Neuroglías:

o
No olvidemos al
90% de las células
del cerebro.

N. Allen and B. Barres, 2009

Alejandro D. Roth Ph.D.
Fac. Ciencias. Universidad de Chile

Neuroglías: ¿Son el 90% de las

células del cerebro?
•“Many original articles, reviews and textbooks affirm that we have 100 billion
neurons and 10 times more glial cells (Kandel et al., 2000; Ullian et al., 2001; Doetsch, 2003;
Nishiyama et al., 2005; Noctor et al., 2007; Allen and Barres, 2009), usually with no references
cited.”

• En realidad, existen múltiples sugerencias de número, pero se puede ver que:

Neuronas Proporción de Glias
Telencéfalo 21-26 x109 1:2
Cerebelo 101 x109 25:2
Núcleos subcorticales:
Tálamo 1:17
pallium ventral 1:12

Herculano-Houzel (2009) Frontiers in Human Neuroscience; 3:31

Herculano-Houzel The human brain in numbers

Table 2 | Expected values for a generic rodent and primate brains of 1.5 kg, and values observed for the human brain (Azevedo et al., 2009 ).

Generic rodent brain Generic primate brain Human brain

Brain mass 1500 g 1500 g 1508 g

Total number of neurons in brain 12 billion 93 billion 86 billion
Total number of non-neurons in brain 46 billion 112 billion 85 billion
Mass, cerebral cortex 1154 g 1412 g 1233 g
Neurons, cerebral cortex 2 billion 25 billion 16 billion
Relative size of the cerebral cortex 77% of brain mass 94% of brain mass 82% of brain mass
Relative number of neurons in cerebral cortex 17% of brain neurons 27% of brain neurons 19% of brain neurons
Mass, cerebellum 133 g 121 g 154 g
Neurons, cerebellum 10 billion 61 billion 69 billion
Relative size of the cerebellum 9% of brain mass 8% of brain mass 10% of brain mass

Notice that although the expected mass of the cerebral cortex and cerebellum are similar for these hypothetical brains, the numbers of neurons that they
contain are remarkably different. The human brain thus exhibits seven times more neurons than expected for a rodent brain of its size, but 92% of what would
be expected of a hypothetical primate brain of the same size. Expected values were calculated based on the power laws relating structure size and number of
neurons (irrespective of body size) that apply to average species values for rodents (Herculano-Houzel et al., 2006) and primate brains (Herculano-Houzel et al.,
2007), excluding the olfactory bulb.

below expectations for a primate brain of 1.5 kg, while the human hominin lineage before humans, should also conform to the same
cerebellum, at 154 g and 69 billion neurons, matches or even slightly cellular scaling rules. An examination of the cellular composition
exceeds the expected (Table 2). of the cerebellum of orangutans and one gorilla shows that the
Although not observed in the comparatively small rodent species sizes of the cerebellum and cerebral cortex predicted for these spe-
analyzed, the enlargement of the cerebral cortex is not, in principle, cies from the number of cells in the cerebellum match their actual
an exclusive feature of the human brain: a similar expansion of the sizes, which suggests that the brain of these animals indeed is built
mass of the cerebral cortex, relative to the whole brain, is predicted according to the same scaling rules that apply to humans and other
by both the rodent and primate cellular scaling rules, irrespec- primates (Herculano-Houzel and Kaas, in preparation). In view of
tive of the number of neurons contained in the cortex (Table 2). the discrepant relationship between body and brain size in humans,
Remarkably, the human cerebral cortex, which represents 82% of great apes, and non-anthropoid primates, these findings suggest
brain mass, holds only 19% of all neurons in the human brain Herculano-Houzel
– a that the rules(2009) Frontiers
that apply in primate
to scaling Humanbrains
Neuroscience;
are much more 3:31
fraction that is similar to the fraction that we observed in several conserved than those that apply to scaling the body. This raises the
other primates, rodents, and even insectivores (Figure 1). The possibility that brain mass and body mass across species are only
•relatively large human cerebral cortex, therefore, is not different correlated, rather than brain mass being determined by body mass,
Las Neuronas no existen en el vacío. Cumplen sus funciones asociadas y condicionadas
from the cerebral cortex of other animals in its relative number as presumed in studies that focus on the variation of residuals after
of por las células gliales.
neurons. regression onto body size. Supportive evidence comes from the
It should be noted that the unchanging proportional number dissociation between brain and body growth in development, in
•of “Glías”
neurons ines the un término
cerebral que agrupa
cortex relative demasiados
to the whole brain does which tipos thecelulares,
former actually incluyendo células
precedes the latter delin Deacon,
(reviewed
not contradict an expansion in volume, function and number of 1997), and from our observation that body mass seems more free to
sistema
neurons of theinmune.
cerebral cortex in evolution: the absolute number vary across species than brain mass as a function of its number of
• Muchas derodent
of neurons in the las enfermedades
and primate cerebralneurológicas
cortex does increase sonneurons.
enfermedades gliales.
In this view, it will be interesting to consider the alternative
much faster in larger brains compared to the number of neurons hypothesis that body size is not a determining variable for brain
•in La vascularización
the combined del SN esandindispensable
brainstem, diencephalon basal ganglia, and isy, alsize
mismo tiempo
in comparative studiesgenera complicaciones
of brain neuroanatomy, ante
and particularly
accompanied by a similarly fast increase in the number of neurons not an (independent) parameter for assessing quantitative aspects
in rupturas
the cerebellum y (Figure
sangrados.
5). ¿Cómo evitar estos problemas? of the human brain.
Because of the diverging power laws that relate brain size and
number of neurons across rodents and primates, the latter can DO WE HAVE THE MOST NEURONS? PREDICTIONS FOR OTHER LARGE- of astrocyte genes. R
hold more neurons in the same brain volume, with larger neuronal BRAINED MAMMALS panies every neurolo
densities than found in rodents. Since neuronal density does not The different cellular scaling rules that apply to rodents and pri-sis clearly is benefici
scale with brain size in primates, but decreases with increasing mates strongly indicate that it is not valid to use brain size as a proxyhelp seal a damaged
brain size in rodents, the larger the brain size, the larger is the for number of neurons across humans, whales, elephants and otherin which it has been
difference in number of neurons across similar-sized rodent and large-brained species belonging to different mammalian orders.
utes substantially to t
primate brains. One consequence of this realization is that sheer size alone, or in
from regenerating (S
relation to body size, is not an adequate parameter to qualify, or
upregulate synapse-
PREDICTIONS FOR GREAT APES disqualify, the human brain as “special”.
The finding that the same cellular scaling rules apply to humans A comparison of expected numbers can nevertheless be very illu-which have the pote
and non-anthropoid primate brains alike, irrespective of body size, minating. For instance, given the cellular scaling rules that we have2008) but may also i
indicates that the brains of the great apes, which diverged from the observed for rodents (Herculano-Houzel et al., 2006), a hypotheticalepilepsy or neuropath
recent studies have fo
foundly neurotoxic sig
Frontiers in Human Neuroscience www.frontiersin.org November 2009 | Volume 3 | Article 31 | 7
ing the SOD1(G93A)
Figure 3. Vascular Cells Are a Major Cellular Constituent in the wild-type motor neu
Human Brain 2007; Lobsiger and C
Blood vessels represent a substantial fraction of the volume of the brain. Ves- A critically importan
sels were visualized by filling them with a plastic emulsion, after which brain
understand the patho
N. Allen and B. Barres, 2009 parenchymal tissue was dissolved (from Zlokovic and Apuzzo, 1998).
mon neurological dis
are not yet good trea
trophic support and differentiation signals to neurons and stem dysfunction after str
cells (Shen et al., 2004; Dugas et al., 2008), and provide a niche treat stroke, we nee
for neural stem cells (Tavazoie et al., 2008). One role commonly the CNS is so much
 Neuroglías, vaina de mielina y nodos de
Ranvier: contexto histórico.

• Leeuwenhoek (1717):

“Observé una neurula completamente rodeada por partes

grasosas” “Numerosas neurulas se extendian desde la
médula de la columna, cruzando la túnica (meninges)…y
emergiendo aumentadas en tamaño y recubiertas de una
nueva túnica”

• Galvani (1791):
“El nervio cumple la función de conductor”
De viribus electricitatis
“Los Nervios contiene elementos conductores y aislantes..la
grasosa capa externa de los nervios previene la dispersión y
permite su acumulación”
“El nervio cumple la función de conductor”
De viribus electricitatis“Los Nervios contiene elementos
conductores y aislantes..la grasosa capa externa de los nervios
previene la dispersión y permite su acumulación”

• Virchow • Ranvier:
– 1846: Tejido conectivo bajo el epéndima – 1871: Los axones contienen interrupciones
periódicas asociadas a constricciones axonales
– 1856: nerven kitt (neuromasilla, no al lado de las cuales se puede observar la
pegamento) presencia de estriaciones transversales
– 1858: Médula=myelos Mielina – 1873: La neuroglía es una forma de tejido
conectivo (ergo, mesodérmico)-
“la médula del nervio rellena el espacio entre el cilindo – 1882: Neuroglías de la médula espinal y
axial y la membrana externa” las células de Müller son equivalentes a
neuroepitelio indiferenciado.
• Schmidt (1874) y Lantermann
(1877)
En la mielina del SNP existen cortes transversales que
atraviesan la vaina de mielina y que llegan hasta el axón.
• Weigert: Formas gliales desprovistas de núcleo

• Santiago Ramón y Cajal:

• 1888, 89,90:
• Descripción de Neuroglías del SNC (capa granular del
Cerebelo vs. médula espina).
• Nodos de Ranvier en el SNC.
• Los nodos son el sitio donde se originan las colaterales.
• Las células gliales son ectodermales
• 1897: Hace referencia a células “estrelladas” (o
astrocitos, tomando la denominación de Lenhossék,
1895). Distingue glías fibrosas, protoplásmicas y
epiteliales.
~ 1900: Diversos estudios en múltiples zonas del SNC
y SNP

Fig. 173. — Trozo de un corte de la substancia gris del cerebro de un hombre adulto. Coloración por el
cloruro de oro. — A, tipo neuróglico grande; B, tipo neuróglico más pequeño; C, pie inserto en un
capilar; D, pirámide cerebral; a, capilar sanguíneo; b, pequeños pedículos perivasculares;d, células
satélites no neuróglicas Cajal > Recuerdos de mi vida > Sumario > Segunda parte, XXV. Centro
Virtual Cervantes. http://cvc.cervantes.es/ciencia/cajal/cajal_recuerdos/recuerdos/labor_25.htm#np5
•Cajal: Describe “Tercer Elemento” células que
no se tiñen y que solo se observan los
núcleos.

•1909: El eje centra es la prolongación del axón

de la neurona. La mielina es una capa externa,
de acuerdo con Remak. En el SNP es producida
por las células de Schwann, pero en el SNC, es
secretada por la Neurona.

• 1913: Descripción clara de los “podos” de

los astrocitos.

Fig. 175. — Substancia blanca del cerebro

humano. Método del sublimado oro. — A,
corpúsculo adendrítico; B, célula neuróglica
ordinaria, intensamente teñida en violado
purpúreo. Cajal > Recuerdos de mi vida >
Sumario > Segunda parte, XXV. Centro
Virtual Cervantes. http://cvc.cervantes.es/
ciencia/cajal/cajal_recuerdos/recuerdos/
labor_25.htm#np5

• Pío del Rio Hortega:

• Caracteriza 4 tipos de Glia,

incluyendo Microglías y
Oligodendrocitos

• W. Penfield (1932)

Alumno de Del Rio Hortega.

“La mantención de la mielina parece ser la función

principal de los oligodendrocitos

Del Rio-Hortega's four types of glia. A: Gray matter protoplasmic

neuroglia. B: White matter fibrous neuroglia. C: Microglia. D: White
matter interfascicular glia (oligodendrocytes) (Somjen 1988, Fig. 4).
Función de las
Neuroglías:
• Golgi (1886): Teoría
Nutricional: Existe
contacto entre las
dendritas y los capilares.
• Weigert (1895): Teoría de
“relleno” sin función.
• P. Ramón: Glías como
aislante (Cajal lo apoya,
pero luego desestima la
función en la Médula
Espinal por que hay
mielina).
• Cajal: Propone función
anti-tóxica y endocítica.
•Lugaro (1907): sugiere
múltiples roles de células
gliales: i guía axonal,
mantención y
detoxificación del
líquido intersticial. Papel
en la sinápsis como
moduladores/
terminadores/
capturadores de
Neurotransmisores. https://wiki.brown.edu/confluence/display/BN0193S04/History+of+Glia

Funciones de las células gliales

• Sostén físico (Virchow, Glia=>¿pegamento? más bien
“masilla”)
• Aceleración de la transmisión neural
– Vaina de Mielina (Oligodendrocitos y Células de Schwann)
• Sostén metabólico
– Remoción de neurotransmisores (astrocitos)
– Manteción del axón (oligodendrocitos)
• Protección
– Inducción y mantención de la Barrera hematoencefálica (BHE)
• Guía del desarrollo neural
– Glia radial
– Inducción de sinápsis.
 Astrocitos

Los astrocitos cumplen una gran variedad
de funciones. ¿Son una población
homogénea?
1. Población células más abundante del SNC
2. Neuroectodemales
3. Sostén metabólico de las neuronas (acumulación de Han et al
2013!
glicógeno, liberación de lactato, liberación de cuerpos Astrocito Fibrilar (sustancia blanca)
cetónicos)
4. Recaptura de Neurotransmisores (glutamato) Estimulación
Astrocitos Protoplásmicos del
(sustancia gris)
5. Producción de factores Neurotróficos (incluida la aprendizaje!
liberación de colesterol). (ratones con glias
6. Selección de Sinápsis durante el desarrollo. humanas)
7. Homeostasis de Iones (K+) y H2O (expresión de
aquaporinas)
8. Inducción de la BHE
9. Formación de cicatriz en caso de daño.
10. Regulación de la respuesta inmune en el SNC:
• Mediación de procesos inflamatorios.
• Función de Macrófagos

Fig. 171 A. — Células neuróglicas del cerebro del perro teñidas por el método del formol-urano. A, corpúsculo que
muestra el aspecto de los teñidos por el cromato de plata; B, pareja neuróglica, cuyas expansiones exhiben ciertos
granos glandulares (gliosomas). Cajal > Recuerdos de mi vida > Sumario > Segunda parte, XXV. Centro Virtual
Cervantes. http://cvc.cervantes.es/ciencia/cajal/cajal_recuerdos/recuerdos/labor_25.htm#np5
Fields et al. 427

Figure 1. A single astrocyte (pink) can ensheath tens of thousands of synapses; modulate synaptic transmission by the
release (red arrow) and removal (blue arrow) of neurotransmitters and neuromodulatory substances, and by controlling ion
concentration and modulating blood flow locally. Coupling of neurons into functional assemblies by astrocytes could increase
information processing and implicates astroglia in complex cognitive function, such as perception and memory. Modified from
Navarrete and Araque (2011).

regions of the brain are essential in all but the most rudi-
mentary forms of learning. Moreover, this broad spatial
integration is achieved across exceedingly wide tempo-
ral scales ranging well beyond the millisecond to sec-
onds of electrical signaling in neurons, to encompass
instead hours, days and months, which are well suited to
Los Astrocitos forman un sincicio coordinado por la presencia
the temporal dynamics of glial communication and
plasticity. de Uniones en hendidura y ondas de Calcio
Connecting All the Parts: Glia in
Spatial Integration
All types of glia can respond to and influence neurotrans-
mission in several ways. The three major glial cell types
in the brain, astrocytes, oligodendrocytes and microglia,
communicate with each other and with neurons by using
neurotransmitters, other small molecules, and gap junc-
tions. Oligodendrocytes greatly increase the speed of
electrical transmission through nerve axons by forming
the axonal myelin sheath and clustering ion channels at
nodes of Ranvier where action potentials are generated
(Nave 2010). Microglia prune synapses in part by moni-
toring synaptic transmission (Wake and others 2013),
thus they rewire neural connections in accordance with
neuronal function (Schafer and others 2012). Astrocytes
can regulate synaptic transmission between neurons by
modifying the concentration of extracellular potassium,
controlling local blood flow, releasing and taking up neu-
rotransmitters and other neuromodulatory substances,
delivering nutrients to neurons, and altering the geometry
and volume of extracellular space between brain cells; all
of these could coordinately couple neurons into func-
tional assemblages.
The large spatial domain over which astrocytes and
oligodendrocytes can couple and regulate neuronal activ-
ity is at odds with traditional thinking of learning where
synapse-specific modification is paramount. Restricting
plasticity mechanisms to individual synaptic connections
is thought to increase the capacity for information storage
and learning, but global changes may help organize the
memory, and in a combinatorial manner increase storage
capacity. If astrocytes modulate synaptic strength and
couple domains of synapses into functional assemblies,
the degrees of freedom for information storage are multi-
plied beyond synapse-specific coding (Fig. 1). Astrocytes
do have anatomical and physiological properties that may
impose a higher order organization on information pro-
cessing in the brain. The volume of human astrocytes is

Verkhratsky y Toescu
J. Cell Mol. Med. (10) 2006
 non-overlapping anatomical domains. In fact, it has been a
estimated that a single astrocyte can associate with mul-
tiple neurons, Neuron and over 100,000 synapses [2, 10] (fig. 1).

Two photon Review confocal time-lapse imaging studies are re-

vealing aVerkhratsky
dynamic and coordinated
y Toescu J. Cell Mol. interplay
Med. (10) between
2006 as-
trocytic processes and dendritic spines in regions of syn-
aptic activity, suggesting astrocytes, like neurons, can rap-
Figure 1. View of the Organization of
Astrocytes in Nonoverlapping Anatomical

idly respond to environmental cues to influence synaptic

Territories and Their Close Association to
Neuronal Dendrites Sin embargo, aún en este
(A) View of two neighboring astrocytes in the CA1
structure and function. Although incapable of firing ac- area of hippocampus labeled with different col-
ored fluorescent dyes (Alexa 488, green; Alexa
sincicio, cada astrocito es
tion potentials, astrocytes secrete a wide array of neuroac- 568, red). The elaborate and dense processes of
each astrocyte do not overlap, and peripheral dominante en una zona y
tive ‘gliotransmitters’ and trophic factors, and they express fine terminal processes interdigitate with one
another (yellow). Pyramidal CA1 neurons appear regula el metabolsimo
many of the same channels, receptors, and cell surface in blue.
(B) View of an astrocyte (green) extending its highly sobre las neuronas que
molecules that neurons do [3, 5, 11]. Together these find- ramified processes in close proximity to a CA1
neuronal dendrite (red). These processes can
rodea. La sobreposición
ings place astrocytes in a central position to actively signal
cover most synapses in the astrocyte domain.

parece ser poca.

Panel (A), courtesy of M.H. Ellisman; panel (B),
modified from Fiacco and McCarthy (2004).
with neurons to coordinate developing neural circuits.
One of the first clues that immature astrocytes might
play an instructive role in developmental plasticity of
neural circuitsAgulhon
cord. came from
et al. (2008)
The morphology aNeuron
study
of an astrocyte in59,1989
resembles bywithMuller
September
a bush andinternal stores, most of them being G -coupled
2008from
zation q

Best [12]processesthat found that injection of immature astrocytes

radiating out from a central cell body (Figure 1A). GPCRs (G GPCRs). While these receptors can be experimen-
q
Within the CA1 stratum radiatum of the hippocampus, an individ- tally activated in situ by exogenous application of agonists (Por-
into theualadult visual
astrocyte cortex
has a soma diameter ofofcats
3
7–9 mm reopened the ter
and, with its fine window
and McCarthy, 1995a, 1995b), they are also activated by neu-
processes, occupies a volume of !66,000 mm (Bushong et al., rotransmitters released from presynaptic terminals (Araque
of ocular2002). dominance (OD) plasticity,
Interestingly, individual astrocytes tendatowell-characterized
occupy dis- et al., 2002; Kang et al., 1998; Navarrete and Araque, 2008; Pasti
form of experience-dependent synaptic remodeling. If vi-
tinct, nonoverlapping domains (Figure 1A) (Bushong et al., et al., 1997; Perea and Araque, 2005; Porter and McCarthy,
2002). The fine processes of an individual astrocyte are con- 1996). This finding is relevant because it demonstrates the exis-
ical domains. In sion
fact, itishas
restricted
been to one
nected a to onlythrough
another one reflexive
eye early in development,
gap junctions the
and to tence of neuron-to-astrocyteb communication and that astrocytic
strocyte can associate with other mul-astrocytes via gap junctions at their boundaries. Patch- G GPCRs appear to be a primary link between neuronal activity
territories
100,000 synapses [2, 10] (fig.
(OD columns) innervated by the deprived eye q

1). a single astrocyte with an electrode filled with a gap- and astrocytic Ca elevations. Evidence for a reciprocal effect
clamping 2+

me-lapse imagingshrink dramatically, whereas those innervated by the

junction-permeable dye rapidly leads to the filling of hundreds, of astrocytes on synaptic transmission through the G GPCR-
studies are re- 2+
if not thousands, of astrocytes (Konietzko and Muller, 1994). As- mediated Ca -dependent release of neuroactive molecules
q

non-deprived
oordinated interplay between as- likely
trocytes eye expand.
function as a syncytiumAfter thisessentially
contacting ‘critical period’,
all (called gliotransmitters) was reported in vitro and in situ when
endritic spines in regions ofother syn-cellular elements in brain, including neurons, oligodendro- G GPCR agonist application elicited Ca increases in astro-
2+

monocular
astrocytes, like neurons, cancytes, deprivation
+ is normally unable q
to induce
rap- NG2 cells, microglia, and vasculature. A striking feature cytes, which ODcorrelated to changes in neuronal ionotropic gluta-
plasticity,
mental cues to influence synaptic but transplantation of astrocytes derived from
of astrocytes is that processes from a single astrocyte can en- mate receptor (iGluR) activity (Parpura et al., 1994; Pasti et al.,
velop approximately 140,000 synapses (Figure 1B) (Bushong 1997). Since these reports, several laboratories have reported
Although incapable of firing
newborn ac-
kittens
et al., was
2002), while >99% sufficient to reintroduce
of the cerebrovascular surface is en- OD
2+
that Caplas- elevations in a small fraction of astrocytes and under
s secrete a wide array of neuroac-
sheathed by astrocyte processes (Kacem et al., 1998; Rama certain conditions in situ can result in the release of gliotransmit-
ticity in
d trophic factors, and they expressadult animals [12] . This was a surprising finding
Rao et al., 2003; Simard et al., 2003; Haydon and Carmignoto, ters, including glutamate, ATP, and D-serine, that bind to pre-
at the
nels, receptors, and cell time,
surface as astrocytes were generally thought to play a
2006; Takano et al., 2006). In addition to the diversity among as- and/or postsynaptic neuronal receptors to modulate synaptic
trocytes, there may be substantial diversity within individual as- transmission and activity (Bezzi et al., 1998; Fiacco and McCar-
do [3, 5, 11]. Together these
passive, find-
supportive
trocytes with respectrole at the with
to interactions synapse.
the local environment. thy, 2004; Kang et al., 1998; Lee et al., 2007; Mothet et al., 2005;
central position to actively signal
For instance, it is possible that, within a single astrocyte, a subset Navarrete and Araque, 2008; Pascual et al., 2005; Serrano et al.,
ate developing neuralMuller
circuits. [13] proposed that ‘structural
of processes interacts autonomously with a neighborhood changes in Yang
of 2006; neu-et al., 2003). Thus, it appears that astrocytes in situ
ronal connectivity
that immature astrocytes might
neuronal synapses,
withof
canwhilebeotherinfluenced or
regions of that astrocytemediated
interact not by glial
only listen and react to ongoing neuronal activity but also
different groups of synapses or with other cellular elements, have the ability to modulate this activity via the release of
in developmental plasticity
cells via such release
m a study in 1989 by Mullerconditions,
and
as theof growth or growth
cerebrovasculature. permissive
Further, under physiological factors on The recognition of the bidirectional communi-
gliotransmitters.

neuronal
injection of immature an activation,
astrocytes astrocyte may not andalwaysbycommunicate
active displacement
with one another. and sub-of the ‘‘tripartite synapse’’ (Figure 2), in which the as-
these local regions of interaction (microdomains) of cation between neurons and astrocytes at the synapse led to
the concept
sequent
tex of cats reopened the window elimination
Understanding how theofdifferent
axonal boutons’.
microdomains Muller
of astrocytes in- and
trocyte,Best
in addition to pre- and postsynaptic compartments, is
D) plasticity, a well-characterized
teract with neighboring cellular elements will be critical to deter- a functional component of the synapse. A primary focus of this
[12] further
ndent synaptic remodeling. mining hypothesized
If vi- their role in neurophysiologythatand immature
neuropathology. astrocytes revieware a recent findings that have shaped our current
is to discuss
2+
requisiteNeuron-Astrocyte
one eye early in development, for
the visual b cortical
Interactions plasticity, and that the end of
understanding of the role of astrocyte G GPCR-mediated Ca
elevations
q
on neuronal-astrocyte communication, focusing on
) innervated by thethedeprived
criticalThe eye periodofisastrocytes
morphology linked placestothem
thein amaturation
unique situation of the astro- Fig. 1. Protoplasmic
concept of ‘‘gliotransmission’’ and discussing astrocytes
both the are intimately associated with
hereas those innervated byto the “ittohas
be able to listen been
and respond estimated
to most cellular elements.that a single
As- issues astrocyte
that are well accepted andacan
synapses. onesassociate
Protoplasmic
the with
astrocyte
that are currently in mul-
of CA1tiple neurons,
region of rat hippo-
cytes. Consistent
nd. After this ‘critical period’, with this idea, chondroitin
2+
trocytes exhibit a large number of GPCRs linked to Ca mobili- dispute. sulfate pro-
and over 100,000 synapses” campus filled with Lucifier Yellow dye revealed thousands of
s normally unable teoglycans
to induce OD(CSPGs), extracellular matrix proteins pro-
dense spongiform processes that ensheath synapses (provided by
ation of astrocytes derived
duced byfrommature astrocytes, are inhibitory for experience- Neuron 59, September 25, 2008 ª2008 Elsevier Inc. 933
fficient to reintroduce OD plas- Fig. 1. Protoplasmic astrocytes are intimately Eric Bushong [2]).
associated b Electron
with synapses. micrograph of the ‘tripartite syn-
a Protoplasmic
dependent
2]. This was a surprising findingplasticity.
astrocyteEnzymatic of CA1 region degradation
of rat hippo- of CSPGs campus apse’
filledin the with rodent
Lucifierbrain,Yellow showingdye several synapsesthousands
revealed (arrows) en-
reactivates
were generally thought to play aOD plasticity in the adult visual cortex [14]. sheathed by astrocytic processes (blue). From Kristen Harris
of dense spongiform processes that ensheath synapses (provided by Eric Bushong [2]). b
at the synapse.
OD plasticity is likely mediated by both the elimina- http://synapse-web.org/anatomy/astrocyte/Astrocyte.stm.
that ‘structural changes in neu- Electron micrograph of the ‘tripartite syn- apse’ in the rodent brain, showing several synapses
tion ofbysynaptic
e influenced or mediated glial
(arrows) inputs en-from sheathed the deprived eye, andprocesses
by astrocytic the (blue). From Kristen Harris http://synapse-
expansion
h or growth permissive factors on and formation of new synapses by inputs from
by active displacement and sub- web.org/anatomy/astrocyte/Astrocyte.stm.
the open
xonal boutons’. Muller eye. While the specific astrocyte-derived signals
and Best Stevens B. Neurosignals 2008;16:278–288
d that immature that mediate
astrocytes are a the reinduction of OD plasticity are not yet
cal plasticity, and that the end of
ked to the maturation of astro- Fig. 1. Protoplasmic astrocytes are intimately associated with
his idea, chondroitin sulfate pro- synapses. a Protoplasmic astrocyte of CA1 region of rat hippo-
campus filled with Lucifier Yellow dye revealed thousands of
racellular matrix Neuron-Astrocyte
proteins pro- denseSignaling during
spongiform processes that ensheath synapses (provided by
Neurosignals 2008;16:278–288 279
tes, are inhibitoryDevelopmental
for experience- Plasticity
Eric Bushong [2]). b Electron micrograph of the ‘tripartite syn-
 Ciclo de Glutamina-Glutamato

1 mM
Δt= ms

Ca+2

Neuroscience (2d Ed) 2001

Purves; Augustine; Fitzpatrick; Katz; Lamantia; Mc Namara; Williams
 Cascada Isquémica
Acumulación de
Iones (Ca+2 entre
otros)
Liberación de
glutamato
Baja de Oxígeno
Disminución de ATP
O2 ATP
Glutamato
Glutamato
Ca
Na/K atp- +2
asa

Depolarización Glutamato
Pro-Inflamatorios

de la membrana
Factores

Canales NMDA.
Entra Ca+2
Ca+
2

Activación de fosfolipasas, calpaína, endonucleasas.

Aumento de radicales libres. Ruptura de membranas,

Excitotoxicidad Neuronal
La sobreactivación de los receptores ionotrópicos
de glutamato (rNMDA y rAMPA) aumenta las
concentraciones intracelulares de Ca+2.. Esto
Ca+
2

induce:

• Activación de fosfolipasas,
Canales NMDA. endonucleasas, y proteasas (ej:
Entra Ca+2 calpaína).
• Acumulación de Ca en la mitocondria
(inhibe ATP e induce liberación CitC)
• Aumento de radicales libres.
• Ruptura de membranas,
• Muerte Celular

!22
http://cnc.cj.uc.pt/~cbduarte/Excitotoxicity.htm
 Regulación del metabolismo de glutamato
Atención, esto
significa que los
astorcitos están
cargados de glutamato.
¿Qué es la
excitotoxicidad?

Magistretti et al. Science, 1999

Otras consideraciones importantes con

respecto a los Astrocitos
¿Cuál es la diferencia celular del genero Homo con respecto a
otros mamíferos?
– Estructuras Neuronales son similares entre muchos
• Densidad de contactos sinápticos es similar entre humanos y roedores (1100-1300
mill/mm3)
• Núm de Neuronas, directamente proporcional al tamaño.
– Células gliales
• Los humanos presentan cell gliales más grandes: astrocitos, 2.75x con vol=27X, y
mucho más ramificados (40 ramas versus 3 en roedores).
• Astrocitos humanos contactan 2 millones de sinapsis c/u, vs. 100.000 en roedores
• Aparición de astrocitos interlaminares, un nuevo grupo de células gliales que
conectan diferentes capas de la corteza. Podrían estar involucrados en procesos de
integración translaminar.
 Protoplasmic astrocytes are
larger and more complicated
than the rodent counterpart

Protoplasmic astrocytes are larger and more

complicated than the rodent counterpart. A,
Typical mouse protoplasmic astrocyte. GFAP,
White. Scale bar, 20 µm. B, Typical human
protoplasmic astrocyte in the same scale.
Scale bar, 20 µm. C, D, Human protoplasmic
astrocytes are 2.55-fold larger and have 10-
fold more main GFAP processes than mouse
astrocytes (human, n = 50 cells from 7
patients; mouse, n = 65 cells from 6 mice;
mean ± SEM; *p < 0.005, t test). E, Mouse
protoplasmic astrocyte diolistically labeled
with DiI (white) and sytox (blue) revealing the
full structure of the astrocyte including its
numerous fine processes. Scale bar, 20 µm.
F, Human astrocyte diolistically labeled
demonstrates the highly complicated network
of fine process that defines the human
protoplasmic astrocyte. Scale bar, 20 µm.
Inset, Human protoplasmic astrocyte
diolistically labeled as well as immunolabeled
for GFAP (green) demonstrating
colocalization. Scale bar, 20 µm.

Oberheim N A et al. J. Neurosci. 2009;29:3276-3287

Human fibrous astrocytes

are significantly larger than
in rodent.

A, Mouse fibrous astrocyte in white

matter. GFAP, White; sytox, blue.
Scale bar, 10 µm. B, Human fibrous
astrocytes in white matter. Scale
bar, 10 µm. C, Human fibrous
astrocytes are ∼2.14-fold larger in
diameter than the rodent
counterpart. *p < 0.0001, t test. D,
Human fibrous astrocyte labeled
with DiI revealing the full structure
of the cell. DiI, Red; sytox, blue.
Scale bar, 10 µm. E, Mouse fibrous
astrocyte labeled with DiI. Scale
bar, 10 µm.

Oberheim N A et al. J. Neurosci. 2009;29:3276-3287

There are four classes of GFAP+ cells in
the human cortex.

Human brains were immunolabeled

with GFAP and analyzed throughout
all layers of the cortex to determine
subclasses of human astrocytes.
Layer 1 is composed of the cell
bodies of interlaminar astrocytes,
whose processes extend over
millimeter lengths through layers 2–4
and are characterized by their
tortuous morphology. Protoplasmic
astrocytes, the most common,
reside in layers 2–6. Polarized
astrocytes are found only in humans
and are seen sparsely in layers 5–6.
They extend millimeter long
processes that are characterized by
varicosities. Fibrous astrocytes are
found in the white matter and contain
numerous overlapping processes.
Yellow lines indicate areas in which
the different classes of astrocytes
reside. Scale bar, 150 µm.
Oberheim N A et al. J. Neurosci. 2009;29:3276-3287
 Otras consideraciones importantes con
respecto a los Astrocitos

• Colombo JA, Reisin HD. Interlaminar astroglia of the cerebral cortex: a marker of the primate
brain. Brain Res 2004; 1006: 126–131

• Oberheim NA, Wang X, Goldman S, Nedergaard M. Astrocytic complexity distinguishes the

human brain. Trends Neurosci. 2006; 29: 547–553.

• Sherwood CC, Stimpson CD, Raghanti MA, Wildman DE, Uddin M, Grossman LI et al.
Evolution of increased glia-neuron ratios in the human frontal cortex. Proc Natl Acad Sci USA
2006; 103: 13606–13611.

• Han X,et al. Forebrain engraftment by human glial progenitor cells enhances synaptic
plasticity and learning in adult mice. Cell Stem Cell. 2013 Mar 7;12(3):342-53. doi: 10.1016/
j.stem.2012.12.015. PubMed PMID: 23472873; PubMed Central PMCID:PMC3700554.
Ejemplo “sencillo”, las células de Müller
Astrocitos especializados de la retina de mamíferos.
Estados Normales

C Giaume et al, (2007) Cell Death and differentiation

Estados patológicos desencadenados por injuria externa

resultan en daño a los fotoreceptores y a toda la arquitectura
de la retina.

Reactive Down-
regulation K-Ch

C Giaume et al, (2007) Cell Death and differentiation

Estados patológicos desencadenados por injuria externa
resultan en daño a los fotoreceptores y a toda la arquitectura
de la retina.

La proliferación y la migración de las células de Müller resultan en una gliosis reactiva

detrimental . El aumento de proliferación genera fuerzas mecánicas que llevan a la formación de
dobleces y desprendimientos (vitreoretinopatía proliferativa).

C Giaume et al, (2007) Cell Death and differentiation

Daño y Cicatriz Glial

• Proliferación de los
astrocitos
• Acumulación de glicógeno
• Fibrosis: aumento de los
filamentos intermedios
(GFAP ppal%)
• Evento parcial: permite la
regeneración de otros
componentes (epitelio
coroídeo, mielina)
• Evento total: excluye todos
los otros componentes y
forma una cicatriz

WilhelmssonPNAS November 14, 2006 vol. 103 no. 46 17513-17518

 Trauma: Lesión por un agente mecánico
Trauma: Lesión por un agente mecánico
• Respuesta sistémica
• Respuesta glial
• Respuesta Inmune

En EEUU
•10,000 a 12,000 lesiones a la columna por año
•250.000 personas viven con daño.
•38.5% ocurren en accidentes de automóviles.
•55% de las víctimas tienen entre 16 y 30 años
•Más del 80% son hombres
 !37

Trauma: Lesión por un agente mecánico

Trauma: Lesión por un agente mecánico
1. Daño Primario (producto de
golpes, tracciones, compresiones y los
fragmentos óseos)
• Compresión directa de elementos
neurales. Daños neuronales
• Daño capilar y hemorragias
• Edema inicial (pocos minutos), resulta
en isquemia y daño secundario al tejido.
• Pérdida de equilibrio iónico genera
daño secundario
2. Daño Secundario:
• Edema e inflamación de la médula
espinal (que llena el canal espinal y
comprime todo el tejido) dan origen a
hipo-perfusión e ISQUEMIA.
• Células dañadas liberan factores
neurotóxicos (y oligodendro-tóxicos) y
que reclutan al sist. inmune.

•
 Trauma: Lesión por un agente mecánico
Trauma: Lesión por un agente mecánico
1. Daño Primario (producto de
golpes, tracciones, compresiones y los
fragmentos óseos)
• Compresión directa de elementos
neurales. Daños neuronales
• Daño capilar y hemorragias
• Edema inicial (pocos minutos), resulta
en isquemia y daño secundario al tejido.
• Pérdida de equilibrio iónico genera
daño secundario
2. Daño Secundario:
• Edema e inflamación de la médula
espinal (que llena el canal espinal y
comprime todo el tejido) dan origen a
hipo-perfusión e ISQUEMIA.
• Células dañadas liberan factores
neurotóxicos (y oligodendro-tóxicos) y
que reclutan al sist. inmune.

•
Objetivos:
1. Reducir la muerte
neuronal
2. Promover la
regeneración de
axones
3. Promover eventos
de re-inervación
compensatoria.
4. Prevenir la
desmielinización
5. Rehabilitar al
individuo

Una Diferencia fundamental es la capacidad de regeneración:

Poliak & Pelles, (2003) Nature Rev Neuros 4:968

 Daño al axón

Poliak & Pelles, (2003) Nature Rev Neuros 4:968

Formación de cicatríz glial (astrocitos). No se

eliminan los restos de la mielina donde existen
inhibidores del crecimiento axonal: MAG,
NoGO, OMgp

Degeneración de las CS desinervadas,

manteción de la lámina basal, proliferación de
precursores, migración de cono axonal

Poliak & Pelles, (2003) Nature Rev Neuros 4:968

¿Inhibidores de la regeneración axonal?
Superar las señales de los
inhibidores de la regeneración
es solo el primer paso de un
problema muy complejo. 

Si logramos que los axones
atraviesen la lesión o la cicatriz
glial, aún deben ser guiados a
sus blancos y mantener la
capacidad de formar sinápsis
funcionales.
Aún así, el primer paso es que
los axones crezcan

Marie T. Filbin
(traducción extremadamente
libre)

Nature Reviews Neuroscience 4, 703-713 (September 2003)

Podios de Astorcitos y la Barrera

hematoencefálica (BHE)
• Lewandoski (1900): “Los capilares cerebrales evitan la entrada de algunas sustancias” (tinciones y
toxinas).
• Barrera selectiva en el endotelio microvascular cerebral caracterizada por la presencia de amplias
uniones estrechas y la ausencia de fenestraciones.
• Los capilares son rodeados por prolongaciones de los astrocitos (glia limitans) los cuales inducen
la formación de uniones estrechas de mayor resistencia .
• Concentración de factores plasmáticos = 1/200 del presente en sangre (Igs, Complemento).
• Los podios de los astrocitos presentan transportadores de glucosa, acuaporinas y canales de
potacio, Existe evidencia que modulan el flujo sanguíneo a diferentes zonas del cerebro de
acuerdo a los requerimientos metabólicos.
 Astrocytic end feet in
rodents and humans.
A, Cortical blood vessel in rat.
GFAP, White; nuclei (DAPI), blue.
Scale bar, 20 µm. B, GFAP in end
feet forms rosettes on the vessel in
the rat. Scale bar, 10 µm. Yellow
circles indicate individual end feet.
C, Human protoplasmic astrocytes
extend processes to the
vasculature. Scale bar, 20 µm. D,
Yellow box seen in C. GFAP in end
feet completely covers the
vasculature. Yellow circles indicate
individual end feet. Scale bar, 10
µm. E, Transverse section of blood
vessel and human astrocyte end
feet. Scale bar, 20 µm. F, Electron
micrograph of aquaporin 4
immunohistochemistry of the
astrocytic end foot on a capillary
(Cap.). Note the presence of
mitochondria in the end foot of the
astrocyte.

Oberheim N A et al. J. Neurosci. 2009;29:3276-3287

•MRI: permite detectar la diferencia que se genera en

el spin de los átomos de hidrógeno en la medida que
estos son alineados y des-alineados en un campo
magnético.

•Functional magnetic resonance imaging

(fMRI):Detecta la diferencia entre hemoglobina
oxigenada y no-oxigenada, lo cual se asocia a mayor
actividad neuronal, pero realmente el cambio es
mediado por astocitos.

• PET (tomografía de emisión de positrones): el

acoplar un electrón de carga positiva (positrón) a
una molécula de glucosa (en un ciclotrón, por
ejemplo Fludeoxyglucose (18F)). El decaimiento del
positrón genera una señal. Da una idea de las zonas
donde se absorbe más glucosa.
Cel. Endotelial • Doble lámina basal (célula
endotelial y astrocitos).

Lámina Basal (1) capilar • Los astrocitos poseen una

Lámina Basal (2)
astrocito
Uniones Estrechas
impresionante batería
metabólica que les permite:
detoxificar (C-P450) ,
degradar todos los ácidos
grasos a Acetil-CoA y
entregarlos como cuerpos
cetónicos (excepto a.g.
esenciales)

• La BHE presenta una

resistencia eléctrica de 1300
Ω/cm2 (10X capilares extra
neurales).

• ¿Como ocurre la
extravasación de leucocitos?

Hawkins y Davis (2005) Pharmacol Rev.57:173

La BHE no es permisiva al
traspaso celular, este ocurre en las
Vénulas post-capilares.



(por lo tanto, cuidado con los trabajos que
sugieren que la inflamación rompe la BHE
producto de la infiltración leucocitaria)

 La señal de apoptósis para los
linfocitos T generada por los
astrocitos conforma UNA parte de Señal pro-apoptótica
los mecanismos de privilegio inmune FAS-L
del SNC.

Espacio de Virchow-Robin

Membranas Basales

Endotelio

Vénula
Media

Bechmann et al 2007 Trends in Immunology 28 (1):5-11

FADD: Fas-associated death domain

RIP: Receptor interacting protein.
DISC: death-inducing signal complex (caspasa 8 activada, que activa a caspasas ejecutoras de
aposptosis: caspasa-3 y -7)
C-FLIP: (FADD-like inhibitory protein) Green y Fergusson, (2001) ,
Nature Reviews Molecular Cell Biology 2, 917-924
 Proceso Inflamatorio: pérdida de privilegio inmune.

• Alta concetración de citoquinas recluta un gran número de células T.

• Ruptura de BHE puede diluir a los inhibidores
• Mediadores pro-inflamatorios inducen sensibilización de astrocitos a FAS-L,
abriendo espacio para la infiltración.
• Respuesta a FAS-L puede ser inhibida en leucocitos, permitiendo el paso a
través de glia limitante.

Neuroinmunología
Resumen

Sistema
Inmune
¿Cómo limitar el daño a un órgano muy
sensible y que presenta bajos niveles de
Sistema Nervioso
regeneración?