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The Synapse: Differences Between Men
and Women
Javier DeFelipe and Lidia Alonso-Nanclares
Abstract For many years, scientists have searched for structural variations
between men’s and women’s brains to explain psychological studies showing
that, overall, the sexes think and act differently. In general, while men on average
have larger brains and some brain regions are structured or shaped differently, the
effect of these differences is not well understood in terms of behavior or brain
function. An additional problem is that there is a virtual lack of knowledge at the
level of the synaptic organization of the human brain because the ultrastructural
preservation of post-mortem human brain tissue is usually rather poor and it is
generally unsuitable for detailed quantitative analysis. However, the examination of
specimens removed during the course of neurosurgery in patients with tumors or
intractable epilepsy represents an excellent opportunity to study human brain
ultrastructure, partly because the resected tissue can be immediately immersed in
the fixative so that post-mortem factors are mainly eliminated. Undoubtedly, this is
why the quality of the electron microscope images of this human biopsy material is
comparable to that obta ined in experimental animals. Here, we will deal mainly
with the finding from our laboratory—using fresh brain tissue removed during brain
surgery of epileptic patients—that there are significant differences between men
and women in terms of synaptic density in all cortical layers of the temporal
neocortex. These differences may represent a microanatomical substrate
contributing to the functional gender differences in brain activity.
J. DeFelipe (*) • L. Alonso-Nanclares
Laboratorio Cajal de Circuitos Corticales, Centro de Tecnologı
´
a Biome
´
dica, Universidad
Polite
´
cnica de Madrid, Campus Montegancedo S/N, Pozuelo de Alarco
´
n, Madrid 28223, Spain
Instituto Cajal (CSIC) and CIBERNED, Avenida Doctor Arce 37, Madrid 28002, Spain
e-mail: defelipe@cajal.csic.es
D.W. Pfaff and Y. Christen (eds.), Multiple Origins of Sex Differences in Brain,
Research and Perspectives in Endocrine Interactions,
DOI 10.1007/978-3-642-33721-5_4,
#
Springer-Verlag Berlin Heidelberg 2013
43
Introduction
Differences between females and males is a topic of general interest in many
different areas (Cahill 2006; Jazi n and Cahill 2010; Semaan and Kauffman 2010)
including art, as reflected in the painting Man and Wom an by Fernando Botero
(2001) shown in Fig. 1. Indeed, scientists have been studying male and female
brains for years, looking for variations that may explain these differences.
It is clear that men and women display different capacities in certain cognitive
functions that are unrelated to differences in the general level of intelligence. The
most consistently reported differences relate to spatial and language abilities, and
while men excel in mental rotation and spatial perception, women perform better in
verbal memory tasks, verbal fluency tasks and in the speed of articulation (Linn and
Petersen 1985; Kimura 2000). These differences are thought to be a conse quence of
not only the influence of sex hormones on brain organization during development
but also genetic factors (De Vries 2004; Bocklandt and Vilain 2007; Cosgrove et al.
2007; Davies and Wilkinson 2006; for a recent review, see Hines 2011). Since
higher brain functions are directly related to the activity of the neocortex, many
studies aimed at identifying possible structural correlations for cognitive gender
differences have focused on the cerebral cortex, using a variety of anatomical and
brain imaging techniques. Here, we will deal with these topics, focusing on our
findings (Alonso-Nanclares et al. 2008) using stereological and correlative light and
electron microscopy methods to examine possible gender differences at the synap-
tic level in the human cerebral cortex.
Sexual Dimorphism of the Human Brain
At the macroscopic level, sexual dimorphism has been reported in the cortical
volume of the Wernicke and Broca areas (Harasty et al. 1997), as well as in the
frontal and medial paralimbic cortices, amygdala and hippocampus (Allen et al.
2003; Amunts et al. 1999, 2007; Goldstein et al. 2001 ; Sowell et al. 2007), and in
the thickness and density of the gray matter in the parietal lobes (for reviews, see
Sowell et al. 2007; Luders and Toga 2010). At the microscopic level, there are two
levels of analysis: (1) at an intermediate resolution (mesoscopic scale), using light
microscopy, which allows us to observe cells, their processes and putative
connections using specific markers; (2) at an ultrastructural resolution (nanoscopic
scale), which can only be studied using electron microscopy (EM) and serves to
map true synaptic contacts.
At the mesoscopic scale, sex differences have been reported in cortical cytoarch-
itecture. Differences have been found in the density of neurons (Haug 1987; Witelson
et al. 1995; Pakkenberg and Gundersen 1997; Rabinowicz et al. 1999; Stark et al.
2007) and in the complexity of the dendritic arbors of the pyramidal cells, as well
as in the density of dendritic spines in several cortical areas (Jacobs et al. 1993).
44 J. DeFelipe and L. Alonso-Nanclares
Nevertheless, as we will discuss in the next section, the functional significance of these
differences remains unknown because no generally valid equation relates neuronal
number or morphology to behavioral complexity (Pakkenberg and Gundersen 1997;
Jacobs et al. 1993).
Brain Size and Intellectual Capabilities
The marked increase in human brain size during evolution, its relationship with
higher brain functions, and the large differences in intellectual abilities between
individuals provoked studies in the nineteenth and early twentieth centuries to
determine whether the brains of people with higher intellectual abilities could be
distinguished from those with ordinary minds, based on anatomical brain features
(sizes or shapes). The significance of the differences in brain size is not clear in our
species. For example, the English poet Lord Byron (1788–1824) seems to have had a
great brain, as demonstrated not only by the quality of his writings but also by the size
of his enormous brain, weighing 2,238 kg. Oliver Cromwell (1599–1658), protector
of the Republic of England, also had a brain that weighed between 2,233 and
2,330 kg, whereas the French writer Anatole France (1844–1924), who won the
Nobel Prize for literature in 1921, had a brain that weighed only 1,100 kg (DeFelipe
2011). As far as we know, the smallest brain reported in a normal person is the case of
Daniel Lyons, who died in 1907 at the age of 41. Daniel was a person with no special
features, with a normal body weight and of normal intelligence, although his brain
weighed no more than 680 g (Wilder 1911). Thus, it appears that a difference of
almost 50 % of brain mass, with its billions of neurons and synapses, may have no
functional significance in terms of intelligence. If it is not brain size that determines
whether a person is adept at music, painting or literature, then it is probably the
individual pattern of connections. In other words, both the quantitative and qualitative
characteristics of connections are likely to influence intelligence, including the
number of connections between particular functional groups of neurons, their molec-
ular and physiological characteristics, etc., which in turn depend on genetic back-
ground and on the influence of the environment (DeFelipe 2006).
Microanatomical Sex Differences of the Neocortex
at the Ultrastructural Level
It is important to bear in mind that connectivity at the light microscope level is in
general rather imprecise. Indeed, axonal boutons are embedded in a comple x
neuropil adjacent to several possible synaptic targets. Th us, the presence of a
labeled terminal in close apposi tion to a given neuronal element can only be
considered a putative synaptic contact. Thus, one of the requirements for
The Synapse: Differences Between Men and Women 45
understanding how neuronal circuits contribute to the functional organization of the
cerebral cortex is to achieve a detailed analysis of neuronal connectivity at the
ultrastructural level. However, the difficulties encountered when attempting to
apply microanatomical techniques to study the huma n brain explain why most
studies of the structure of the neocortex have been performed at the light micro-
scopic level. When performing ultrastructural studies, the main problems are
related to the lack of suitabl e human brain tissue to study synaptic circuitry, for
which the only source of control tissue might be autopsy material (i.e., from
individuals who did not suffer brain pathologies or psychiatric illness). Unfortu-
nately, the ultrastructural preservation of post-mortem human brain tissue is usually
rather poor, and it is generally unsuitable for the detailed quantitative analysis that
can be perf ormed on biopsy material. Indeed, this is one of the main reasons for the
paucity of data regarding the synaptic circuitry in the normal human brain.
The analysis of specimens removed during the course of neurosurgery in patients
with tumors or intractable epilepsy represents an excellent opportunity to study
human brain materia l. Furthermore, it is inevitable that surgical excisions pass
through cortical regions that are normal. Hence, this material can be exploited to
analyze various ultrastructural aspects of the neocortex in detail, helping us to better
understand the microorganization of the human cerebral cortex that would other-
wise be impossible to define. This resected tissue facilitates the study of the human
brain at the electron microscope level, in part because this type of tissue can be
immediately immersed in the fixative and post-mortem factors are mainly non-
existent. Undoubtedly, this is why the quality of the immunocytochemical staining
at both light and electron microscopy levels in human biopsy material has been
shown to be comparable to that obtained in experimental animals (e.g., del Rı
´
o and
DeFelipe 1994).
Hence, using correlative light and electron microscopy coupled to stereological
techniques, we showed for the first time that there is significant sexual dimorphism
in the density of synapses in all cortical layers of the human temporal neocortex
(Alonso-Nanclares et al. 2008). These differences may represent a microanatomical
substrate that contributes to gender functional differences in brain activity. What
follows is a summary of the results of this study.
Cytoarchitecture of the Temporal Neocortex from Men and Women
We analyzed the thickness and neuronal density in layers I, II, IIIA, IIIB, IV, V and
VI, of 100-mm Nissl-stained sections from human postoperative brain tissue
obtained from eight patients suffering pharmaco-resistant mesial temporal lobe
epilepsy secondary to hippocampal alterations (Fig. 1). Tissue was obtained from
four women—26, 31, 31 and 41 years of age—and from four men—24, 27, 32 and
36 years of age. Video-EEG monitoring of bilateral foramen ovale electrodes was
indicative of left mesial temporal lobe epilepsy in all patients. Furthermore, during
surgery, the epileptogenic regions were identified through subdural recordings with
46 J. DeFelipe and L. Alonso-Nanclares
a 20-electrode grid (lateral neocortex) and a four-electrode strip (uncus and
parahippocampal gyrus). Int raoperative electrocorticographic recordings revealed
spiking activity localized in the mesial structures, while the lateral neocortex of all
these patients displayed normal activity; no spikes, sharp waves or slow activities
were observed during intraoperative electrocorticography. All of the patients were
right-handed and they had normal intelligence quotients (IQ).
Neuronal density was estimated using optical dissectors, as described by West and
Gundersen (1990; see also Williams and Rakic 1988). No significant differences were
found between men and women in regard to neuronal density (Fig. 2;Table1).
However, other reports have shown greater neuronal density in the posterior temporal
neocortex of women when compared to men (Witelson et al. 1995). The discrepancy
between the results of Witelson et al. (1995) and our present results may be attributed
to the cytoarchitectonic differences of the regions examined. We examined the
anterior part of the middle temporal gyrus, corresponding to area 21 of Brodman
(Fig. 1), whereas Witelson et al. (1995) analyzed the superficial surface of the
posterior part of the superior temporal gyrus, also denominated the TA1 area (von
Economo and Koskinas 1925)orarea22byBrodman(1909).
Furthermore, the cell body (glia and neurons), neuropil and blood vessel volume
fractions (V
v
) were examined in each of these cortical layers in 2-mm thick semithin
sections stained with toluidine blue by applying the Cavalieri principle (Fig. 3a).
Fig. 1 (a) Brodman’s map of the human brain to illustrate the specific part of the temporal lobe
corresponding to area 21 (in yellow), which we examined (Alonso-Nanclares et al. 2008). Red
dotted line indicates the surgical excision line. (b) Low-power photomicrograph of a 100 mm-thick
section stained with toluidine blue to identify the cortical layers (WM white matter)
The Synapse: Differences Between Men and Women 47
Again, no significant differences were found. In summary, no cytoarchitectonic
differences were observed in the tissue obtained from men and women (Fig. 3b).
Ultrastructural Analysis
A variety of synaptic relationships has been observed, including dendro-dendritic,
somato-somatic, somato-dendritic, dendro-somatic, dendro-axonic and somato-
axonic synapses (Peters et al. 1991). In addition, neurons are not only connected
by chemical synapses but may also be coupled electrically and through gap
junctions (Bennett 2000), which permit bidirectional transmission. The plasma
membranes of adjacent neurons are separated by a gap of about 2 nm, although
they contain small channels (gap junctions) that connect the cytoplasm of the
adjoining neurons, permitting the diffusion of small molecules and the flow of
electric current (Bennett and Zukin 2004; Hormuzdi et al. 2004). Furthermore, the
Fig. 2 Neuronal densities (mean s.e.m.) in each cortical layer, demonstrating that there are no
significant differences between men and women
Table 1 Number of neurons per mm
3
(mean SEM) and the percentage of synapses per layer
Layer
Neuronal density Percentage of synapses
Women Men
Women Men
%AS %SS %AS %SS
I 11,558 1,200 11,034 850 76 24 72 28
II 54,915 3,200 49,127 2,900 80 20 83 17
IIIa 18,112 510 17,279 560 85 15 92 8
IIIb 15,869 430 15,907 220 84 16 86 14
IV 49,754 3,200 47,758 970 86 14 89 11
V 26,393 1,200 24,070 830 88 12 92 8
VI 16,520 430 16,291 380 88 12 91 9
AS asymmetric synapses, SS symmetric synapses
48 J. DeFelipe and L. Alonso-Nanclares
transmitter releas ed at synaptic or non-synaptic sites may diffuse and act on other
synaptic contacts, or on extrasynaptic receptors (Fuxe et al. 2007). In certain
cases, rather than being simply a non-specific phenomenon, this neurotransmitter
spill-over may represent an intermediate situation between conventional point-to-
point synapses and volume transmission (Mercha
´
n-Pe
´
rez et al. 2009).
Finally, not only are glial cells key components of the nervous system because of
their numerous structural, metabolic and protective functions but it has also been
proposed that astrocytes are involved in information processing through their
bidirectional signaling with neurons (Perea and Araque 2010; Halassa and Haydon
2010; Heneka et al. 2010; Hamilton and Attwell 2010). Nevertheless, chemical axo-
dendritic synapses are by far the most common type of synapse (followed by axo-
somatic synapses). Other types of synapses are not found in all regions of the
nervous system and, when present, they are usually only established between
specific types of neurons. It can be concluded that there are two main morphological
types of chemical synapses in the cerebral cortex, Gray’s type I and type II synapses
(Gray 1959 ); they correspond to the asymmetric and symmetric types of Colonnier,
respectively (Colonnier 1968; see also, Colonnier 1981; Peters et al. 1991; Peters
and Palay 1996). In general, asymmetric synapses are considered to be excitatory
(glutamatergic) and symmetric synapses inhibitory (GABAergic). Moreover, asym-
metric synapses are much more abundant (75–95 % of all neocortical synapses)
than symmetric synapses, but there are cortical area and layer differences as well as
between-species difference s (5–25 %: for review, see DeFelipe et al. 2007). Thus,
Fig. 3 (a) Photomicrograph of a semithin section (2 mm) stained with toluidine blue, from cortical
layer III, to illustrate the Cavalieri method used to estimate the V
v
of cells, blood vessels and
neuropil. Scale bar 20 mm. In this example, the total area of the image is 30,400 mm
2
. A grid of
small intersections is displayed overlying the tissue. Each grid point has an associated area of
10 10 ¼ 100 mm
2
. Yellow asterisks indicate the intersections in the grid that lie within cells
(n ¼ 20, 23 100 ¼ 2,300 mm
2
). Red asterisks indicate the intersections in the grid that lie
within blood vessels (n ¼ 4, 4 100 ¼ 400 mm
2
). The V
v
of cells, blood vessels and neuropil
was estimated with the following formulae: V
v cells
¼ 7.5 %, V
v blood vessels
¼ 1%,V
v neuropil
¼100(7.5 + 1) ¼ 91.5 %. (b) Comparison of the V
v
between men and women, calculated for the
neuropil, cell bodies (including those from glia and neurons) and blood vessels in each cortical
layer. Note that the neuropil represents between 90 % and 98 % of the volume, for which no
significant differences were found between men and women
The Synapse: Differences Between Men and Women 49
in general, the examination of possible differences in the density and proportion of
excitatory and inhibitory synapses among cortical areas, genders or species is
extraordinarily important in terms of function.
For these reasons, we studied the morphology and density of synaps es in each
cortical layer. We found that the ultrastructure of the neuro pil in women was
indistinguishable from that in men (Fig. 4a, b). The synapses were classified into
three categories: asymmetric, symmetric and uncharacterized (Tables 1 and 2).
In the case of asymmetric and symmetric types, the synaptic cleft could be
visualized and synapses were identified based on the morphology of the postsynap-
tic density. Asymmetric synapses had a prominent post synaptic density whereas
symmetric synapses had a thin postsynaptic density (Fig. 4c, d; Gray 1959;
Colonnier 1968, 1981; for review, see Peters et al. 1991; Peters and Palay 1996).
In the uncharacterized synapses, the synaptic cleft could not be visualized, due to
the oblique plane of section. Synaptic density per unit area (N
A
) was estimated from
electron microscopy samples of the neuropil from each cortical layer (for a detailed
description, see DeFelipe et al. 1999). In this study, uncharacterized synapses were
included in the final estimate of the total synaptic density. Furthermore,
uncharacterized synapses were include d as asymmetric and symmetric types,
according to the frequency of both types of synapses. Therefore, the proportion of
each type of synapse in this study is an estimate of the real ratio (see DeFelipe et al.
2007). When the mean cross-sectional lengths of asymmetric, symmetric and
uncharacterized synapses were analyzed, no significant differences were found
between men and women in any layer (Table 2).
Gender Difference s in Synaptic Density of Temporal Neocortex
Synapses were quantified in the neuropil (i.e., avoiding the neuronal and glial
somata, blood vessels, large dendrites and myelinated axons; DeFelipe et al.
1999), and we found that men had a higher synaptic density in all layers (Fig. 5).
The smallest difference in density was found in layer II, in which the synaptic
density was 18 % higher in men than in women (Fig. 5), whereas the greatest
difference was found in layer V, where the synaptic densi ty in men was 52 % higher
than in women (representing an additional 678 million synapses in men). Consid-
ering all layers, men also had a significantly higher average synaptic density of
12.9 10
8
/mm
3
, compared to 8.6 10
8
/mm
3
in women. Thus, there was a 33 %
difference in synaptic density between men and women. Nevertheless, whe n con-
sidering all layers together, the proportion of asymmetric and symmetric synapses
(Tables 1 and 2) was similar in men and women, 86 % and 14 % in men and 84 %
and 16 % in women, respectively.
50 J. DeFelipe and L. Alonso-Nanclares
Caveats
It was certainly a striking finding that, despite the well-known anatomical and
functional interindividual variability in the brain (e.g., Uylings et al. 2005; Caspers
et al. 2006), we consistently observed a lower synaptic density in women in all
cortical layers of the temporal neocortex. Since we examined relatively few cases
(four women and four men), we consider that these differences must be very robust
in the general population. Nevertheless, we would caution the reader that the main
limitation in this kind of study is that we have virtually no data about the synaptic
density in biopsy samples of the strictly normal human neocortex. Indeed, it is well
known that synaptic reorgani zation occurs in the epileptic brain, although these
changes occur in regions with neuronal loss and gliosis, such as the sclerotic
hippocampus (e.g., Houser 1999; Arellano et al. 2004) or the peritumoral or
dysplastic cortex (e.g., Alonso-Nanclares and DeFelipe 2005; Alonso-Nanclares
et al. 2005). The eight biopsies used in the present study can be considered to be
Fig. 4 Electron micrographs illustrating the ultrastructure of the human temporal neocortex. (a, b)
Low-power electron micrographs showing the neuropil from layer IIIb of the temporal neocortex
from a woman (a) and a man (b). Some synapses are indicated by arrows.(c, d) High-power
electron micrographs showing the two major morphological types of synapses in the neuropil.
Asymmetric synapses (arrows) had a prominent postsynaptic density, whereas symmetric
synapses (arrowhead) had a thin postsynaptic density. de dendritic shaft, ds dendritic spines, T
axon terminals. Scale bar (in d): 0.9 mmina, b and 0.4 mminc, d
The Synapse: Differences Between Men and Women 51
close to normal conditions for the following reasons: first, the epileptic activity was
clearly of mesial origin; second, the whole neocortex in all of these patients
displayed non-spiking activity and; third, they presented normal cytoarchitectonic
and ultrastructural characteristics. In addition, while we cannot rule out that synap-
tic changes may also occur in the neocortex, there is no reason to believe that the
differences in synaptic density observed between men and women were due to the
epileptic condition, given that all of the subjects were epileptic. Thus, it is likely
that these differences are truly due to gender differences.
Table 2 Accumulated data from all cortical layers. Data of all synapses including asymmetric,
symmetric and uncharacterized synapses
Women Men
Mean cross-sectional length of asymmetric synapses
(mean SD, in mm)
0.30 0.09 0.30 0.08
Mean cross-sectional length of symmetric synapses
(mean SD, in mm)
0.21 0.10 0.20 0.09
Mean cross-sectional length of all synapses (mean SD,
in m m)
0.29 0.06 0.27 0.05
Mean no. of asymmetric synapses (10
8
/mm
3
,
mean SD)
3.17 2.08 4.23 2.59
Mean no. of symmetric synapses (10
8
/mm
3
, mean SD) 1.06 1.84 1.42 2.00
Mean no. of all types of synapses (10
8
/mm
3
, mean SD) 7.17 3.29 10.61 4.97
Percentage of asymmetric synapses 86 84
Percentage of symmetric synapses 14 16
No. of neurons/mm
3
(mean SD) 27,589 16,854 25,924 15,110
Vv cell bodies (glia and neurons) 5.3 5.2
Vv blood vessels 0.8 1.2
Vv neuropil 93.9 93.3
Fig. 5 Comparison of synaptic density (mean s.e.m.) between men and women in each cortical
layer.*p < 0.05, **p < 0.01
52 J. DeFelipe and L. Alonso-Nanclares
Significance of Sexual Differences in Synaptic Density
Importantly, no differences in cytoarchitecture were observed. More specifically,
no significant differences were found between men and women regarding the
thickness of the gray matter, the volume fraction of cortical elements (neuropil,
cells and blood vessels) and neurons per volume. As a consequence, the number of
synapses in each layer was greater in men than in women, and thus, in this particular
region of the neocortex, the general connectivity in men appeared to be more
extensive than in women. Accordingly, gender appears to influence synaptic con-
nectivity and this phenomenon is regulated independently of other cytoarchi-
tectonic features.
If we consider the columnar organization of the input connections, the differences
in connectivity between neighboring neurons, and the combinations of the interlami-
nar connections of both pyramidal and non-pyramidal neurons, it is clear that neurons
in different layers do not process the same information (Rockland and Ichinohe 2004;
DeFelipe 2005). Furthermore, pyramidal neurons located in different layers project to
different cortical and subcortical nuclei (Jones 1984;Lund1988;White1989).
Hence, it is likely that the differences in synaptic density between men and women
observed in all cortical layers represent a microanatomical substrate for sex
differences in the fine-tuning of several functions. The larger number of synaptic
connections in men does not necessarily mean that all cortical circuits in this region
are more complex than in women. Rather, specific circuits may be more complex in
the male brain. The temporal lobe is a complex, associative and multi-integrative
cortical region (Brodman 1909; for a review, see Olson et al. 2007). Therefore, the
functional consequences of the differences in synaptic circuitry observed here are
particularly difficult, if not impossible, to correlate with specific functions related to
men or women. Indeed, it could simply mean that men’s brains are just more
redundant. In addition, we have the tendency to think that a higher complexity (i.e.,
higher synaptic density) is always related to a greater functional capability or greater
performance. However, in this case, “less may be more,” since the temporal cortex is
involved in language processing and, overall, women perform better on language
tasks; fewer synapses in women may represent increasing specialization of the
temporal cortex for language processing.
Furthermore, pyramidal neurons in the human prefrontal, temporal and visual
cortex display clear differences in their number of dendritic spines (Jacobs et al.
2001; Elston et al. 2001). For example, the basal dendritic arbors of layer III
pyramidal cells in the prefrontal cortex are considerably more spinous (average
total number of dendritic spines; 15,138) than those in the temporal lobe (12,700)
and in the occipital lobe (human, 2,417; Elston et al. 2001). Since the vast majority
of dendritic spines establish synaptic contacts (Arella no et al. 2007), the total
number of dendritic spines is practically equivalent to the total number of excitatory
glutamatergic synaptic inputs of the pyramidal cells. Thus, there are clear
differences in total numbers of synaptic inputs to pyramidal cells in these cortical
areas. This of course does not imply that the degree of functional performance of
The Synapse: Differences Between Men and Women 53
prefrontal cortex, temporal cortex and visual cortex differs. Rather, it means that
cortical microorganization differs between different cortical areas and that it is
related to their respective functional specializations. These observations underscore
the point that a higher synaptic density is not necessarily related to greater func-
tional capability.
Interestingly, a recent study on synaptic density carried out in the monkey
prefrontal cortex seems to indicate that there are no differences between males
and females (Peters et al. 2008). However, many studies have shown variations
between species and cortical areas in terms of density, proportion and types of
neurons, as well as in the density of synapses (e.g., DeFelipe et al. 2007). Thus,
whether these gender differences are unique to the human cerebral cortex or if
similar conditions arise in monkeys and grea t apes should be specifically analyzed
in each species and cortical area. Finally, and in line with this consideration, we
would advise the reader to exercise caution in extrapolating the present data to the
whole brain. Indeed, it was reported that the anterior commissure, which connects
several regions of the frontal and temporal lobes, is 12 % larger in women than in
men, suggesting that women would have more commissural associative
connections (Allen and Gorski 1991). Further work will be necessary to examine
whether synaptic density is similar or different in other cortic al areas.
Acknowledgements We would like to thank Dr. G. Sola (“Hospital de la Princesa,” Madrid,
Spain) for supplying human tissue. This work was supported by grants from the following entities:
Ministerio de Ciencia e Innovacio
´
n (grants SAF2009-09394 and the Cajal Blue Brain Project,
Spanish partner of the Blue Brain Project initiative from EPFL), Centre for Networked Biomedical
Research into Neurodegenerative Diseases (CIBERNED, CB06/05/0066) and Fundacio
´
n CIEN.
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