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Fig. 46.2 P14 Purkinje cells expressing calbindin (red) and NT3
(green)
both showed increased granule cell death. The reduced number of CGNs would likely decrease the trophic support available to the Purkinje cells, including the secretion of
neurotrophins. Additionally, the electrical stimulation provided by the parallel bers of the CGN has proven to be
crucial for Purkinje cell dendritic development (Morrison
and Mason 1998; Hirai and Launey 2000). Therefore, in a
situation with reduced granule cell survival, a decrease in
electrical stimulation of Purkinje cells would be expected,
with a consequent effect on dendritic maturation.
NT-3 also plays an important role in the morphological
development of Purkinje cells. NT-3 can promote Purkinje
cell differentiation in culture and invivo (Lindholm etal.
1993a). Moreover, in vivo studies using sparse deletion of
TrkC from Purkinje cells in combination with NT-3 deletion
from granule cells demonstrated that Purkinje cells compete
for a limiting amount of NT-3 produced by the granule cells
to induce Purkinje dendritic morphogenesis in a TrkCdependent manner (Joo etal. 2014) (Fig.46.2).
46.1.4.2 BDNF/TrkB inGranule Cell
Dierentiation
Although BDNF and TrkB remain expressed in the internal
granule layer of adult animals, understanding of the specic
function of this signaling complex is very limited. BDNF
and NT-4, but not NT-3 or NGF, promoted neurite extension
in the granule cells, and this effect was blocked by the tyrosine kinase inhibitor, K-252a. Interestingly, no additive
effects with the combination of BDNF and NT-4 were
observed, conrming that both neurotrophins act via TrkB
(Gao etal. 1995).
In the developing cerebellum, granule cell maturation
depends on changes in the composition of NMDA receptors,
J. P. Zanin and W. J. Friedman
where the NR2B subunit is switched for NR2C.This receptor modication plays an important role in the establishment
of functional granule cell-mossy ber synaptic transmission
in the adult cerebellum. BDNF can upregulate NR2C mRNA
via TrkB activation of the ERK 1/2 (extracellular signalregulated kinase) signaling pathway, promoting the maturation of the cerebellar network (Suzuki etal. 2005).
46.1.5 Eects ofNeurotrophins inCerebellar
Circuit Establishment
andMaintenance
46.1.5.1 BDNF/TrkB inClimbing Fiber
Maturation
Early in cerebellar development, Purkinje cells are initially
innervated by multiple climbing bers which is then rened
such that one of these synapses is strengthened, while the
rest are eliminated to assume the mature nal ratio of one
climbing ber per Purkinje cell. Unlike what has been
observed in other synapses, TrkB is necessary for the pruning of the excess climbing bers (Johnson et al. 2007).
Moreover, BDNF produced by the Purkinje cell facilitates
the elimination of the excess synapses in a mechanism that
involves retrograde TrkB signaling in the climbing bers
(Choo etal. 2017).
46.1.5.2 p75NTR inAdult Cerebellum
p75NTR is highly expressed in proliferating granule cell
progenitors and is absent from postmitotic, mature granule
cells. However, p75NTR is also expressed in Purkinje cells,
where it remains present through adulthood (Carter et al.
2003; Zanin etal. 2016). In addition to the effects of TrkB
and TrkC, p75NTR has also been linked to the maturation of
the Purkinje cell dendritic tree, with aberrant arborization in
the absence of p75NTR.However, in adult animals, the role
of p75NTR in Purkinje neurons remains largely undetermined. Purkinje cell spontaneous activity can be divided into
tonic ring (with a relatively constant rate) or phasic ring
(intermittent activity with variable length pauses).
Spontaneous activity of Purkinje cells from p75NTR−/−
exhibits an increased mean ring rate in the tonic phase.
Purkinje cells from p75NTR −/− animals showed reduced
activation of Rac1, which reduced SK (Ca2+-activated potassium) channel function, which is important to maintain synaptic activity and regulate the spontaneous activity of
Purkinje cells (Tian etal. 2014). Thus, in contrast to granule
cells, p75NTR has a continuing role in the function of mature
Purkinje cells.
46.1.5.3 Cerebellar Interneurons
Few studies have investigated the trophic requirements of the
inhibitory interneurons of the cerebellum. Deletion of TrkB
46 Neurotrophic Factors inCerebellar Development andFunction
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303
from the CNS did not affect Purkinje cell development; however, these animals had a reduction of GABAergic markers
and reduced GABAergic boutons in inhibitory interneurons
(Rico etal. 2002). Moreover, treatment of cerebellar explants
with BDNF and NT-4 promoted the development of inhibitory synapses onto Purkinje cells (Seil 1999; Seil and Drakebaumann 2000). Additionally, chronic BDNF treatment of
cerebellar slices resulted in a drastic decrease in the numbers
of parvalbumin-positive cells (Koscheck etal. 2003).
In cultures of postnatal cerebellar granule cells, BDNF
signicantly accelerated the expression of GABA receptor a6 mRNA, suggesting that BDNF might modulate the
maturation of GABAergic synapses in the cerebellum
(Bao etal. 1999). Using conditional KO mice for BDNF,
mossy bers (from cells outside of the cerebellum) were
identied as one of the sources of BDNF in the
IGL. Although deletion of BDNF from the cerebellum
itself did not affect the maturation of GABAergic synapses in the IGL, specic deletion of BDNF from mossy
bers resulted in decits in the Golgi- Granule cell connectivity affecting the establishment of inhibitory circuits
in adult mice (Chen etal. 2016).
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The Cerebellar Neuroimmune System
https://t.me/medicina_free
DonnaL.Gruol
47
Abstract
Emerging research has revealed that glial cells of the
brain can produce many of the same signaling factors as
cells of the peripheral immune system and, as such, can
function as a brain immune system, referred to as the neu-
roimmune system. Both neurons and glial cells of the
brain express receptors and intracellular signaling path-
ways that can interpret the signals communicated by these
factors, which are called neuroimmune factors when pro-
duced by brain cells, and in response adjust their function.
The neuroimmune system serves many roles both in nor-
mal brain biology and in brain pathology. To date, the
majority of studies on the characteristics and function of
the neuroimmune system comes from brain regions out-
side of the cerebellum, but recent studies of the cerebel-
lum have shown that the neuroimmune system plays an
important role in cerebellar development, function, and
disease. This new and expanding area of research will
likely bring greater understanding to the cellular and
molecular mechanisms that mediate cerebellar function.
Keywords
Neuroimmune factor · Cytokine · Chemokine · Astrocyte
Microglia · Signal transduction · Neuroinammation
Development
system of the brain. The neuroimmune system is not only a
critical homeostatic regulator of brain development and
function, contributes to repair and recovery processes during
pathological conditions, but can also be an active player in
pathology by contributing to cell damage and impaired brain
function.
Astrocytes and microglia are the primary cell types that
comprise the neuroimmune system of the brain and are distributed throughout the brain. However, in the cerebellum,
microglia are more populous in gray matter than white matter, whereas the opposite is the case for other brain regions
(Lawson etal. 1990). Also, the density of microglia in the
cerebellum is lower than for other brain regions that have
been studied (e.g., the cortex), and lower than the mean level
for the brain in general (Lawson etal. 1990; Stowell etal.
2018). Recent studies show that astrocytes and microglia in
different brain regions have many characteristics and functions in common, but they also have properties that are
unique to the brain region and local microenvironment that
they are associated with (Araujo et al. 2019; Kana et al.
2019; Stoessel and Majewska 2021).
Several types of astrocytes populate the cerebellum
(Fig.47.1) (Cerrato 2020). The Bergmann glia are considered
47.1 The Neuroimmune System
oftheCerebellum
As in other brain regions, glial cells of the cerebellum play
many roles essential for normal cerebellar development and
function, including as key components of the neuroimmune
D. L. Gruol (*)
Neuroscience Department, The Scripps Research Institute,
La Jolla, CA, USA
e-mail: gruol@scripps.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_47
Fig. 47.1 Diagram illustrating glial cell types of the cerebellar neuroimmune system
305
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D. L. Gruol
a specialized type of astrocyte and are unique to the cerebellum. Bergmann glia are large cells with cell bodies situated
between the Purkinje neuron and molecular layers and prominent processes that extend into the molecular layer. The processes of the Bergman glia have a close functional relationship
with Purkinje neuron dendrites, especially at synaptic sites,
and play an important regulatory role in synaptic function
(Bellamy 2006). Astrocytes located in the granule neuron
layer and cortical region are considered velate protoplasmic
astrocytes and have highly branched bushy processes. Velate
astrocyte processes are in close contact with mossy ber to
granule neuron synapses where they play an important role in
dening the structure of the synapses and controlling the diffusion of neurotransmitters and other signaling factors (Araujo
et al. 2019). Fibrous astrocytes are present in the cerebellar
white matter and are characterized by straight long processes.
Microglia are commonly viewed as resident macrophages
of the brain. They serve important surveillance and phagocytic
functions that maintain the brain pathogen and debris- free,
consistent with immune function (Hickman et al. 2018).
Microglia are mobile, constantly survey the brain parenchyma,
and provide the rst line of defense against pathogens and
other detrimental conditions (e.g., injury). In contrast, astrocytes are often considered to be supportive in nature, as evidenced by their role in providing structural and nutritional
support for neurons and glia, and as regulators of the blood–
brain barrier and the extracellular environment. However, it is
now evident that both microglia and astrocytes act as brain
immune cells, both have a role in normal and pathological
conditions, and both contribute to many aspects of normal
brain function and development often with overlapping or
complementary actions. For example, in the healthy brain,
both cell types have essential roles in synaptogenesis, renement of synaptic structure, establishment of brain architecture,
regulation of synaptic transmission and plasticity, and as engineers in the recovery processes after injury or other adverse
conditions (Nedergaard et al. 2003; Colonna and Butovsky
2017; Verkhratsky and Nedergaard 2018; Cunningham etal.
2019; Wright-Jin and Gutmann 2019; Vainchtein and
Molofsky 2020). Many of these actions reect the neuroimmune functions of glial cells in that they are accomplish
through the production and action of neuroimmune factors,
which are a large group of signaling factors that are identical
to many of the immune factors produced by the peripheral
immune system. Both astrocytes and microglia can produce
similar neuroimmune factors, although the conditions under
which the factors are produced, and the amount produced varies. Bidirectional regulation of function occurs between astrocytes and microglia through various intercellular signaling
molecules and is fundamental to the function of the brain neuroimmune system (Jha etal. 2019; Vainchtein and Molofsky
2020). Under some conditions, neurons also produce neuro-
immune factors (e.g., (Bacher etal. 1998; Banisadr etal. 2005;
Park etal. 2012; Balzano etal. 2020)).
In the healthy brain, astrocyte and microglia production of
neuroimmune factors typically occurs constitutively at low levels, with production being upregulated in response to important
environmental signals as part of normal brain homeostasis and
function. However, adverse conditions that cause glial activation can result in upregulated production of neuroimmune factors, a condition referred to as neuroinammation, which is
initially designed for protection, repair, and recovery (Kempuraj
etal. 2016). However, if excessive glial activation occurs, dysregulated production of neuroimmune factors can occur and
result in levels sufcient to produce detrimental effects on the
brain, a condition characteristic of neurodegenerative diseases,
brain injury or infection, and other pathological conditions
(Fig.47.2). A large number of neuroimmune factors can be pro-
Fig. 47.2 Contrasting actions
of neuroimmune factors
in the brain
47 The Cerebellar Neuroimmune System
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307
duced under pathological conditions, a challenging situation in
terms of understanding cellular and molecular actions of neuroimmune factors, which are complex and interactive.
47.2 Neuroimmune Factors
A majority of neuroimmune factors are small secreted peptides (~5–20kD) that are members of a large cytokine superfamily of proteins, which includes chemokine, interleukin
(IL), interferon (IFN), colony-stimulating factor (CSF),
transforming growth factor (TGF), and tumor necrosis factor
(TNF) superfamilies (Dinarello 2007). These superfamilies
are comprised of multiple families, each consisting of a
group of related members. The superfamilies differ structurally and functionally, although there is often redundancy in
function. For example, chemokines are a family of chemotactic cytokines that play an important role in cell migration.
They are classied structurally into four groups, C, CC,
CXC, and CX3C, based on the positions of key cysteine residues, with each group containing multiple members (Bajetto
etal. 2001). The interleukins consists of at least 33 families,
including the IL-6 and IL-1 families. Within the IL-6 family,
there are several members including IL-6, leukemia inhibi-
tory factor (LIF), IL-11, oncostatin, ciliary neurotropic factor and cardiotropic-1. The IL-1 family has 11 members
including IL-1α, IL-1β, IL-18, and IL-33. One member of
the IL-1 family is a natural antagonist (e.g., IL-1R antagonist, IL-1Ra) and can block the action of other interleukins, a
situation that also occurs in other neuroimmune families
(Palomo etal. 2015).
Neuroimmune factors produce their biological actions
through the intervention of specic membrane receptors.
Binding of a neuroimmune factor to its cognate receptor on
target cells typically results in activation of signal transduction pathways, which vary for different neuroimmune factors. For example, members of the chemokine superfamily
utilize receptors linked to G-protein-coupled pathways,
whereas members of the IL-6 family utilize receptors link to
tyrosine kinase pathways (Fig.47.3). Members of the transforming growth factor-beta (TGF-β) family link to receptors
coupled to the Smad signaling pathway. Activation of the
signal transduction pathways and the production of second
messengers induce biochemical changes and/or gene expression resulting in diverse cellular responses (Bajetto et al.
2001). For instance, most chemokines can utilize a Gi-
protein- coupled pathway involving activation of phospholipase C (PLC) resulting in the production of second
Fig. 47.3 Simplied diagrams showing signal transduction pathways
and partners utilized by chemokines and IL-6. The IL-6 receptor
(IL-6ra) does not have signal transduction capabilities but when com-
bined with gp130 signal transduction proteins forms a receptor complex
capable of signal transduction
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D. L. Gruol
messengers diacylglycerol (DAG) and inositol
1,4,5- trisphosphate (IP3). IP3 produces an increase in intracellular Ca2+, another important second messenger, by activating IP3 receptors (IP3R) on the endoplasmic reticulum,
an intracellular organelle that serves as a storage vessel for
intracellular Ca2+ among other functions, resulting in efux
of Ca2+ to the cytosol. As a second messenger, Ca2+ has a
wide range of activities extending from gene expression to
regulation of ion channel function and, consequently, cell
excitability. Other signal transduction partners utilized by
chemokines include adenylate cyclase (Acyc), mitogenactivated protein kinase (MAPK) (e.g., p44/42 MAPK, p38
MAPK), phosphoinositide 3-kinase (PI3-K), and JAK/STAT
(Janus kinase–signal transducer of activators of transcription) (Bajetto etal. 2001).
Chemokines are noted for their promiscuity relative to
receptor activation in that some chemokines can act through
both specic and shared receptors. For example, the chemokine CCL5, also known as RANTES, can act at three chemokine receptors, CCR1, CCR2, and CCR5, whereas the
chemokine CXCL12 (also known as stromal cell-derived
factor-1; SDF-1) primarily acts at the chemokine receptor
CXCR4. CXCL12 acting at CXCR4 plays an important role
in granule neuron migration during cerebellar development,
which is critical for establishing cerebellar circuitry and
structure (Tiveron and Cremer 2008). Other chemokines are
also thought to be involved in cerebellar development based
on the expression of the chemokine and/or its receptor during cerebellar development.
47.3 Evidence forExpression
ofNeuroimmune Factors andtheir
Receptors intheCerebellum
The neuroimmune system of the cerebellum is a relatively
unexplored area and little is known about the roles it plays in
cerebellar function or the dysfunction that occurs in pathological conditions. Much work is needed on this issue, which
is complicated by the difculty in measuring the low invivo
levels of neuroimmune factors, limited information on the
conditions that induce release of the factors from cerebellar
glial cells, and the short half-life of most factors, which are
small proteins and very susceptible to proteases that abound
in the extracellular environment.
One of the rst lines of evidence that neuroimmune factors played a role in cerebellar function was the demonstration of cerebellar expression of specic neuroimmune factors
or their receptors at the protein or mRNA level. Several types
of studies in developing and adult cerebellum of experimental animals or humans contributed to this area. For example,
studies using reverse transcriptase polymerase chain reaction
(RT-PCR) showed that mRNA for tumor necrosis factor
alpha (TNF-α) and its receptors, TNFR1 and TNFR2, were
expressed in the developing mouse cerebellum during the
postnatal period (P) from day P1 to P8 (other ages not studied) (Oldreive and Doherty 2010). RT-PCR analyses also
identied expression of CXCL14in the developing and adult
mouse cerebellum, but CXCL14 protein was observed only
during development (from day P1 to P8) and primarily localized to the dendrites of Purkinje neurons (Park etal. 2012).
CCR1 mRNA was detected by RT-PCR and immunohistochemistry in postnatal and adult rat cerebellum with cellular
expression showing developmental changes (Cowell and
Silverstein 2003). A variety of cell types showed CCR1immunoreactivity including neurons and glia (granule neurons, Purkinje cells, Golgi cells, molecular layer interneurons,
Bergmann glia, astrocytes, and resting microglia) depending
on developmental age, but in the adult expression was limited to granule neurons (Cowell and Silverstein 2003). In the
same study, immunoreactivity for MIP-1α (also known as
CCL3), which binds to CCR1, was also observed during cerebellar development (Cowell and Silverstein 2003).
Expression of CXCR2 mRNA in the cerebellum was
demonstrated by RT-PCR and expression of CXCR2 protein
was demonstrated by Western blot and immunohistochemistry (immunostaining observed in Purkinje neurons and granule neurons) (Giovannelli et al. 1998). Monocyte
chemoattractant protein-1 (MCP-1; also known as CCL2)
expression, detected by immunohistochemistry, was
observed transiently in the fetal human cerebellum but disappeared by 1–2years of age (Meng etal. 1999). In this study,
MCP-1 expression was primarily in Purkinje neurons, dentate nucleus neurons and inferior olive neurons (Meng etal.
1999). The expression of neuroimmune factors or their
receptors in the developing cerebellum suggested a role in
cerebellar development. Consistent with this idea, a number
of studies have shown that chemokines are critical to the
establishment of normal cerebellar architecture during development (Ragozzino 2002; Vilz etal. 2005; Yu et al. 2010;
Araujo etal. 2016, 2019; Ozawa etal. 2016).
High expression of IL-1 receptor mRNA was observed in
the cerebellum of adult rats by RNase protection assay
(Gayle et al. 1997) and in the Purkinje neurons of the rat
cerebellum by in situ hybridization (Wong and Licinio 1994).
Expression of IL-6 and IL-6 receptor mRNA was demonstrated (RT-PCR, in situ hybridization and Northern blot) in
the developing and adult rat cerebellum (Schobitz etal. 1993,
1994; Gadient and Otten 1997). In situ hybridization showed
high levels of IL-1β RNA in the granule layer of the cerebellum (Bandtlow etal. 1990). IL-15 expression has been identied by both ELISA and immunohistochemistry in the
developing and adult mouse cerebellum, with the highest
level of expression on the plasma membrane of the soma and
processes of cerebellar neurons, although expression was
also identied in astrocytes (Gómez-Nicola et al. 2008).
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Prominent IL-33 immunoreactivity was observed in the
mouse cerebellum at postnatal day 9 but not at other ages
(Wicher etal. 2013). Expression of TGF-β family members
and receptors in the cerebellum during development and in
the adult was demonstrated by RT-PCR and immunohistochemistry. (Araujo etal. 2016).
47.4 Neuroimmune Factors
andCerebellum Function
While the expression of genes and proteins suggest a role for
neuroimmune factors in the cerebellum, evidence for a functional consequence to receptor activation is critical to establishing such a role. Pharmacological and developmental
studies using exogenous application of neuroimmune factors
or selective antagonists have started to provide this evidence.
However, with respect to pharmacological studies, it is often
difcult to discern if results reect normal physiology (i.e.,
baseline or non-inammatory stimulatory conditions) or
pathological conditions. In general, when tested at low levels
(e.g., pico-molar), the actions of neuroimmune factors may
be more relevant to physiological processes, whereas at
higher levels the actions may be more relevant to adverse or
pathological conditions.
A number of pharmacological studies have demonstrated
that neuroimmune factors can alter neuronal function in the
cerebellum, consistent with a physiological or pathological
role. Several examples are noted below. Both acute application and chronic exposure have been studied. In some cases,
chronic exposure was accomplished by construction of transgenic mice that persistently expressed elevated levels of a
specic neuroimmune factor in the brain. Knockout mice
have also been useful, although the decit occurs in both the
brain and periphery complicating interpretation. Most of the
pharmacological studies involved rodent cerebellar neurons
in an invitro preparation such as cultured neurons or exvivo
slices of cerebellum.
In one of the few in vivo studies, direct application of
IL-1β to Purkinje neurons of rat cerebellum by microiontophoresis increased the ring rate suggesting that IL-1β can
regulate Purkinje neuron excitability (Motoki etal. 2009). In
mouse cerebellar slices, application of IL-1β enhanced spontaneous excitatory synaptic responses in Purkinje neurons,
whereas similar application of TNFα had no effect, indicating a potential role for IL-1β as a regulator of synaptic transmission (Mandolesi et al. 2013). Stimulus-evoked GABA
receptor-mediated inhibitory responses recorded in Purkinje
neurons in rat cerebellar slices were reduced by exposure to
IL-1, consistent with a role for IL-1 as a regulator of synaptic
transmission (Pringle etal. 1996).
Chronic treatment of primary cultures of rat cerebellum
with IL-6 during neuronal development resulted in altered
active (i.e., action potential generation) and passive (membrane resistance) electrophysiological properties and Ca2+
signaling of the cultured Purkinje neurons (Nelson et al.
2002, 2004). In cultures of rat granule neuron, chronic expo-
sure to IL-6 enhanced NMDA receptor-mediated membrane
depolarizations and associated Ca2+ responses (Qiu et al.
1998) and reduced L-type Ca2+ currents (Ma et al. 2012).
Chronic exposure to IL-6 during granule neuron development in culture affected neuronal viability and sensitivity to
NMDA induced toxicity (Conroy etal. 2004). Exposure to
TGF-beta 1 enhance K+ currents in cultures of rat granule
neurons, increased expression of the GABAA receptor alpha
6 subunit, which is a key subunit in GABA receptors that
mediate tonic inhibition, and increased the number of excitatory synapses (Zhuang etal. 2012; Araujo etal. 2016).
In transgenic mice where genetic modication of astrocytes resulted in elevated expression of IL-6 in the brain,
Purkinje neurons exhibited altered electrophysiological
properties (spike ring, response to synaptic activation),
expression of synaptic proteins and expression of IL-6 signal
transduction partners (Nelson etal. 1999; Gruol etal. 2020).
In transgenic mice in which genetic modication of astrocytes resulted in elevated expression of IL-3, decits in
cerebellar- mediated motor functions (e.g., gait characteristics, performance in the rotorod test) were observed along
with pathological changes in the cerebellum (Chiang etal.
1996). Genetic deletion of CSF-1in mice resulted in loss of
cerebellar microglia and Purkinje neurons, alterations in cerebellar structure, and defects in motor learning (Kana etal.
2019). Genetic deletion of CSF-1 receptor severely impaired
climbing ber elimination during cerebellar development, an
effect attributed to microglial enhancement of GABAergic
synaptic transmission to Purkinje neurons (Nakayama etal.
2018).
A number of invitro studies using rodent cerebellar slices
showed that chemokines could alter synaptic transmission,
suggesting a role as a synaptic modulator. For example,
exposure of mouse cerebellar slices to the chemokine GRO-β
(growth-related gene product beta) enhanced excitatory postsynaptic responses evoked by stimulation of parallel bers
and recorded in Purkinje neurons (Ragozzino et al. 1998).
Spontaneous synaptic responses recorded in Purkinje neurons in mouse cerebellar slices were also increased by exposure to GRO-α as well as the chemokine IL-8 (Giovannelli
etal. 1998). In a similar study, exposure to SDF-1α depressed
synaptic transmission at the parallel ber to Purkinje neuron
synapse in mouse cerebellar slices, an effect that involved
reduced transmitter release (Ragozzino 2002).
Several studies showed that application of chemokines to
cerebellar neurons increased intracellular Ca2+ levels, consistent with activation of a receptor coupled to a G-protein signal transduction pathway. For instance, GRO-α and IL-8
increased intracellular Ca2+ levels in Purkinje neurons in
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D. L. Gruol
mouse cerebellar slices and GRO-α increased intracellular
Ca2+ levels in cultured Purkinje neurons (IL-8 not tested in
cultures) (Giovannelli et al. 1998). MCP-1 also increased
resting Ca2+ levels in cultured Purkinje neurons, enhanced
the Ca2+ response evoked by activation of metabotropic glutamate receptor 1 (mGluR1; a G-protein coupled receptor),
and depressed action potential generation (van Gassen etal.
2005).
47.5 The Neuroimmune System
andCerebellum andDisease
Much of our knowledge about the neuroimmune system in
the brain comes from studies involving conditions where
neuroimmune factors are produced at elevated levels by activated glial cells and, therefore, are more easily detected. The
state of increased glial activation, referred to as neuroinammation, has been shown to occur in the cerebellum in a number of conditions associated with detrimental effects (Ferro
etal. 2019; Revuelta etal. 2020). For example, pre- and neonatal exposure of rat pups to lead produced a signicant
increase in levels of IL-1β, IL-6, and TGF-β in the cerebellum and other brain regions (Chibowska etal. 2020). In studies of the brain from deceased human autistic patients,
TGF-β and MCP-1 were found to be signicantly elevated in
the cerebellum, the main site of neuroinammation in autism
(Vargas etal. 2005). Immunohistochemical staining of the
cerebellum in this study indicated that MCP-1 was produced
by activated astrocytes, whereas both astrocytes and neurons
produced TGF-β (Vargas etal. 2005). In neonatal mouse,
conditions of hypoxia induced prominent increases in TNF-α
and IL-1β in microglia and their receptors in Purkinje neurons (Kaur etal. 2014).
Activated microglia and astrocytes and elevated levels of
neuroimmune factors are expressed in the cerebellum in several experimental models of neurological conditions associated with ataxia (e.g., spinocerebellar ataxia, multiple
sclerosis, and experimental autoimmune encephalomyelitis)
(Cvetanovic etal. 2015; Ferro et al. 2019; Revuelta et al.
2020). For instance, depending on age, increased levels of
IL-6, IFN gamma, IL-1β, and IL-10 were observed in the
cerebellum of MRL-lpr/lpr mice, an experimental model for
the autoimmune disease Lupus Erythematosus (SLE)
(Tomita etal. 2001). Spinocerebellar ataxia type 1 (SCA1), a
neurodegenerative disorder that affects the cerebellum, is
characterized by pathogenic polyglutamine expansion in the
coding region of gene for ATXN1 (ataxin-1), which results in
a toxic protein. In a mouse model for this disease, transgenic
ATXN1[82Q] mice, the toxic protein is expressed in Purkinje
neurons and is associated with microglial and astrocyte activation and increased levels of cerebellar TNF-α, MCP-1, and
IL-6 (Cvetanovic et al. 2015). Detrimental mutations that
affect the physiology of Purkinje neurons underlie many
types of spinocerebellar ataxias (Marcián etal. 2016; Meera
etal. 2016; Hoxha etal. 2018) but emerging research indicate that astrocytes and microglia can also play a role in
these and other diseases associated with ataxia (Ferro etal.
2019; Cerrato 2020; Revuelta etal. 2020). Much is left to be
learned about the cerebellar neuroimmune system and its
function in health and disease.
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