Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_24_библиотеки_им_акад_М_И_Перельмана
.pdf
400
bc
https://t.me/medicina_free
T. Ikenaga
a
Fig. 62.1 (a) Mid-sagittal plane of the goldsh brain. (b, c) Transverse
sections of the goldsh brain including the cerebellum through lines indicated in (a). Abbreviations: CCe corpus cerebelli; EG eminentia granu-
guishable structure in mormyrid sh and protrudes from the
caudal edge of the corpus cerebelli (Campbell etal. 2007).
On the basis of its strong morphological relationship with the
central lateral line sensory region, it is suggested that the
vestibulolateral lobe is homologous with the tetrapodian
occulus (Meek 1992).
The teleost corpus cerebelli consists of three layers, which
is consistent with the structure in other vertebrates
(Fig.62.1c). Parallel bers from granule cells and dendrites
of Purkinje cells represent the major components of the
molecular layer of the teleost cerebellum. The presence of
laris; OB olfactory bulb; SC spinal cord; Tel telencephalon; Te O optic
tectum; VCl lateral lobe of valvula cerebelli; VCm medial lobe of valvula
cerebelli. Scale bar=500μm. (Adapted from Ikenaga etal. 2006)
stellate cells has been reported (Nieuwenhuys et al. 1974;
Han and Bell 2003), but to date, there is no evidence to indicate the existence of basket cells in the teleost. The Purkinje
cell layer in the teleost cerebellum is referred to as the ganglionic layer in some studies. This is because it contains both
Purkinje cells and efferent cells termed eurydendroid cells
(Meek 1992; Han and Bell 2003). The morphology of teleost
Purkinje cells is basically similar to those of other vertebrates; one thick primary dendrite emerges from the apical
part of the cell body and branches are distributed into the
molecular layer and oriented sagittally. Axons of Purkinje
62 The Teleost Fish
https://t.me/medicina_free
401
cells of the corpus cerebelli run within the ganglionic layer
and terminate onto the somata and main dendrites of the
efferent cells (Nieuwenhuys etal. 1974; Ikenaga etal. 2005;
Bae etal. 2009), and also onto other Purkinje cells (Meek
and Nieuwenhuys 1991). The climbing ber makes glutamatergic inputs onto somata or the proximal region of the primary dendrites of Purkinje cells, but does not climb to the
distal section of dendrites, unlike in mammals (Han and Bell
2003). Efferent cells, another kind of neuron in the gangli-
onic layer, will be mentioned in detail later. The granule cell
layer is located in the deepest portion of the teleost corpus
cerebelli (Fig.62.1c) and contains granule cells and Golgi
cells.
62.2 Eerent Neurons oftheTeleost
Cerebellum
One unique feature of the teleost cerebellum is the lack of
deep cerebellar nuclei. Instead, cerebellar efferent neurons
are distributed in the ganglionic layer. The cerebellar efferent
cells of teleost sh have two or more primary dendrites
(Fig.62.2) (Nieuwenhuys etal. 1974; Murakami and Morita
1987; Ikenaga etal. 2005). Like Purkinje cells, the efferent
cells have an extensive dendritic arbor along the parasagittal
dimension and are spread within the molecular layer. The
shape of the efferent cells can vary even within a single species; in goldsh, they are classied into three types according to their morphology (Fig.62.2) (Ikenaga etal. 2005). The
efferent cell dendrites have fewer spines than those of the
Purkinje cells (Nieuwenhuys et al. 1974; Murakami and
Morita 1987; Campbell etal. 2007). In the goldsh corpus
cerebelli, large numbers of neurons in the ganglionic layer
were labeled with anti-GABA antibody, but retrograde
labeled efferent cells were not labeled with the same antibody, suggesting that Purkinje cells utilize GABA as a neurotransmitter, whereas efferent cells are mediated by a
different one (Ikenaga etal. 2005). In zebrash, some effer-
ent neurons strongly express vglut2a/b mRNA (vesicular
glutamate transporter), suggesting that teleost cerebellar
efferent neurons are glutamatergic (Bae et al. 2009). The
axons of Purkinje cells terminate onto the somata and the
main dendrites of the efferent cells in the mormyrid corpus
cerebelli (Nieuwenhuys etal. 1974). Experiments combining
retrograde labeling and immunohistochemistry indicate that
efferent cells receive GABAergic inputs from Purkinje cells
in the goldsh corpus cerebelli (Ikenaga etal. 2005). This
relationship between the efferent cells and Purkinje cells is
similar to that between the deep cerebellar nuclei and
Purkinje cells in the mammalian cerebellum. A subset of cerebellar efferent neurons in larval zebrash receive inputs
from 1 to 3 Purkinje cells (Harmon etal. 2020). Therefore,
teleost cerebellar efferent neurons have some similarities
with neurons of the deep cerebellar nuclei of mammals. The
information about the cerebellar efferent system used by
other ray nned sh is not sufcient. There is a need for
additional studies of the cerebellar efferent systems of these
sh to gain further insight into cerebellar evolution in
vertebrates.
62.3 Aerent andEerent Fiber
Connections
The teleost cerebellum receives inputs via climbing bers
and origin of them is in the inferior olive, as is the case in
other vertebrates. Additionally, the corpus receives inputs
from the diencephalon, pretectal area, mesencephalon,
rhombencephalon, and spinal cord in goldsh (see detail in
Wullimann and Northcutt 1988). The afferent source of the
lateral lobe of the valvula in goldsh partially overlaps with
that of the corpus (Wullimann and Northcutt 1989). Recent
retrograde transsynaptic tracing experiments with recombinant rabies viruses infected the granule cells revealed that the
zebrash cerebellum receives inputs from similar areas to
those of the goldsh (Dohaku etal. 2019).
abc
Fig. 62.2 Photomicrographs of retrogradely labeled cerebellar efferent neurons in the goldsh corpus cerebelli. (a) Fusiform type neurons.
(b) Polygonal type neurons. (c) Monopolar type neurons. Arrowheads
indicate cell bodies of efferent neurons. Scale bar=50μm. (Adapted
from Ikenaga etal. 2006)
402
https://t.me/medicina_free
T. Ikenaga
The efferent targets of the goldsh corpus cerebelli are
also widely distributed and include the diencephalon, pretectal area, mesencephalon, and rhombencephalon (see detail in
Wullimann and Northcutt 1988, Ikenaga etal. 2002). The
efferent targets of the medial lobe of the valvula cerebelli are
very similar to those of the corpus cerebelli. Conversely, the
lateral lobe of the valvula cerebelli projects only to a limited
area (see detail in Ikenaga etal. 2002). These observations
suggest that the roles of the corpus and the medial lobe of the
valvula include both motor control and functions carried out
by the mammalian higher cerebellum. It is also suggested
that there are functional divisions between the medial and
lateral lobes of the valvula cerebelli.
62.4 Functions oftheTeleost Cerebellum
Ablation of the corpus in rainbow trout resulted in individuals being unable to maintain a steady position and subsequently being swept backwards in fast owing water,
suggesting that the corpus cerebelli is essential for smooth
shifts between different motor programs, but has no role in
the generation of motor programs (Roberts et al. 1992).
Matsumoto etal. (2007) reached a similar conclusion based
on observations of the swimming performance of goldsh
with a partially ablated corpus cerebelli. In addition to the
function in motor control, recent studies also suggest that the
teleost corpus cerebelli has a critical role in learning, memory, and cognition. Ablation of the corpus cerebelli of goldsh impairs classical fear conditioning and spatial cognition
(Yoshida etal. 2004; Gómez etal. 2010). Additionally, local
anesthetization of the corpus cerebelli with drug application
resulted in similar impairment (Yoshida and Hirano 2010).
Genetical inhibition of a subset of granule cell transmission
in the l corpus cerebelli of zebrash larvae by expressing
botulinum toxin, which inhibits the release of neurotransmitters, does not interfere classical conditioning but rather
prolonged conditioning stimulus evoked bradycardia
responses (Matsuda et al. 2017). In addition, inhibition of
synaptic transmission of the granule cells and Purkinje cells
by expressing botulinum toxin inhibit active avoidance conditioning (Koyama etal. 2021). The combined application of
new techniques and traditional electrophysiology and behavioral analysis continues to improve our understanding of the
function of the teleost cerebellum.
References
Campbell HR, Meek J, Zhang J, Bell CC (2007) Anatomy of the pos-
terior caudal lobe of the cerebellum and the eminentia granularis
posterior in a mormyrid sh. J Comp Neurol 502:714–735
Dohaku R, Yamaguchi M, Yamamoto N, Shimizu T, Osakada F, Hibi M
(2019) Tracing of afferent connections in the zebrash cerebellum
using recombinant rabies virus. Front Neural Circuits 13:30
Gómez A, Durán E, Salas C, Rodríguez F (2010) Cerebellum
lesion impairs eyeblink-like classical conditioning in goldsh.
Neuroscience 166:49–60
Han VZ, Bell CC (2003) Physiology of cells in the central lobes of the
mormyrid cerebellum. J Neurosci 23:11147–11157
Harmon TC, McLean DL, Raman IM (2020) Integration of swimming-
related synaptic excitation and inhibition by olig2+ eurydendroid
neurons in larval zebrash cerebellum. J Neurosci 40:3063–3074
Ikenaga T, Yoshida M, Uematsu K (2002) Efferent connections of the
cerebellum of the goldsh, Carassius auratus. Brain Behav Evol
60:36–51
Ikenaga T, Yoshida M, Uematsu K (2005) Morphology and immuno-
histochemistry of efferent neurons of the goldsh corpus cerebelli. J
Comp Neurol 487:300–311
Ikenaga T, Yoshida M, Uematsu K (2006) Cerebellar efferent neurons
in teleost sh. Cerebellum 5:268–274
Ito H (1978) A catalogue of histological preparations of the teleost
brains. Med J Osaka Univ 28:219–228
Koyama W, Hosomi R, Matsuda K, Kawakami K, Hibi M, Shimizu T
(2021) Involvement of cerebellar nural circuits in active avoidance
conditioning in zebrash. eNeuro 8:0507–0520
Matsuda K, Yoshida M, Kawakami K, Hibi M, Shimizu T (2017)
Granule cells control recovery from classical conditioned fear
responses in the zebrash cerebellum. Sci Rep 7:11865
Matsumoto N, Yoshida M, Uematsu K (2007) Effects of partial ablation
of the cerebellum on sustained swimming in goldsh. Brain Behav
Evol 70:105–114
Meek J (1992) Comparative aspects of cerebellar organization. From
mormyrids to mammals. Euro J Morphol 30:37–51
Meek J, Nieuwenhuys R (1991) Palisade pattern of mormyrid Purkinje
cells: a correlated light and electron microscopic study. J Comp
Neurol 306:156–192
Murakami T, Morita Y (1987) Morphology and distribution of the pro-
jection neurons in the cerebellum in a teleost, Sebastiscus marmo-
ratus. J Comp Neurol 256:607–623
Nelson JS (2006) Fishes of the world. Wiley, Hoboken
Nieuwenhuys R, Pouwels E, Smulders-Kersten E (1974) The neuronal
organization of cerebellar lobe C1in the mormyrid sh Gnathonemus
petersii (Teleostei). Z Anat Entwickl-Gesch 144:315–336
Roberts BL, Van Rossem A, de Jager S (1992) The inuence of cerebel-
lar lesions on the swimming performance of the trout. J Exp Biol
167:171–178
Wullimann MF, Northcutt RG (1988) Connections of the corpus cer-
ebelli in the green sunsh and common goldsh: a comparison of
perciform and cypriniform teleost. Brain Behav Evol 32:293–316
Wullimann MF, Northcutt RG (1989) Afferent connections of the val-
vula cerebelli in two teleosts, the common goldsh and the green
sunsh. J Comp Neurol 289:554–567
Yoshida M, Okamura I, Uematsu K (2004) Involvement of the cere-
bellum in classical fear conditioning in goldsh. Behav Brain Res
153:143–148
Yoshida M, Hirano R (2010) Effect of local anesthesia of the cer-
ebellum on classical fear conditioning in goldsh. Behav Brain
Functions 6:20
Bae YK, Kani S, Shimizu T, Tanabe K, Nojima H, Kimura Y, Higashijima
S, Hibi M (2009) Anatomy of zebrash cerebellum and screen for
mutations affecting its development. Dev Biol 330:406–426
Lurcher Mouse
https://t.me/medicina_free
JanCendelin, JanTuma, andZdenkaPurkartova
63
Abstract
Lurcher mutant mouse is a natural model of hereditary
cerebellar degeneration which is caused by a mutation in
the δ2 glutamate receptor encoding gene. Heterozygous
Lurcher mice suffer from virtually complete loss of
Purkinje cells and the degeneration of cerebellar interneurons, deep cerebellar nuclei, and inferior olive neurons.
Progressive cerebellar degeneration in Lurcher mice
affects motor and cognitive functions, as well as emotional processing and behavior.
Keywords
Ataxia · Cerebellar degeneration · Grid2
Lc
63.1 Introduction
The Lurcher mouse, one of the most studied animal models
of cerebellar degeneration and ataxia, was discovered as a
spontaneous mutant in a colony at the Medical Research
Council Radiobiological Research Unit at Harwell, England
in 1954, and was rst described by Phillips in 1960 (Phillips
1960). The cerebellar degeneration is caused by a semidomi-
nant Grid2Lc mutation in the δ2 glutamate receptor (GluRδ2)
encoding gene on chromosome 6 (Phillips 1960; Zuo etal.
1997). Later, a second Lurcher allele (LcJ), which is pheno-
typically indistinguishable from Grid2Lc, was found (De
Jager et al. 1997). Homozygous Lurcher mice (Lc/Lc) die
shortly after birth, due to the massive degeneration of midand hindbrain neurons during late embryogenesis, which
results in their inability to suck after birth (Cheng and Heintz
1997). Heterozygous Lurcher mice (+/Lc) are viable with a
normal lifespan, but suffer from olivocerebellar degeneration
(Figs.63.1 and 63.2). Wild-type (+/+) littermates are normal,
healthy mice, which can serve as controls in experiments.
J. Cendelin (*)
Department of Pathophysiology, Faculty of Medicine in Pilsen,
Charles University, Plzen, Czech Republic
Laboratory of Neurodegenerative Disorders, Biomedical Center,
Faculty of Medicine in Pilsen, Charles University,
Plzen, Czech Republic
e-mail: jan.cendelin@lfp.cuni.cz
© 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_63
J. Tuma · Z. Purkartova
Department of Pathophysiology, Faculty of Medicine in Pilsen,
Charles University, Plzen, Czech Republic
e-mail: jan.tuma@lfp.cuni.cz; zdenka.purkartova@lfp.cuni.cz
403
404
ab
https://t.me/medicina_free
Fig. 63.1 Cerebellum of a wild-type mouse (a) and substantially reduced cerebellum of an adult Lurcher mouse (b). Sagittal sections, Nissl
staining
J. Cendelin et al.
abc
Fig. 63.2 Cerebellar cortex of a wild-type mouse (a) and the cerebel-
lum of a Lurcher mouse with residua of Purkinje cells (b) aged 20days.
Degenerating Purkinje cell, with two main dendrites, in a 17-day-old
63.2 Morphological Changes
intheLurcher Mutant Central
Nervous System
Lurcher mouse (c). Arrows indicate Purkinje cells. Double staining
with Lucifer yellow and DiD oil
of synaptogenesis with parallel bers (Caddy and Biscoe
1979; Dumesnil-Bousez and Sotelo 1992; Purkartová and
Vo žeh 2013) (Fig.63.2c).
About 56% of granule cells die between postnatal days
Heterozygous Lurcher mouse pathology consists of early
onset postnatal loss of cerebellar Purkinje cells (Fig.63.2)
and the degeneration of cerebellar interneurons, deep cerebellar nuclei, and inferior olive neurons. About 95% of
Purkinje cells die between postnatal days 8 and 25 and virtually all of them degenerate by 3months after birth (Caddy
and Biscoe 1979). Nevertheless, in the paraocculus, occulus, and nodular zone, several hundred surviving Purkinje
cells can be found as late as postnatal day 146 (Dufn etal.
2010). Degenerating Purkinje cells show typically hyperspi-
nous dendrites, increased numbers of nucleoli, multiple primary dendrites, and, after postnatal day 10, decreased rates
8 and 12, and by day 60, only 10% are still alive (Caddy
and Biscoe 1979). There is also extensive loss of Golgi,
stellate, and basket cells (Caddy and Biscoe 1979; Zanjani
etal. 2006). On the other hand, degeneration of the deep
cerebellar nuclei is relatively mild (Heckroth 1994; Sultan
etal. 2002). Loss of inferior olive neurons becomes appar-
ent by postnatal day 11 and represents about 70–75% of
the population (Caddy and Biscoe 1979). The reduction of
neuronal populations and overall cerebellar volume
(Fig.63.1) are accompanied by increased relative densities of microvessels in the Lurcher cerebellum (Kolinko
etal. 2016).
63 Lurcher Mouse
https://t.me/medicina_free
405
63.3 Pathogenesis
oftheNeurodegeneration
inLurcherMice
GluRδ2 is expressed at high levels in Purkinje cells and at
lower levels in some hindbrain neurons (Araki etal. 1993).
The Grid2Lc mutation is a base-pair substitution (G-to-A)
that replaces a non-polar alanine with a polar threonine in the
transmembrane domain III of the GluRδ2 (Zuo etal. 1997).
It is a gain-of-function mutation, changing the receptor into
a leaky membrane channel (Zuo et al. 1997). Therefore,
Lurcher Purkinje cells have a depolarized resting potential,
due to the presence of a constitutive inward Na+ current (Zuo
etal. 1997). Permanent excitation of the cells accompanied
by Na+–K+ ATPase over-activation increases the demand for
energy and induces ATP depletion (Nishiyama and Yuzaki
2010). Depolarization is probably the primary reason for
cell-autonomous Purkinje cell death in Lurcher mice (Wetts
and Herrup 1982a, b; Zuo etal. 1997).
Zuo etal. (1997) suggested excitotoxic apoptosis as the
mechanism of Purkinje cell extinction. The role of apoptosis
is supported by the presence of apoptotic bodies engulfed by
glial cells, the absence of inltration with leukocytes
(Norman etal. 1995), and by the increase in pro-caspase 3
expression (Selimi et al. 2000). On the other hand, some
ultrastructural signs, including enlarged mitochondria with
dilated cristae, indicate necrotic cell death (DumesnilBousez and Sotelo 1992). Yue et al. (2002) suggested an
autophagic death mechanism, and Wang et al. (2006)
described an accumulation of autophagosomes in axonal
dystrophic swellings of Lurcher Purkinje cells. Induction of
autophagy could be a response to a lack of ATP (Nishiyama
and Yuzaki 2010). Finally, there is some evidence that multiple cell death pathways are induced (Nishiyama and Yuzaki
2010; Zanjani etal. 2013).
Apoptosis of granule cells and inferior olive neurons, and
probably the degeneration of stellate and basket cells as well,
are target-related (transsynaptic) cell death, secondary to the
extinction of Purkinje cells (Wetts and Herrup 1982a, b;
Vogel etal. 1989; Zanjani etal. 2006).
Markers of inammation and glial reaction have been
detected in the Lurcher mouse cerebellum during the degenerative process (Vernet-der Garabedian et al. 1998, 2013;
Cairns etal. 2017).
63.4 Functional Impairments
Progressive cerebellar degeneration in Lurcher mutant mice
affects a broad spectrum of neural functions and provides
insights into the role of the cerebellum in circuitries related
to motor, cognitive, and emotional processing.
63.4.1 Motor Functions
Lurcher mice are characterized by marked cerebellar ataxia.
The gait is wobbly, lurching and with a tendency to fall to
either side. It is not accompanied by trembling to the extent
seen in other cerebellar mutants, but rather by jerky up-anddown movements (Phillips 1960). Particularly, locomotion
speed-dependent gait parameters are changed in Lurcher
mice (Cendelin et al. 2010). The step ratio and inter-limb
coupling are highly variable, and disorganization of cyclic
limb movements accompanied by an irregular EMG pattern
are seen during walking, but not during swimming (Fortier
et al. 1987). The abnormal locomotion pattern is even
reected in changed bone biomechanical properties (Jindrová
etal. 2016). The motor disabilities of Lurchers result in poor
performances on many of the tests that assess various aspects
of motor function. Affected dynamic equilibrium and motor
coordination were observed on the rotarod (Thullier et al.
1997; Hilber and Caston 2001; Cendelin et al. 2014). The
wooden beam (Le Marec etal. 1997) and unstable platform
(Hilber etal. 1999) tests showed impaired static equilibrium.
Although Lurcher mice possess both optokinetic and
vestibulo- ocular compensatory reexes, they exhibited
altered dynamics and an inability to modify these reexes in
the course of training (Van Alphen etal. 2002). Despite their
motor decits and an age-related decline in learning ability,
Lurchers are still capable of some motor task learning (Hilber
and Caston 2001).
63.4.2 Cognitive andBehavioral
Abnormalities
Lurcher mice show a wide spectrum of cognitive and
behavioral disturbances. Belzung etal. (2001) found that
both spatial working memory and reference memory are
impaired. In the Morris water maze, Lurchers show
impairment in both hidden and visible platform tasks
(Lalonde etal. 1988; Cendelin etal. 2014). Therefore, the
decit in visuomotor coordination has been suggested as
one of the key factors (Lalonde and Thifault 1994),
although Lurchers are in part able to use visual navigation
to the visible goal (Tuma etal. 2015). Anyway, certain
residuum of learning capacity in the water maze is preserved, but it is not clear whether it is spatial learning or
whether performance improvement is due to procedural
learning (Tuma etal. 2017). All of these ndings suggest
that Lurcher mutants are unable to construct a cognitive
map and use an associative route strategy rather than a
true spatial strategy based on cognitive mapping (Hilber
etal. 1998). It has also been proposed that the poor performance of Lurcher mice in spatial learning tests might
406
https://t.me/medicina_free
J. Cendelin et al.
be of complex origin, combining specic cognitive
impairment, motor decit, and abnormal affective and
behavioral abnormalities (Tuma etal. 2015). Disturbance
of classically conditioned eyelid responses has also been
reported (Porras-Garcia etal. 2005), with changes in the
performance of conditioned responses rather than in their
acquisition (Lopez-Ramos etal. 2018).
Lurcher mutants have higher corticosterone release
after the exposure to the stressful environment during the
behavioral test (Frederic etal. 1997; Hilber etal. 2004;
Tuma et al. 2017). Higher stress reactivity on the hormonal level is supported by the nding of larger adrenal
glands in Lurcher mice (Tuma etal. 2017). The contrast
between enhanced corticosterone elevation and less anxiety-like behavior during stressful situations suggests that
Lurcher mice have a reduced capacity to inhibit selective
components of natural behaviors (Frederic et al. 1997;
Hilber etal. 2004). An inhibition decit was demonstrated
by their inability to produce prepulse inhibition of the
acoustic startle response (Porras-Garcia etal. 2005), the
immobility response (Lalonde 1998; Tuma etal. 2015),
and abnormal behavior in various anxiogenic situations
(Lorivel etal. 2014, 2021). The discrepancy between the
hypothalamic-pituitary-adrenal axis reaction and the disproportional neural control of behavior could be due to an
affection of the sensorimotor gating mechanism (PorrasGarcia etal. 2005). Behavioral disinhibition and loss of
motivation could also inuence exploratory behavior,
which is signicantly reduced despite an increase in spontaneous activity (Caston etal. 1998).
On the neuronal circuitry level, cerebellar degeneration
is associated with reorganization or dysfunction of connections with other brain structures in Lurcher mice. For
instance, Lurcher mice have attenuated modulation of
medial prefrontal cortex dopamine transmission (Rogers
etal. 2013).
63.5 Concluding Remarks
Lurcher mice can originate from one of several background
strains, e.g., B6CBA, C3H, and B6× BALB.Even though
the genetic background affects the complex features of the
mice, the Grid2Lc mutation leads to a strong pathological
phenotype that is independent of the strain of origin (Cendelin
etal. 2014). In 2015, analogous mutation was discovered in
human patients with cerebellar ataxia and Lurcher mouse
became a model of a specic human disease (Coutelier etal.
2015). For these reasons, as well as for well-dened neuron
loss, Lurcher mice are still a valuable model for investigation
of pathogenesis, manifestations, and experimental therapy of
hereditary cerebellar degenerations.
References
Araki K, Meguro H, Kushiya E, Takayama C, Inoue Y, Mishina M
(1993) Selective expression of the glutamate receptor channel
delta 2 subunit in cerebellar Purkinje cells. Biochem Biophys Res
Commun 197:1267–1276
Belzung C, Chapillon P, Lalonde R (2001) The effects of the lurcher
mutation on object localization, T-maze discrimination, and radial
arm maze tasks. Behav Genet 31:151–155
Caddy KW, Biscoe TJ (1979) Structural and quantitative studies on the
normal C3H and Lurcher mutant mouse. Philos Trans R Soc Lond
Ser B Biol Sci 287:167–201
Cairns J, Swanson D, Yeung J, Sinova A, Chan R, Potluri P, Dickson
P, Mittleman G, Goldowitz D (2017) Abnormalities in the structure
and function of cerebellar neurons and neuroglia in the Lc/+ chimeric mouse model of variable developmental purkinje cell loss.
Cerebellum 16:40–54
Caston J, Chianale C, Delhaye-Bouchaud N, Mariani J (1998) Role of
the cerebellum in exploration behavior. Brain Res 808:232–237
Cendelin J, Voller J, Vozeh F (2010) Ataxic gait analysis in a mouse
model of the olivocerebellar degeneration. Behav Brain Res
210:8–15
Cendelin J, Tuma J, Korelusova I, Vozeh F (2014) The effect of genetic
background on behavioral manifestation of Grid2(Lc) mutation.
Behav Brain Res 271:218–227
Coutelier M, Burglen L, Mundwiller E, Abada-Bendib M, Rodriguez
D, Chantot-Bastaraud S, Rougeot C, Cournelle MA, Milh M,
Toutain A, Bacq D, Meyer V, Afenjar A, Deleuze JF, Brice A, Heron
D, Stevanin G, Durr A (2015) GRID2 mutations span from congenital to mild adult-onset cerebellar ataxia. Neurology 84:1751–1759
De Jager PL, Zuo J, Cook SA, Heintz N (1997) A new allele of the
lurcher gene, lurcherJ.Mamm Genome 8:647–650
Dufn CA, McFarland R, Sarna JR, Vogel MW, Armstrong CL (2010)
Heat shock protein 25 expression and preferential Purkinje cell
survival in the lurcher mutant mouse cerebellum. J Comp Neurol
518:1892–1907
Dumesnil-Bousez N, Sotelo C (1992) Early development of the Lurcher
cerebellum: Purkinje cell alterations and impairment of synaptogenesis. J Neurocytol 21:506–529
Fortier PA, Smith AM, Rossignol S (1987) Locomotor decits in the
mutant mouse, Lurcher. Exp Brain Res 66:271–286
Frederic F, Chautard T, Brochard R, Chianale C, Wollman E, Oliver
C, Delhaye-Bouchaud N, Mariani J (1997) Enhanced endocrine
response to novel environment stress and endotoxin in Lurcher
mutant mice. Neuroendocrinology 66:341–347
Heckroth JA (1994) Quantitative morphological analysis of the cerebel-
lar nuclei in normal and lurcher mutant mice. I.Morphology and
cell number. J Comp Neurol 343:173–182
Hilber P, Jouen F, Delhaye-Bouchaud N, Mariani J, Caston J (1998)
Differential roles of cerebellar cortex and deep cerebellar nuclei in
learning and retention of a spatial task: studies in intact and cerebellectomized lurcher mutant mice. Behav Genet 28:299–308
Hilber P, Lalonde R, Caston J (1999) An unsteady platform test for mea-
suring static equilibrium in mice. J Neurosci Methods 88:201–205
Hilber P, Caston J (2001) Motor skills and motor learning in Lurcher
mutant mice during aging. Neuroscience 102:615–623
Hilber P, Lorivel T, Delarue C, Caston J (2004) Stress and anxious-
related behaviors in Lurcher mutant mice. Brain Res 1003:108–112
Cheng SS, Heintz N (1997) Massive loss of mid- and hindbrain neu-
rons during embryonic development of homozygous lurcher mice. J
Neurosci 17:2400–2407
Jindrová A, Tuma J, Sládek V (2016) Impact of non-invasively induced
motor decits on tibial cortical properties in mutant lurcher mice.
PLoS One 11:e0158877
63 Lurcher Mouse
https://t.me/medicina_free
407
Kolinko Y, Cendelin J, Kralickova M, Tonar Z (2016) Smaller absolute
quantities but greater relative densities of microvessels are associated
with cerebellar degeneration in lurcher mice. Front Neuroanat 10:35
Lalonde R, Lamarre Y, Smith AM (1988) Does the mutant mouse
lurcher have decits in spatially oriented behaviours? Brain Res
455:24–30
Lalonde R, Thifault S (1994) Absence of an association between motor
coordination and spatial orientation in lurcher mutant mice. Behav
Genet 24:497–501
Lalonde R (1998) Immobility responses in Lurcher mutant mice. Behav
Genet 28:309–314
Le Marec N, Caston J, Lalonde R (1997) Impaired motor skills on
static and mobile beams in lurcher mutant mice. Exp Brain Res
116:131–138
Lopez-Ramos JC, Houdek Z, Cendelin J, Vozeh F, Delgado-Garcia JM
(2018) Timing correlations between cerebellar interpositus neuronal
ring and classically conditioned eyelid responses in wild-type and
Lurcher mice. Sci Rep 8:10697
Lorivel T, Roy V, Hilber P (2014) Fear-related behaviors in Lurcher
mutant mice exposed to a predator. Genes Brain Behav 13:794–801
Lorivel T, Cendelin J, Hilber P (2021) Familiarization effects on the
behavioral disinhibition of the cerebellar Lurcher mutant mice: use
of the innovative Dual Maze. Behav Brain Res 398:112972
Nishiyama J, Yuzaki M (2010) Excitotoxicity and autophagy: lurcher
may not be a model of “autophagic cell death”. Autophagy 6:568–570
Norman DJ, Feng L, Cheng SS, Gubbay J, Chan E, Heintz N (1995)
The lurcher gene induces apoptotic death in cerebellar Purkinje
cells. Development 121:1183–1193
Phillips RJS (1960) “Lurcher”, a new gene in linkage group XI of the
house mouse. J Genet 57:35–42
Porras-Garcia E, Cendelin J, Dominguez-del-Toro E, Vozeh F, Delgado-
Garcia JM (2005) Purkinje cell loss affects differentially the execu-
tion, acquisition and prepulse inhibition of skeletal and facial motor
responses in Lurcher mice. Eur J Neurosci 21:979–988
Purkartová Z, Vožeh F (2013) Cerebellar degeneration in Lurcher
mice under confocal laser scanning microscope. Microsc Res Tech
76:545–551
Rogers TD, Dickson PE, McKimm E, Heck DH, Goldowitz D, Blaha
CD, Mittleman G (2013) Reorganization of circuits underlying cer-
ebellar modulation of prefrontal cortical dopamine in mouse models
of autism spectrum disorder. Cerebellum 12:547–556
Selimi F, Doughty M, Delhaye-Bouchaud N, Mariani J (2000) Target-
related and intrinsic neuronal death in Lurcher mutant mice are both
mediated by caspase-3 activation. J Neurosci 20:992–1000
Sultan F, Konig T, Mock M, Thier P (2002) Quantitative organization
of neurotransmitters in the deep cerebellar nuclei of the Lurcher
mutant. J Comp Neurol 452:311–323
Thullier F, Lalonde R, Cousin X, Lestienne F (1997) Neurobehavioral
evaluation of lurcher mutant mice during ontogeny. Brain Res Dev
Brain Res 100:22–28
Tuma J, Kolinko Y, Vozeh F, Cendelin J (2015) Mutation-related dif-
ferences in exploratory, spatial, and depressive-like behavior in
pcd and Lurcher cerebellar mutant mice. Front Behav Neurosci
9:116
Tuma J, Kolinko Y, Jelinkova D, Hilber P, Cendelin J (2017) Impaired
spatial performance in cerebellar-decient Lurcher mice is not associated with their abnormal stress response. Neurobiol Learn Mem
140:62–70
Van Alphen AM, Schepers T, Luo C, De Zeeuw CI (2002) Motor per-
formance and motor learning in Lurcher mice. Ann N Y Acad Sci
978:413–424
Vernet-der Garabedian B, Lemaigre-Dubreuil Y, Delhaye-Bouchaud N,
Mariani J (1998) Abnormal IL-1beta cytokine expression in the cerebellum of the ataxic mutant mice staggerer and lurcher. Brain Res
Mol Brain Res 62:224–227
Vernet-der Garabedian B, Derer P, Bailly Y, Mariani J (2013) Innate
immunity in the Grid2Lc/+ mouse model of cerebellar neurodegeneration: glial CD95/CD95L plays a non-apoptotic role in persistent
neuron loss-associated inammatory reactions in the cerebellum. J
Neuroinammation 10:65
Vogel MW, Sunter K, Herrup K (1989) Numerical matching between
granule and Purkinje cells in lurcher chimeric mice: a hypothesis for
the trophic rescue of granule cells from target-related cell death. J
Neurosci 9:3454–3462
Wang QJ, Ding Y, Kohtz DS, Mizushima N, Cristea IM, Rout MP, Chait
BT, Zhong Y, Heintz N, Yue Z (2006) Induction of autophagy in
axonal dystrophy and degeneration. J Neurosci 26:8057–8068
Wetts R, Herrup K (1982a) Interaction of granule, Purkinje and inferior
olivary neurons in lurcher chimaeric mice. I.Qualitative studies. J
Embryol Exp Morpholog 68:87–98
Wetts R, Herrup K (1982b) Interaction of granule, Purkinje and infe-
rior olivary neurons in lurcher chimeric mice. II.Granule cell death.
Brain Res 250:358–362
Yue Z, Horton A, Bravin M, DeJager PL, Selimi F, Heintz N (2002) A
novel protein complex linking the delta 2 glutamate receptor and
autophagy: implications for neurodegeneration in lurcher mice.
Neuron 35:921–933
Zanjani HS, Lohof AM, McFarland R, Vogel MW, Mariani J (2013)
Enhanced survival of wild-type and Lurcher Purkinje cells invitro
following inhibition of conventional PKCs or stress-activated MAP
kinase pathways. Cerebellum 12:377–389
Zanjani SH, Selimi F, Vogel MW, Haeberle AM, Boeuf J, Mariani J,
Bailly YJ (2006) Survival of interneurons and parallel ber synapses in a cerebellar cortex deprived of Purkinje cells: studies in
the double mutant mouse Grid2Lc/+;Bax(−/−). J Comp Neurol
497:622–635
Zuo J, De Jager PL, Takahashi KA, Jiang W, Linden DJ, Heintz N
(1997) Neurodegeneration in Lurcher mice caused by mutation in
delta2 glutamate receptor gene. Nature 388:769–773
The Tottering Mouse
https://t.me/medicina_free
RussellE.Carter andTimothyJ.Ebner
64
Abstract
In the late 1950s, a novel spontaneous mutation was found
in the same litter of mice while breeding by Green and
Sidman at the Roscoe B.Jackson Memorial Laboratory in
Maine. Mice harboring this mutation, which was found to
be recessive, were termed tottering (tg/tg) mice, and
exhibited a series of neurological abnormalities, includ-
ing a paroxysmal motor disturbances (dyskinesia/dysto-
nia), a wobbly ataxic gait, and absence seizures. Since the
initial discovery of this mutation, numerous studies have
investigated the underlying genetics and behavioral con-
sequences in the tg/tg mouse, and this mouse has proven
useful in our understanding of several episodic neurologi-
cal disorders involving the cerebellum. Caused by a muta-
tion in the Cacna1a gene that encodes the P/Q-type
voltage-gated Ca2+ channel, the tg/tg mouse is a model for
the human disorder episodic ataxia type 2 (EA2) and has
provided insights into the mechanisms of episodic cere-
bellar dysfunction.
Keywords
Ataxia · EA2 · Channelopathies · Dystonia · CACNA1A
64.1 Introduction
In the late 1950s, a novel spontaneous mutation was found in
the same litter of mice while breeding at the Roscoe
B. Jackson Memorial Laboratory in Maine (Green and
Sidman 1962). Mice harboring this mutation, which was
found to be recessive, were termed tottering (tg/tg) mice and
exhibited a series of neurological abnormalities, including
paroxysmal motor disturbances (dyskinesia/dystonia), a
R. E. Carter · T. J. Ebner (*)
Department of Neuroscience, University of Minnesota,
Minneapolis, MN, USA
e-mail: recarter@umn.edu; ebner001@umn.edu
wobbly ataxic gait, and absence seizures (Green and Sidman
1962; Noebels and Sidman 1979). Since the initial discovery
of this mutation, numerous studies have investigated the
underlying genetics and behavioral consequences in the tg/tg
mouse, and this mouse has proven useful in our understanding of several episodic neurological disorders involving the
cerebellum.
64.2 Tottering Mouse: ACalcium
Channelopathy
The spontaneous recessive mutation was identied as a missense mutation, resulting in a substitution of leucine for proline, in the Cacna1a gene encoding the α 1A subunit of the
P/Q-type voltage-gated Ca2+ channel (CaV2.1) (Fletcher etal.
1996). This mutation results in an approximate 30–40%
reduction in P/Q-type Ca2+ channel current without changes
in the kinetics of the channel (Wakamori etal. 1998). Many
neurological disorders are caused by mutations in genes
encoding ion channels, termed channelopathies. A common
feature among channelopathies is the occurrence of episodic
symptoms, including hemiplegic migraine, seizures, periodic paralysis, paroxysmal dyskinesia/dystonia, and episodic
ataxia (for reviews see (Jen etal. 2004; Ptacek and Fu 2001;
Pietrobon 2010; Ryan and Ptacek 2010)). These episodic
symptoms can often have external triggering factors, such as
fatigue, exercise, ethanol, caffeine, and emotional or psychological stress (Ptacek and Fu 2001; Ryan and Ptacek 2010).
However, the mechanisms by which a permanent abnormality in an ion channel leads to transient dysfunction of the
nervous system are generally unknown.
The tg/tg mouse has been a widely used model to investigate an autosomal dominant Ca2+ channelopathy that occurs
in humans called episodic ataxia type 2 (EA2). Over 70
known mutations in the human CACNA1A gene encoding the
α1A subunit of the P/Q-type Ca2+ channel can lead to the
development of EA2 (Jen et al. 2004; Pietrobon 2010;
Rajakulendran et al. 2010). EA2 patients suffer from epi-
© 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_64
409
410
https://t.me/medicina_free
R. E. Carter and T. J. Ebner
sodic cerebellar dysfunction, and for periods lasting from
tens of minutes to days at a time, they can exhibit severe
ataxia and dyskinesia/dystonia (Jen etal. 2004; Baloh etal.
1997). In addition to these episodic cerebellar symptoms,
patients also show non-cerebellar symptoms including
migraine, hemiplegic paralysis, vertigo, and weakness (Jen
etal. 2004). Stress, caffeine, and alcohol act as triggers for
episodic dysfunction in tg/tg mice and EA2 patients
(Fureman etal. 2002; Raike etal. 2005). Additionally, the
episodic motor dysfunction in EA2 patients and tg/tg mice is
decreased by both carbonic anhydrase inhibitors, such as
acetazolamide (Griggs etal. 1978), as well as 4- aminopyridine
(Strupp et al. 2004), further suggesting that studying the
underlying mechanisms in the tg/tg mouse can be a useful
tool to understand and develop further treatments for EA2.
64.3 Tottering Behavioral Phenotype
The behavioral phenotype of the tg/tg mouse is quite complex, and typically has three major components that appear
3–4weeks after birth (Green and Sidman 1962). One of the
main neurological features of the tg/tg mouse is absence seizures, dened by bilateral, synchronous 6–7 Hz cortical
spike-and-wave or polyspike discharges in electroencephalographic (EEG) recordings (Noebels and Sidman 1979),
which can last for 1–3s at a time and can occur very frequently, more than 30 times per hour.
Secondly, and most striking of the neurological symptoms in the tg/tg mouse, is the occurrence of paroxysmal
motor attacks. Originally referred to as a focal seizure (Green
and Sidman 1962), these motor attacks have more recently
been conrmed to be episodic dyskinesia/dystonia, as they
have no comparable seizure-like EEG activity and do not
respond to antiepileptic drugs (Noebels and Sidman 1979;
Campbell and Hess 1999). The episodic attacks progress
from the hind limbs toward the head (a “Jacksonian march”),
until the entire body is undergoing the dystonic attack.
Recovery occurs in the same order that the attack started,
with the hind limbs recovering rst and progressing toward
the head. These attacks can last from 30 to 60min and occur
one to two times a day (Green and Sidman 1962).
The nal major feature of the tg/tg mouse is a baseline
mild ataxia that primarily involves the hind limbs and tail,
and was originally described as a wobbly gait (Green and
Sidman 1962). Recently, a study using high-speed video and
EMG documented poorly coordinated movements and
reduced muscle activity during treadmill locomotion in the
tg/tg mice (Scholle etal. 2010).
64.4 P/Q-Type Ca2+ Channel andCerebellar
Dysfunction
P/Q-type Ca2+ channels have a wide distribution in the nervous system and are found in the presynaptic terminals,
soma, and dendrites of neurons (Mintz etal. 1992; Fletcher
etal. 1996; Westenbroek etal. 1995), with moderate to high
levels of expression in the cerebellum, cerebral cortex, hippocampus, and olfactory bulb. With high expression levels in
the presynaptic terminals, P/Q-type Ca2+ channels are the
major contributors of neurotransmitter release (for review,
see (Pietrobon 2010)). There is abundant expression of P/Q- type Ca2+ channels in cerebellar granule and Purkinje cells
(Westenbroek et al. 1995; Mintz et al. 1992). With the
decreased current ow through the P/Q-type Ca2+ channels
in tg/tg mice, there is an impairment in the parallel berPurkinje cell synaptic transmission (Matsushita etal. 2002;
Chen etal. 2009). This decrease in synaptic transmission is
age-related, and develops in parallel with the behavioral phenotype. Additionally, one of the outputs of Purkinje cells, the
simple spikes, exhibits higher variability in tg/tg mice compared to wild-type, and similar variability can be induced in
wild-type mice by blocking P/Q-type Ca2+ channels (Walter
et al. 2006; Hoebeek et al. 2005). While these changes in
cerebellar synaptic transmission are static, and likely contribute to the baseline ataxia in tg/tg mice, it remains unclear
how episodic dysfunctions such as dystonic attacks can arise.
Recently, episodic, low-frequency neuronal oscillations
(0.03–0.1Hz) were observed spontaneously in the cerebellar
cortex of tg/tg mice invivo (Chen etal. 2009). While present,
the oscillations disrupted the beam-like response evoked by
parallel ber stimulation, suggesting that cerebellar cortical
physiology is highly abnormal during the oscillations.
Additionally, in awake animals, caffeine administration signicantly increased the oscillations and induced episodic
dystonic attack (Chen et al. 2009). It was also found that
similar low-frequency oscillations are also prominent in the
cerebral cortex, implying that the tg/tg mutation can lead to
instabilities throughout the entire CNS (Cramer etal. 2015).
These low-frequency oscillations provide a potential mechanism for how cerebellar and non-cerebellar episodic dysfunctions occur in the tg/tg mouse.
64.5 Beyond P/Q-Type Channels
Several other alterations in cerebellar protein expression
have been reported in the tg/tg mouse. There is an increased
expression of L-type Ca2+ channels in the cerebellum, and it
Соседние файлы в папке Библиотека им академика М.И. Перельмана