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64 The Tottering Mouse
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was observed that blocking L-type Ca2+ channels in the cerebellum alleviated the episodic dystonia (Campbell and Hess
1999). Additionally, blocking L-type Ca2+ channels was
effective in reducing the low-frequency oscillations observed
in the tg/tg mouse cerebellar and cerebral cortices (Chen
etal. 2009; Cramer etal. 2015), suggesting that L-type Ca2+
channels are involved in the episodic motor phenotype of the
tg/tg mouse.
There are also alterations in GABAA receptors in the adult
tg/tg mouse. In the cerebellum, there is a 40% reduction in
the number of GABAA receptors in the granular layer (Kaja
etal. 2007). Recently, a study found that there was a compro-
mised development of GABA signaling in the hippocampus
of tg/tg mice (Nakao etal. 2015); however, it remains to be
determined if these alterations affect cerebellar function in
the tg/tg mouse. Additional changes have been reported for
neuronal nitric oxide synthase (nNOS) (Rhyu etal. 2003),
tyrosine hydroxylase (Hess and Wilson 1991), calretinin and
ryanodine receptor type 1 (Cicale et al. 2002). How these
changes affect cerebellar function or their involvement in the
tg/tg phenotype remains unclear.
64.6 Eectiveness ofEA2 Therapies
intheTottering Mouse
Both acetazolamide and 4-aminopyridine have been shown
to signicantly reduce the frequency and severity of the episodic cerebellar symptoms in EA2 (Strupp et al. 2004;
Griggs etal. 1978), and these drugs have also shown to be
effective in alleviating the episodic dystonia and lowfrequency oscillations in tg/tg mice (Chen et al. 2009;
Cramer etal. 2015). It remains to be determined how these
two drugs act to provide the benecial effects, but the common overlap between the tg/tg mouse and EA2 patients suggests that the tg/tg mouse has the potential to serve as a
model for testing new EA2 therapeutic agents.
64.7 Conclusion
In conclusion, the tg/tg mouse is an extremely useful model
and has the potential to provide insights into a class of
genetic disorders that exhibit cerebellar dysfunction, including EA2. However, there is a great deal more to learn from
this model. Understanding how the episodic neurological
symptoms initiate and progress would not only be benecial
toward better treatment of EA2 patients, but could also help
us understand how episodic neurological dysfunction occurs
in numerous other disorders.
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The Rolling Nagoya Mouse
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JaapJ.Plomp, ArnM.J.M.van den Maagdenberg,
andElseA.Tolner
65
Abstract
The natural mutant mouse rolling Nagoya is severely
ataxic and frequently shows body roll-overs. The phenotype is inherited in an autosomal recessive way. A missense mutation has been identied in Cacna1a, the gene
encoding the pore-forming α1 subunit of CaV2.1 type
voltage-gated Ca2+ channels. These ion channels are crucially involved in neuronal Ca2+ signaling and, importantly, in neurotransmitter release from nerve terminals at
many central nervous system synapses and the peripheral
neuromuscular junction. We here review the main phenotypic, motor behavioral, histological, biochemical, neurophysiological, and electrophysiological ndings in this
mouse mutant. In addition, the relevance to human neurological disorders associated with CaV2.1 dysfunction
(“Ca2+-channelopathies”), either resulting from mutation
or autoimmunity, is discussed.
Keywords
Ataxia · Cacna1a · Cav2.1 · Episodic ataxia type 2
Familial hemiplegic migraine type 1 · Lambert-Eaton
myasthenic syndrome · Neuromuscular junction · Synapse
Rolling Nagoya · Voltage-gated Ca
J. J. Plomp (*)
Department of Neurology, Leiden University Medical Centre,
Leiden, The Netherlands
e-mail: j.j.plomp@lumc.nl
A. M. J. M. van den Maagdenberg · E. A. Tolner
Department of Neurology, Leiden University Medical Centre,
Leiden, The Netherlands
Department of Human Genetics, Leiden University Medical
Centre, Leiden, The Netherlands
e-mail: a.m.j.m.van_den_maagdenberg@lumc.nl;
e.a.tolner@lumc.nl
2+
channels
65.1 Rolling Nagoya Phenotype
The rolling Nagoya (RN) mouse was identied in Nagoya,
Japan, as a natural recessive mutant almost 50years ago. It
appeared in a litter from mating between two inbred strains,
i.e., SIII and C57Bl/6Nga (Oda 1973). The autosomal recessive RN mutation was subsequently back-crossed onto a
C3Hf/Nga background to remove a reduced fertility characteristic present within the SIII strain (Tamaki et al. 1986).
The RN mutation appeared as a new allele of the tottering
locus, mapped to chromosome 8. Tottering is another natural
mutant mouse, now known to harbor a different recessive
Cacna1a missense mutation (P601L) (Fletcher etal. 1996;
Doyle etal. 1997).
Homozygous RN mice are severely ataxic with abnormal hind limb movements and typical sideway lurching
(Fig. 65.1a). In swimming tests, RN mice swim slowly
and clumsy with disturbed rhythm and inconsistent hind
limb paddling (Tamaki et al. 1986). Early ataxia symptoms can be detected already in the second postnatal week
(Takahashi etal. 2010b). There is no epilepsy or tremor,
unlike in various other natural Cacna1a mouse mutants
(Felix 2002). Adult homozygous RN mice have 25–30%
reduced body weight (Nakamura etal. 2005; Kaja etal.
2007). Although fertile, their motor disturbances hamper
reproduction and breeding is therefore best achieved by
heterozygous mating. Most homozygous RN mice have a
normal life span, although some die in the rst few postnatal weeks.
The disturbed motor coordination is paralleled by fatigable muscle weakness, as indicated by reduced performance
in grip strength and inverted mesh tests (Kaja etal. 2007).
Furthermore, autonomic dysregulation seems present as
heart rate is decreased by ~20% (Ohba et al. 2009) and
breathing rate by ~35% (JJ Plomp, unpublished). In addition,
RN mice show hypoalgesic responses to thermal, mechanical, and chemical nociceptive stimuli (Fukumoto etal. 2009).
© 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_65
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Heterozygous RN mice display no overt neurological
symptoms. However, detailed studies revealed motor and
memory decits at old age (18–22months), indicating that
the phenotype is not purely recessive. An increase in relative expression of RN-mutated versus wild-type CaV2.1-α1A
mRNA may be underlying these late-onset effects in heterozygotes (Takahashi etal. 2009a, b). This may also be the
reason why old (18months) heterozygous RN mice have a
milder epileptic response to injection of kainate than
younger heterozygotes (2 months), possibly related to
impaired glutamatergic transmission (Kim et al. 2014).
Consequently, neuronal damage and the number of activated astrocytes in response to kainate remained relatively
limited in older heterozygotes. This age-related neuroprotective effect in the context of seizures appears linked to
lower levels of postsynaptic p38 mitogen-activated protein
kinase in the hippocampus (Kim etal. 2014). Furthermore,
older heterozygous RN mice also have reduced levels of
anxiety and depression as compared to wild-types in behavioral test models for these emotional states (Takahashi etal.
2011).
Relative to other natural Cacna1a mouse mutants, the
overall phenotype in RN mice can be rated as being of intermediate severity. While ataxia is more severe than in totter-
ing, it is less severe than in leaner mice (Felix 2002). There
are no signs of epilepsy, which is clearly present in leaner.
Furthermore, RN mice have no paroxysmal dyskinesia, as
seen in tottering mice.
65.2 The Rolling Nagoya Mutation Resides
inCacna1a-Encoded CaV2.1 Ion
Channels
Neuronal voltage-gated Ca2+ channels are membrane proteins which translate electrical signals into Ca2+ inux,
thereby inuencing many crucial processes such as excitability, transmitter release, gene regulation, and axonal growth.
CaV2.1 channels belong to the group of high-voltageactivated Ca2+ channels that also include CaV1 (L-type),
CaV2.2 (N-type), and CaV2.3 (R-type) channels (Dolphin and
Lee 2020). CaV2.1 channels reside in the membrane of neuronal cell bodies but are particularly present in presynaptic
nerve terminals, governing neurotransmitter release (Dolphin
and Lee 2020). Although distributed throughout the brain,
CaV2.1 channels are particularly highly expressed in the cerebellum. The channel contains a pore-forming α1 subunit and
modulatory α2δ, β and γ subunits, each encoded by different
genes (Dolphin and Lee 2020). These auxiliary subunits are
important for trafcking and positioning of the CaV2.1 channel into the neuronal membrane and for modulation of the
biophysical and electrophysiological properties of the poreforming α1 subunit. The CaV2.1-α1A pore-forming subunit is
encoded by the Cacna1a gene, located on mouse chromosome 8. The RN mutation is a C-to-G change at nucleotide
3784, causing an arginine to glycine change at amino acid
1262 of the protein (Mori et al. 2000) (Fig. 65.1b). This
R1262G mutation localizes in a voltage sensing segment of
a b
Fig. 65.1 (a) Picture of a typical sideway body roll of a homozygous
rolling Nagoya mouse. (b) Schematic representation of the CaV2.1-α1A
pore-forming subunit, with indication of the position of the rolling
Nagoya R1262G mutation in the voltage sensing segment of the third
repeating domain
65 The Rolling Nagoya Mouse
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the channel and disturbs its function. A number of other neurological mouse mutants carry Cacna1a mutations (Felix
2002). Importantly, human CACNA1A mutations exist in
inherited forms of hemiplegic migraine and episodic and spinocerebellar ataxia, which can be associated with epileptic
seizures or fatal coma (Ferrari etal. 2015). De novo mutations in CACNA1A have been associated with a broad phenotypic spectrum, including early developmental delay, early
onset paroxysmal dystonia, autism and epileptic encephalopathy (for review, see Indelicato and Boesch 2021).
65.3 Rolling Nagoya Brain Morphology
RN brain anatomy and morphology as well as the expression
and distribution of neurotransmitter receptors have been
studied in detail, with special focus on the cerebellum. Some
early studies showed reduced RN cerebellum volume, weight
and cell numbers, but this was not conrmed by others (for a
summary, see Introduction of Tomoda et al. 1992). Later
studies reported normal cerebellar anatomy without apoptosis and normal cell densities (Mori etal. 2000; Sawada etal.
2001a, b), while others observed apoptosis (Rhyu et al.
1999). The reasons for these different observations remain
unclear. In RN deep cerebellar nuclei, a larger proportion of
neurons showed CaV2.1-α1 expression, as compared to wildtype nuclei, possibly compensating for reduced CaV2.1 channel function (see below) (Sawada etal. 2001a, b).
Tyrosine hydroxylase (TH) in cerebellar Purkinje cells is
normally expressed only transiently but persists in RN mice
(Mori etal. 2000; Sawada etal. 2001a). This phenomenon
appears in a typical parasagittal striping pattern (Sawada and
Fukui 2010; Sawada et al. 2010), partly overlapping the
staining pattern for zebrin II, a Purkinje cell marker.
Interestingly, no enzymatically active form of TH, i.e., phosphorylated at serine residue 40, was identied in the RN cerebellum (Sawada et al. 2004), suggesting that there is no
aberrant catecholamine synthesis and release. Disturbed
intracellular Ca2+ concentration in Purkinje cells may be the
key factor in aberrant TH expression (Fureman etal. 1999).
Levels of some other proteins are changed in the RN cerebellum as well. Corticotropin-releasing factor is increased,
correlating with TH-positive Purkinje cells (Sawada et al.
2001b). This factor modulates glutamate and γ-aminobutyric
acid (GABA) sensitivity in Purkinje cells (Bishop et al.
2000). It also potentiates CaV1 currents (Kanno etal. 1999),
perhaps inuencing TH expression in this way. In addition,
levels of ryanodine receptors (channels which allow Ca2+
efux from the endoplasmic reticulum) are altered in RN
cerebella (Sawada etal. 2008). This may also underlie aberrant TH expression.
Synaptic abnormalities likely exist in RN brains. GABAA
and adenosine A1 receptors in the cerebellum and A1 recep-
tors in the cerebral cortex and caudate-putamen were found
reduced in RN mice (Yamaguchi etal. 1984; Onodera etal.
1988). In the cerebellum, there seems to be a preferential
loss of (extrasynaptic) δ-subunit containing GABAA receptors (Kaja et al. 2015). However, GABAA receptors in
forebrain remain unaltered (Nielsen and Kaja 2014).
Morphological deformations were observed in RN cerebellar
synapses (Rhyu et al. 1999; Oda et al. 2010) and Ca2+/
calmodulin-dependent protein kinase II is downregulated at
hippocampal nerve terminals (Takahashi etal. 2010a).
The ataxia of RN mice is generally typied as being
purely cerebellar. However, some components of the movement difculties are also compatible with dysfunction of
brain regions outside the cerebellum. Enhanced neuronal
activity in the basal ganglia as well as electrophysiological
abnormalities recorded in the globus pallidus suggested that
motor disturbances of RN mice may perhaps be also due to
striatal dysfunction (Kato etal. 1982; Tomoda etal. 1992). In
addition, radiochemical studies have shown increased preproenkephalin and preprotachykinin mRNA in the striatum
(Taniwaki etal. 1996). Therefore, next to being a model for
cerebellar ataxia, the RN mouse may to some extent also be
a model of basal ganglia dysfunction. However, the prominent presence of CaV2.1 channels in the normal cerebellum
(Dolphin and Lee 2020) and the histological changes
observed in the RN cerebellum suggest a major and primary
role for this area in RN motor dysfunction.
65.4 Eect oftheRolling Nagoya Mutation
ontheElectrophysiology ofCaV2.1
Channels andNeuronal Function
Electrophysiological studies showed that expression of
RN-mutated CaV2.1 channels is reduced and that their activation voltage is shifted ~10mV in the positive direction,
i.e., mutated channels require larger voltage stimuli to cause
their opening (Mori etal. 2000; Fukumoto etal. 2012). The
shift in activation potential is compatible with the position of
the R1262G mutation in the CaV2.1 channels, i.e., in the voltage sensor of domain III (Fig.65.1b). The diminished CaV2.1
activity due to reduced expression and reduced voltage-gated
opening in Purkinje and other cells expressing this channel
likely forms the primary factor in the cascade that ultimately
results in the ataxia of RN mice. In addition, reduced CaV2.1
expression and activity in neurons outside the cerebellum
including dorsal root ganglia, hippocampus, and cortex may
underlie the higher pain threshold (Fukumoto et al. 2012)
and the reduced neuronal damaging effects of experimentally induced seizures (Kim etal. 2014) or ischemia (Tian
etal. 2013).
One secondary effect of reduced CaV2.1 channel activity
may be premature abortion of action potential ring in RN
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Purkinje cells due to insufcient stimulation of Ca2+-activated
K+-channels, important for post-spike repolarization.
Furthermore, Ca2+-mediated action potentials are hard to
evoke and not followed by the usual Na+-mediated action
potential bursts (Mori etal. 2000). These ndings suggest
impaired RN Purkinje cell responses to (integrated) synaptic
excitation, affecting neuronal network function. Besides,
considering the presynaptic function of CaV2.1 channels,
cerebellar synapses in RN mice presumably have aberrant
neurotransmitter release. Neurochemistry studies indeed
showed neurotransmitter level changes (Muramoto et al.
1981; Nakamura et al. 2005). Glutamatergic synaptic cur-
rents in RN brain slices are either enhanced or reduced in
parallel ber and climbing ber synapses, respectively, on
Purkinje cells (Matsushita etal. 2002). Apparently, disturbed
Ca2+ homeostasis in RN cerebellar Purkinje cells leads to a
differential regulation of glutamate receptors at different
synapses. These changes in RN glutamatergic transmission
may contribute to the observed protection against experimental excitotoxicity induced by either pharmacological or
cryogenic means (Kim etal. 2014, 2016, 2017).
Similarly, synaptic defects exist at the RN NMJ (Kaja
etal. 2007). In this peripheral synapse, the nerve stimulation-
evoked release of the neurotransmitter acetylcholine (ACh)
fully depends on presynaptic CaV2.1 channels (Plomp etal.
2015). At RN NMJs, a large reduction (50–75%, depending
on the muscle type) of evoked ACh release is present. It is
accompanied by a approximately threefold increase of spontaneous uniquantal ACh release, measured as miniature endplate potential frequency. Most likely, the opposing effects
on evoked and spontaneous release result from a complex
effect of the mutation on different functional channel parameters, allowing for increased Ca2+ inux at resting potential
while limiting Ca2+ inux upon depolarization by a nerve
impulse. The reduced impulse-evoked ACh release at NMJs
is the most likely cause of the muscle weakness and fatigue
observed in grip strength and inverted grid hanging tests of
RN mice. NMJ malfunction was further substantiated by a
reduced and decrementing compound muscle action potential in invivo repetitive nerve stimulation electromyography.
Furthermore, enhanced sensitivity to d-tubocurarine (a
reversible ACh receptor antagonist) in exvivo muscle contraction experiments conrmed a reduced safety factor of
neuromuscular synaptic transmission. Altogether, these NMJ
studies strongly indicate that the gait abnormality of RN
mice is in fact a combination of ataxia and muscle weakness.
Therefore, the RN mouse may model, besides ataxia, aspects
of the human neuroimmunological disease Lambert-Eaton
myasthenic syndrome (LEMS)(see below), in which presynaptic CaV2.1 channels at the NMJ are targeted by autoantibodies, causing muscle weakness (Titulaer etal. 2011).
65.5 Relevance oftheRolling Nagoya
Mouse toHuman CaV2.1
Channelopathies?
The RN mouse is a rather “pure” ataxia model (i.e., no associated epilepsy) and may be used for ataxia drug testing, particularly related to human CACNA1A mutation-associated
cerebellar ataxia (Jen etal. 2007). However, surprisingly few
anti-ataxic drug studies have been performed using the RN
mouse mutant. Some studies have shown anti-ataxic effects
of thyrotropin-releasing hormone or an analogue with only
minor hormonal activity, taltirelin, in RN mice, possibly due
to unknown neuroprotective or metabolic effects (Kinoshita
etal. 1997; Nakamura etal. 2005). Recently, a new analogue
with improved pharmacological properties, rovatirelin, was
shown to activate the cerebellum and other parts of the central nervous system and to improve motor function of RN
mice (Ijiro etal. 2020). Ca2+-activated K+-channels might be
interesting drug targets, regarding their likely involvement in
aborted action potential ring of RN Purkinje cells (Mori
et al. 2000). Use of RN mice in ataxia drug studies may,
however, be limited by the fatigable muscle weakness interfering with (prolonged) motor performance testing.
Human CACNA1A mutations underlie familial hemiplegic migraine type-1 (FHM1), an inherited monogenic
migraine variant which may model the more common, multifactorial migraine forms (Ferrari etal. 2015). Interestingly,
~20% of FHM1 patients has (permanent) cerebellar ataxia.
However, electrophysiological studies of FHM1-mutated
CaV2.1-transfected cells (Pietrobon 2005) and dissociated
cerebellar neurons from Cacna1a knockin mice carrying the
FHM1 CACNA1A mutations R192Q or S218L (van den
Maagdenberg etal. 2004, 2010), all indicate that the consequences of FHM1 mutations on CaV2.1 channel function are
in several important aspects opposite to those of the RN
mutation (i.e., a shift of activation voltage in the negative
instead of positive direction and an increase instead of
decrease in CaV2.1 current density, jointly resulting in
increased neuronal Ca2+ current in FHM1). Therefore, the
RN mouse does not seem to be a good model for (familial
hemiplegic) migraine.
RN mice show certain similarities with LEMS, in which
auto-antibodies target NMJ CaV2.1 channels and cause muscle weakness. ACh release at LEMS NMJs is greatly reduced
(Cull-Candy etal. 1980), as it is in RN (Kaja etal. 2007).
Similarly reduced ACh release was shown in muscle biopsy
NMJs of three congenital myasthenic syndrome patients
without anti-CaV2.1 antibodies or identied CACNA1A
mutation, but with symptoms of ataxia (Maselli etal. 2001)
and, furthermore, at biopsy NMJs of two episodic ataxia
type-2 patients with CACNA1A truncation mutations (Maselli
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et al. 2003). In three episodic ataxia type-2 patients with
CACNA1A loss-of-function mutations, functional NMJ
abnormalities were shown (Jen etal. 2001). Conversely, a
proportion of the LEMS patients has accompanying symptoms of cerebellar ataxia (Titulaer etal. 2011). Thus, in spite
of different causes of RN and LEMS (i.e., genetic mutation
of CaV2.1 vs. autoimmunity), the RN mouse can serve as a
non-immunological model, particularly in relation with the
NMJ symptomatic aspects of LEMS. It may, therefore, be
useful in studies of drugs aiming to improve NMJ function.
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Lesions oftheCerebellum
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MariaTeresaViscomi andMarcoMolinari
66
Abstract
Since the end of the nineteenth century, the simplicity of
the neuronal architecture of the cerebellar system has
attracted neuroscientists and thus cerebellum has become
one of the favorite targets for testing the functional
hypothesis of brain plasticity. Thus, the classical lesion
approach, which consists in damaging a structure to test
the function, has been applied many times.
Keywords
Cerebellar system · Brain injury · Brain plasticity ·
Neuronal degeneration · Remote degeneration ·
Inammation
Since the end of the nineteenth century, the simplicity of the
neuronal architecture of the cerebellar system has attracted
neuroscientists and thus cerebellum has become one of the
favorite targets for testing the functional hypothesis of brain
plasticity. Thus, the classical lesion approach, which consists
in damaging a structure to test the function, has been applied
many times.
Much of what is known about cerebellar function comes
from ndings on experimental approaches using small selective lesions, as well as large lesions removing the entire cerebellum. One of the most employed experimental paradigms
of cerebellar lesion is the hemicerebellectomy (HCb), consisting in the ablation of half of the cerebellum. This approach
M. T. Viscomi (*)
Department of Life Sciences and Public Health- Section of
Histology and Embryology, Università Cattolica del S.Cuore,
Rome, Italy
e-mail: mariateresa.viscomi@unicatt.it
M. Molinari
Santa Lucia Foundation, Rome, Italy
e-mail: m.molinari@hsantalucia.it
is widely employed by many groups in various contexts of
neuroscience and over the decades has provided interesting
results on cerebellar functions as well as on mechanisms of
lesion-induced plasticity.
Furthermore, the HCb paradigm has been proven to be a
reliable and reproducible model for examining remote
degeneration mechanisms after a focal brain injury and testing pharmacological approaches.
66.1 Hemicerebellectomy
Hemicerebellectomy (HCb) is an experimental model of cerebellar lesion characterized by surgical ablation of half the
vermis with one cerebellar hemisphere, including the deep
cerebellar nuclei and cerebellar peduncle, while sparing the
vestibular nuclei and all surrounding structures (Fig.66.1).
This model of cerebellar damage can be considered as a
mixed experimental model of both deafferentation and axotomy of CNS.In fact, this type of lesion by removing the cerebellar cortex and deep cerebellar nuclei (DCN) of one side
produces a complete axotomy of both mossy and climbing
afferent ber systems. Furthermore, HCb lesions all efferent
projections from Deep Cerebellar Nuclei (DCN) to the red
nucleus and thalamus as well as to brain stem precerebellar
nuclei (deafferentation).
Based on the unilaterality of the lesion and the nearly
complete crossover of the cerebellar input–output organization, it is possible to study an intact and a lesioned cerebellar
circuit in the same animal using this experimental model of
cerebellar injury.
This approach is simple, affects low mortality, and has a
high degree of reproducibility. Because in human pathology,
focal cerebellar lesions due to stroke, bleeding, trauma, or
surgery are often unilateral, HCb is suitable for examining
functional, morphological, and molecular changes occurring
in remote regions after a focal cerebellar lesion (Viscomi
et al. 2009a, 2015) as well as for testing neuroprotective
© 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_66
419
420
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Purkinje
Cell
Inferior Olive
Fig. 66.1 Schematic of the hemicerebellectomy (HCb) model in
rodent. Due to the crossed input–output organization of the cerebellar
connections, unilateral lesion of a cerebellar hemisphere induces axotomy and subsequent degeneration of almost all neurons of the contralateral (lesioned side) precerebellar nuclei (Inferior Olive and Pontine
Nuclei), with sparing of the neurons on the ipsilateral side (unlesioned
side). Thus, in the same section (lower part of the gure), both axotomized and spared neuronal populations can be observed and studied.
DCN deep cerebellar nuclei; icp inferior cerebellar peduncle
Granule Cell
Lesion
DCN
icp
Pontine Nuclei
Unlesioned sideLesioned side
approaches (Viscomi etal. 2008a, b, 2009b, 2012; Bisicchia
etal. 2013, 2018; Sasso etal. 2016).
Furthermore, since cerebellar circuits are equipped with
great plastic capacities, HCb represents an excellent model
of lesion-induced plasticity (Centonze et al. 2008; Burello
etal. 2012; Laricchiuta etal. 2016).
M. T. Viscomi and M. Molinari
66.2 Eects ofCerebellar Lesion
onPrecerebellar Nuclei: Inferior Olive
andPontine Nuclei
Cerebellar focal lesion has effects on the main target of cerebellar output system, namely red nucleus and thalamus, and
profoundly affects cerebro-cerebellar functional interactions
(Giannetti and Molinari 2002). Effects of cerebellar damage
on red nucleus anatomy and functions have been addressed
by Tsukahara (Tsukahara etal. 1983) and were among the
rst demonstration of postlesional brain plasticity mechanisms in the brain. Thalamic and cortical changes have been
addressed by many authors in humans (Jissendi etal. 2008;
Clausi etal. 2009), but seldom analyzed in animal models.
The well-described anatomical efferent-afferent organization of the cerebellar system and the density of the major
afferent sources in two well-dened brainstem structures—
the inferior olive and pontine nuclei—constitute an optimal
model that can be used to examine the mechanism of transsynaptic degeneration—retrograde or anterograde—occurring in brain regions that are far, but functionally connected
to the lesion site. Because of the crossed input–output cerebellar organization (Fig.66.1), HCb damages the axons of all
neurons of the contralateral inferior olive (IO) and pontine
nuclei (Pn)—retrograde effects—and nearly deprives the
contralateral cerebral cortex of cerebellar input—anterograde effects.
In general, axonal injury leads to the activation of several
signaling pathways that transmit specic molecular messages
from the site of injury to the soma of damaged neurons.
Interestingly, this signaling occurs in two distinct temporal
phases: a rapid and a delayed phase. The rst one is mainly
characterized by a retrograde calcium wave that propagates
into the soma; the delayed phase is characterized by the retrograde transport of several injury-responsive signaling molecules (Mahar and Cavalli 2018). In the HCb model, as in other
remote damage models, not all reactive/degenerative phenomena observed in axotomized neurons of precerebellar nuclei
develop simultaneously after injury (Viscomi et al. 2004,
2009b, 2015; Cavallucci etal. 2014). It has been shown that
after HCb injury, remote signals reach the axotomized neurons
of contralateral inferior olive and pontine nuclei at different
time points after the damage (Fig.66.1). For this reason, at any
given point, remote axotomized neurons exist in various functional/morphological states, suggesting differences in neuronal sensitivity and time-specic activation of several reactive/
compensative mechanisms (Viscomi etal. 2004, 2005, 2012).
Different cellular and molecular phenomena are crucial in specic time windows and differently contribute to the nal fate
of neurons (Viscomi etal. 2010; Viscomi and Molinari 2014;
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