage of Cux1-
octant 1 and octant 3 of WT littermates
1.76%; octant 3: 31.42 ? 4.07%, p ? 0.01)
and L100P (octant 1: 7.43 ? 2.61%, p ?
0.01; octant 3: 35.11 ? 4.81%, p ? 0.05)
mice. In contrast, WT controls (12.85 ?
4.84%) displayed a significantly lower pro-
portion of Cux1?cells in octant 4 than in
(22.04 ? 9.1%, p ? 0.01) (Fig. 4B). For
Brn2, WT mice showed a significantly
of octants 4, 5, and 6 when compared to
edge of Cux1fluorescently labeled cells and
saw a higher ratio in Q31L (0.433 ? 0.039,
p ? 0.01) and L100P (0.432 ? 0.041, p ?
0.01) mutants versus WT (0.417 ? 0.031;
lates neurite outgrowth and dendritic
arborization; therefore, we performed a
detailed morphological analysis of den-
Q31L and L100P mutants and WT mice.
Golgi staining provides a clear and com-
plete image for a subgroup of neurons
without interference by neighboring neu-
rons. Representative neurons from WT,
ure 5A. We observed a significantly
shorter apical dendritic length (ADL) in
Q31L (208.9 ? 68.9 ?m, p ? 0.01) and
L100P mutants (242.4 ? 94.9 ?m, p ?
0.03) when compared to WT (328.3 ?
55.5 ?m). Consistently, basal dendritic
length (BDL) showed a similar trend with significant differences
in Q31L (690.6 ? 100.5 ?m, p ? 0.01) and L100P (786.8 ? 90.1
?m, p ? 0.021) versus WT (884 ? 109.6 ?m) (Fig. 5B). We also
found a significantly lower total dendritic surface area (DSA) of
Leeetal.•NeuronalDevelopmentinDisc1MutantMiceJ.Neurosci.,March2,2011 • 31(9):3197–3206 • 3201
Q31L (4250.9 ? 514.1 ?m2, p ? 0.001)
p ? 0.005) when compared to WT
(5708.5 ? 439.5 ?m2) (Fig. 5B).
Cell soma size has been reported to cor-
relate with dendritic structure (Somogyi
and Klausberger, 2005). Thus, we normal-
ized the measured parameters described
above to soma surface area. Interestingly,
neurite outgrowth was significantly lower
by 40.5% (p ? 0.014), 23% (p ? 0.042),
and 27.7% (p ? 0.007) in ADL, BDL, and
DSA, respectively, within Q31L mutants
We evaluated dendritic arbor com-
plexity in our Disc1 mutant mice versus
WT via Sholl analysis. There were no sig-
dex (Q31L: 2.3 ? 0.2, p ? 0.37; L100P:
dendritic bifurcations (Q31L: 7.2 ? 2.1,
p ? 0.39; L100P: 7.5 ? 0.5, p ? 0.48; vs
WT: 8.1 ? 2.0), Sholl’s regression coeffi-
cient (Q31L: 0.089 ? 0.005, p ? 0.97;
L100P: 0.091 ? 0.007, p ? 0.92; vs WT:
0.090 ? 0.004), or the number of den-
dritic intersections per radial segments
between Q31L and L100P and WT con-
trols (Fig. 5D–F).
In addition to the frontal cortex, the
hippocampus is another important brain
area of interest in SZ (Harrison, 2004).
Hence, we extended our morphological
analyses to pyramidal neurons in hip-
pocampal CA1 regions. In our study, we
did not observe any alterations in den-
dritic length, surface area, ramification
index, number of bifurcations of den-
drites, and Sholl’s regression coefficient
in either mutant line within the hip-
pocampus (Fig. 6).
Cognitive deficits associated with SZ have
been attributed to altered synaptic trans-
mission and plasticity in which dendritic
spines play a critical role (Calabrese et al.,
2006). DISC1 is involved in dendritic
spine development via Kalirin-7 (Penzes
and Jones, 2008; Hayashi-Takagi et al.,
2010). To determine whether our Disc1
point mutations affect dendritic spine development, we mea-
pus of Q31L, L100P, and WT mice. Golgi images of 100?
magnification were captured, and all spine types were counted
(Fig. 7A). Both Disc1 mutants had significantly reduced spine
density in the frontal cortex with an average spine density of
0.39 ? 0.063 spines/?m in Q31L ( p ? 0.001) and 0.391 ? 0.057
spines/?m in L100P ( p ? 0.001) compared to 0.449 ? 0.071
spines/?m in WT (Fig. 7B). Similarly, spine density was also
reduced in the hippocampus (Q31L: 0.363 ? 0.087 spines/?m
?m; p ? 0.001). Thus, DISC1 mutations appear to affect spine
density in both the frontal cortex and hippocampus.
There is increasing evidence for a strong association between
DISC1 and several major mental illnesses. The mechanism by
which DISC1 gene variants produce both cellular and behavioral
mutants had significant differences in all three parameters, while no significant effects were observed with L100P mutants.
However, a similar trend was still visible across all groups. D, No significant difference in dendritic branching complexity was
Morphology of neurons from the frontal cortex in Q31L and L100P ?/? mutants. A, Golgi-stained images of an
3202 • J.Neurosci.,March2,2011 • 31(9):3197–3206 Leeetal.•NeuronalDevelopmentinDisc1MutantMice
abnormalities is still unclear. We used two previously described
mouse lines with point mutations in Disc1 that have behavioral
changes relevant to SZ and depression (Clapcote et al., 2007). In
this study, we report a relative decrease in neuron number and
decreased neuronal proliferation in the Disc1 mutants compared
to WT mice. The mutant mice have differences in neuron posi-
tioning and morphology similar to some findings in human SZ
However, other histological abnormalities observed in postmor-
tem schizophrenia brain, such as interneuron deficits, have not
yet been investigated in our Disc1 mutant mice.
We found relatively fewer neurons and decreased neuronal
proliferation in Q31L and L100P mutant mice compared to WT.
Decreased neuronal density is a common
finding of postmortem studies on pa-
tients with SZ. Reductions in neuron
density in the primary visual cortex
glutamatergic neurons in the orbitofron-
tal cortex have been reported (Garey,
2010). Presently, the DISC1 status of the
patients reported in those studies is un-
known. Human studies combining ge-
netic markers and histopathological
analysis are required.
DISC1 has been well established as a
regulator of neurogenesis (Mao et al.,
2009). DISC1 participates in a glycogen
synthase kinase 3? (GSK3?) signaling
pathway involving ?-catenin via a direct
interaction with GSK3? at two different
domains of DISC1, spanning amino acids
1–220 and 356–595. Moreover, DISC1
knockdown results in a reduction of pro-
liferation progenitors likely caused by
early cell cycle exit (Mao et al., 2009).
However, our Disc1 mutations showed a
premature neuronal differentiation. It is
possible that the Q31L and L100P muta-
tions in DISC1 may only affect part of its
interaction with GSK3? and that prema-
ture cell cycle exit may not be the sole
determinant of neuronal proliferation.
Recently, the L100P Disc1 mutant mouse
was shown to have reduced interaction
with both GSK3? and ? (Lipina et al.,
cological inhibition of GSK3 activity res-
cued DISC1-mediated behavioral effects
in these mice.
Examination of neuronal distribution
using layer-specific protein markers re-
vealed altered neuron location in Q31L
and L100P mice compared to WT. Corti-
cal neuronal positioning can be affected
by changes in neurogenesis and neuronal
migration. Later-born neurons migrate
to more superficial layers of the cortex
through radial migration (Marín and
Rubenstein, 2003). As DISC1 regulates
neurogenesis and neuronal migration, we
hypothesized that aberrant neuronal dis-
tribution in the cortex may be due to DISC1-mediated effects on
both processes (Kamiya et al., 2005; Mao et al., 2009). It was
recently shown that DISC1 may participate in neurogenesis and
neuronal migration via separate and distinct signaling pathways
(Singh et al., 2010). Abnormal cortical cytoarchitecture may also
result from malfunctioning of the cytoskeletal machinery medi-
ating neuronal migration. Recent studies have reported several
rial 1 (PCM1) (Kamiya et al., 2008), amyloid precursor pro-
tein (APP) (Young-Pearse et al., 2010), neuregulin-1/ErbB4
(Jaaro-Peled et al., 2009), and LIS1/NDEL1 (Morris et al.,
2003; Wynshaw-Boris, 2007). However, complete details of
Leeetal.•NeuronalDevelopmentinDisc1MutantMice J.Neurosci.,March2,2011 • 31(9):3197–3206 • 3203
the mechanisms by which neurogenesis
and neuronal migration interact to modu-
late cortical cytoarchitecture remain to
The observed differences in frontal
cortical neuron morphology in the Disc1
mutants compared to WT may also be
mediated by DISC1 interactions with the
actin and microtubule cytoskeleton (Ishi-
zuka et al., 2006). Loss of normal DISC1
function or expression of mutant DISC1
disrupts its interaction with NDEL1 and
causes abnormal neurite outgrowth in
PC12 cells (Ozeki et al., 2003; Kamiya et
mice expressing truncated Disc1 have an
inhibition of neurite outgrowth and a re-
duction of apical dendritic length (Kvajo
similar findings of significant reductions
of DISC1 in neurodevelopment. Recent
studies with transgenic Disc1 mice have
shown a disturbance in neuronal ar-
borization both in the developing cere-
bral cortex and hippocampus (Kamiya et
In contrast, Kvajo reported no significant
cated transgenic Disc1 (Kvajo et al., 2008). Our Disc1 point mu-
consistent with Kvajo et al. Dendritic arbor development is a
complicated and strictly regulated multistep process involving
tion (Urbanska et al., 2008). Proper formation and stabilization
(Urbanska et al., 2008).
morphological changes in size, organization, and perhaps shape
(Harrison, 2004). Other Disc1 mutant mouse models show sim-
DISC1 have been associated with altered hippocampal structure
postmortem studies are consistent in finding abnormal hip-
pocampal neuronal morphology (Benes et al., 1998). We did
not detect any significant changes in hippocampal neuronal
morphology with our Disc1 mutations, similar to the findings
from Kvajo (Kvajo et al., 2008). Duan et al. (2007) recently
demonstrated an acceleration of neuronal integration when
downregulating DISC1 in adult hippocampal neurons. As the
developmental origin of hippocampus is distinct from the ce-
rebral cortex, DISC1 may modulate different developmental
programs in the hippocampus.
deficits in SZ. Dendritic spines are the postsynaptic targets for
synaptic transmission, and decreased spine density in prefrontal
in human postmortem SZ studies (Garey et al., 1998; Glantz and
measure of neural connectivity (Benes, 2000). DISC1 interacts
with Kalirin-7 to modulate Rac1, an important regulator of den-
dritic spine development and functional plasticity (Penzes and
(Hayashi-Takagi et al., 2010). Our observations are consistent
with these previous data, since we see a significant reduction in
spine density in both mutants for frontal cortex and hippocam-
pus. Our results further confirm that DISC1 regulates spine de-
velopment and may represent a possible link between DISC1
genetic variants and cognitive deficits observed in SZ.
Intriguingly, although Q31L and L100P mutant mice have
distinct behavioral abnormalities, they have similar histological
deficits. Subtle disruption of neuronal architecture and connec-
tions can have diverse effects on complex behaviors and on the
activity of other brain regions. Q31L and L100P mutants also
PDE4B binding (Clapcote et al., 2007). The discrepancy between
histology and behavior may require further histological and bio-
chemical characterization of the effects of these point mutations.
Our study provides a general overview of cortical histology, de-
velopment, and neuronal morphology in two independent Disc1
of drastic reductions in DISC1 expression or by expression of a
truncated protein. Our study is novel in characterizing histo-
pathological findings in two mouse lines with Disc1 SNPs. Al-
though the human disease-associated DISC1 SNPs are not the
same as the Q31L and L100P mutations in our mice, we argue
that our mouse SNPs are more similar to the DISC1 SNPs in the
general human population than the truncated Disc1 mutants.
Previous studies with truncated DISC1 or severe suppression
of DISC1 expression are more relevant to understanding the
pathophysiology of the original Scottish translocation pedi-
gree. Ongoing experiments to further understand the molecu-
lar mechanisms by which DISC1 regulates brain development are
dendritic spines. B, Quantification of spine density (number of spines/?m) in all groups showed a significant lower density in
3204 • J.Neurosci.,March2,2011 • 31(9):3197–3206Leeetal.•NeuronalDevelopmentinDisc1MutantMice
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