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Neuroactive Steroids
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C.FernandoValenzuela andSamanthaVarela
37
Abstract
Neuroactive steroids regulate neuronal and glial function
via non-genomic mechanisms by interacting with ion
channels and neurotransmitter receptors. The adrenal
glands and gonads are important sources of neuroactive
steroids. In addition, neuroactive steroids can be produced
locally within the central nervous system and these agents
are denoted as neurosteroids. Enzymes involved in
neurosteroid biosynthesis are expressed in the cerebel-
lum, where these agents modulate the development of
cerebellar neurons as well as glial cells. Neurosteroids
also exert neuroprotective actions and modulate synaptic
transmission and plasticity in mature neurons. Decits in
cerebellar neuroactive steroid signaling may play a role in
the pathophysiology of several conditions involving the
cerebellum, including Niemann–Pick type C disease, ges-
tational dietary deciency of methyl donors (folate and
vitamin B12), prenatal stress, brain tumors, schizophre-
nia, autism, mood disorders, and alcohol use disorder. In
addition, neuroactive steroids are emerging as potential
therapeutic agents for a number of diseases that impair
cerebellar function.
Keywords
Steroid · Neurotransmitter · Receptor · Channel
Synaptic · Plasticity · Enzyme
37.1 Introduction
Steroid hormones are derived from cholesterol and bind to
ligand-dependent nuclear receptors that act as transcription
factors, controlling the expression of a wide range of genes
involved in numerous physiological and pathophysiological
processes in many brain regions, including the cerebellum
(Mahfouz et al. 2016; Pillerová et al. 2021; Zsarnovszky
etal. 2018). Steroids also regulate neuronal function via non-
genomic mechanisms by interacting with ion channels and
metabotropic receptors; these agents are known as neuroactive steroids. Major sources of neuroactive steroids (or their
precursors) are the adrenal glands and gonads; because steroids are lipophilic, they can efciently cross the blood–
brain barrier (Gatta et al. 2021; Guennoun 2020; Kudova
2021; Lloyd-Evans and Waller-Evans 2020). In addition,
neuroactive steroids are produced locally in glial and neuronal cells of the central nervous system—independently of
peripheral organs—and these compounds are known as
neurosteroids (Kudova 2021; Schverer et al. 2018).
Neuroactive steroids regulate many neuronal functions
including neurotransmitter release, neuronal plasticity, and
neuronal excitability (Kudova 2021; Lloyd-Evans and
Waller-Evans 2020; Schverer etal. 2018). These agents have
important roles in a variety of neuropsychiatric disorders,
including epilepsy, substance abuse, multiple sclerosis,
depression, and Alzheimer’s disease (Lloyd-Evans and
Waller-Evans 2020; Gatta etal. 2021). In the next sections,
we will discuss the specic roles of neuroactive steroids on
cerebellar physiology and pathophysiology.
C. F. Valenzuela (*) · S. Varela
Department of Neurosciences, MSC08 4740, School of Medicine,
University of New Mexico Health Sciences Center,
Albuquerque, NM, USA
e-mail: FValenzuela@salud.unm.edu; SaVarela@salud.unm.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_37
37.2 Physiological Eects
37.2.1 Developing Cerebellum
Several of the enzymes involved in neurosteroid biosynthesis
are expressed in the cerebellum (Fig. 37.1) (Ukena et al.
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C. F. Valenzuela and S. Varela
Fig. 37.1 Neurosteroid Biosynthetic Pathway. Enzymes shown in bold
and italics have been identied in the cerebellum. Steroid 17 alphahydroxylase/17,20 lyase (P450
); pregnenolone sulfate (PREGS);
C17
1998, 1999; Agís-Balboa etal. 2006; Kiyokage etal. 2014;
Sakamoto etal. 2003; Kríz etal. 2008; Yarim and Kabakci
2004). Purkinje cells (PCs) express cholesterol side chain
cleavage enzyme (P450
) during neonatal life and adult-
scc
hood (Ukena etal. 1998). Pregnenolone sulfate, a neuroactive steroid formed through the P450scc pathway, potentiates
glutamatergic transmission at climbing ber-PC synapses in
neonatal rats, an effect mediated by an increase in presynaptic Ca2+ levels acting on steroid-sensitive transient receptor
potential melastatin 3 receptors (Zamudio-Bulcock et al.
2011; Zamudio-Bulcock and Valenzuela 2011). During neo-
natal life, rat PCs and external granule cells (GrCs) express
3β-hydroxysteroid dehydrogenase (3β-HSD) and generate
progesterone (Fig. 37.1)(Ukena et al. 1999). Progesterone
promotes dendritic outgrowth and increases spine density in
PCs via intracrine and/or paracrine activation of nuclear
receptors (Sakamoto et al. 2003). Progesterone and its
metabolites also promote cerebellar myelination (Ghoumari
etal. 2003). Allopregnanolone has also been detected in the
neonatal cerebellum where it promotes the survival of PCs
and GrCs (Sakamoto etal. 2003; Tsutsui etal. 2011; Yawno
etal. 2009). In samples from adolescent rats, immunohistochemical studies showed that 5α-reductase type I protein is
expressed in glial cells, indicating that these cells can synthesize 5α-dihydroprogesterone and possibly allopregnanolone
(Fig.37.1) (Kiyokage etal. 2014). In juvenile quails, allopregnanolone generated in the pineal gland promotes PC survival (Haraguchi etal. 2012).
In PCs and external GrCs from neonatal rats, high levels
of both aromatase (P450
) and estrogen can be detected
aromatase
(Fig. 37.1)(Sakamoto et al. 2003). Estradiol injection near
the vermis of postnatal day 6–9 rats increased dendritic
dehydroepiandrosterone (DHEA); DHEA sulfate (DHEAS). For other
enzyme abbreviations, see text
growth and spine density in PCs, perhaps via nuclear estrogen receptor-driven production of brain-derived neurotrophic
factor (Sakamoto et al. 2003; Sasahara et al. 2007). In
10–12-day-old rats, intracerebral injection of prostaglandin
E2 stimulated P450
activity and estradiol synthesis;
aromatase
this was associated with a decrease in dendritic length,
reduced spinophilin content, and altered excitability of PCs
(Dean et al. 2012). Estrogen administration was found to
affect levels of presynaptic (SNAP25, VAMP1, VAMP2) and
postsynaptic (PSD95) proteins in developing deep cerebellar
nuclei neurons (Manca etal. 2014).
37.2.2 Mature Cerebellum
Adult mice express 5α-reductase type I and 3α-HOR-II mRNA
in PCs and to a lesser extent in GrCs (Agís-Balboa etal. 2006).
The cerebellum of mature rodents can produce allopregnanolone (Grifn etal. 2004; Caruso etal. 2013). Allopregnanolone
and allotetrahydrodeoxycorticosterone potentiate synaptic
GABAA receptor function in PCs and GrCs (Cooper et al.
1999; Kelley etal. 2011). In GrCs and stellate cells, the effect
of allotetrahydrodeoxycorticosterone on synaptic GABAA
receptors depends on the presence of δ subunits (Vicini etal.
2002). Allotetrahydrodeoxycorticosterone potentiates tonic
currents mediated by δ subunit-containing extrasynaptic
GABAA receptors in rat cerebellar GrCs (Hamann etal. 2002).
Mature cerebellar PCs and GrCs express estrogen receptors (Hedges etal. 2012). Estrogen exerts rapid modulatory
effects on locomotor activity-induced PC ring in female
rats (Smith 1989). Gonadal estradiol facilitates the induction
of long-term potentiation and increases synaptic density at
37 Neuroactive Steroids
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239
parallel ber-to-PC synapses; activation of β-estrogen receptors in PCs enhances gain-decrease vestibulo-ocular reex
learning in mice (Andreescu etal. 2007). Subsequent optical
imaging studies demonstrated that endogenous estrogen
facilitates glutamatergic transmission at parallel ber-to-PC
synapses (Hedges et al. 2012). More recently, Dieni etal.
(2018a, b) found that blockade of 17β-estradiol synthesis
with a P450
inhibitor (letrozole, administered orally)
aromatase
in adult (150–170 days old) male rats abolished gain
increases and decreases in vestibulo-ocular reex adaptation
(similar effect was observed in 30–34 days old rats).
Letrozole prevented long-term potentiation but not longterm depression at parallel ber-to-PC synapses (Dieni etal.
2018a). Interestingly, P450
is expressed at low levels
aromatase
in adult PCs, suggesting that localized synthesis of
17β-estradiol mediates its effects on PC synaptic plasticity,
contributing to the regulation of vestibulo-ocular reex adaptation (Dieni etal. 2020, b; Tozzi etal. 2020).
37.3 Roles inCerebellar Diseases
37.3.1 Developing Cerebellum
In a mouse model of Niemann–Pick type C disease, a lysosomal lipid storage disorder, expression of 3α-hydroxysteroid
oxidoreductase II (3α-HOR-II) activity was found to be
reduced in the cerebellum and neonatal administration of
allopregnanolone increased survival of both PCs and GrCs
by a mechanism involving nuclear pregnane X receptors
(Grifn etal. 2004; Langmade etal. 2006).
Using a rat model of gestational dietary deciency of
methyl donors (folate and vitamin B12), El Hajj Chehadeh
etal. (2014) detected a reduction in the levels of the steroidogenic acute regulatory protein (involved in the transfer of
cholesterol from the outer to the inner mitochondrial membrane), P450
izing hormone receptors in PCs of postnatal day 21 female
offspring. Progesterone and estradiol levels were also found
to be decreased in the cerebellum of these female rats. These
ndings indicate that methyl donor deciency during gestation induces persistent decits in neuroactive steroids synthesis and function in PCs.
Mice pups decient in reelin, which have been used to
model some aspects of schizophrenia and autism, display
alterations in cerebellar neuroactive steroid levels at postnatal day 5 (increased testosterone and 17β-estradiol levels and
decreased dihydrotestosterone levels) as well as PC degeneration at postnatal day 15 that could be corrected by
17β-estradiol administration at postnatal day 5 (Biamonte
etal. 2009).
, estrogen receptors α and β, and lutein-
aromatase
The effect of prenatal stress on the actions of neurosteroids in the cerebellum was studied in guinea pigs (Bennett
etal. 2017). The investigators hypothesized that the developing cerebellum could be vulnerable to prenatal stress because
of its relatively high levels of glucocorticoid receptor expression. Guinea pigs were exposed to strobe light for 2hr. on
gestational days 50, 55, 60, and 65 (average guinea pig pregnancy duration is 67days). Advantages of using guinea pigs
include that the placental structure and function is more
similar to that of humans, gestation duration is more prolonged than in rodents, and newborns are more mature
(Morrison etal. 2018). It was found that prenatal stress produced age-dependent reductions in mature oligodendrocyte
numbers and reactive astrocytes in cerebellar lobule VIII of
term female offspring, but this effect disappeared by postnatal day 21. Levels of neurosteroid-sensitive GABAA receptors expressed in the extra-synaptic compartment of GrCs
(i.e., containing α6 and δ subunits) were reduced in a sex- and
age-dependent manner, whereas cerebellar 5α-reductase levels (Fig.37.1) were increased, which may represent a compensatory mechanism to maintain tonic GABAergic
inhibition (Bennett etal. 2017). These ndings indicate that
prenatal stress disrupts the actions of neurosteroids in the
developing cerebellum.
Studies suggest that neuroactive steroids play an important role in the pathophysiology of childhood tumors. One of
the most common malignant pediatric tumors is medulloblastoma, which originates in GrC-like precursors that
express elevated estrogen receptor levels (Belcher 2008).
Activation of these receptors with low physiologically relevant concentrations of estradiol rapidly activates extracellular signal-regulated kinase (ERK)1/2 via a G
protein-dependent mechanism and stimulates migration in a
cell line of cerebrocortical origin (Belcher 2008). More
recently, it was shown that estrogen stimulates growth of
medulloblastomas via estrogen receptor β-induced insulinlike growth factor-1 receptor signaling that increases survival of tumor cells (Cookman and Belcher 2015). Estrogen
and soy isoavonoids reduce medulloblastoma cell sensitivity to chemotherapy (Belcher et al. 2017). Antagonism of
estrogen receptors blocked the tumor-promoting effects of
estrogen in cultured cells and medulloblastoma human xenograft models (Belcher etal. 2009). These studies suggest that
estrogen receptor β signaling contributes to medulloblastoma tumorigenesis and that adjuvant antiestrogen therapy
could be benecial in the management of these tumors. It is
important to determine if neuroactive steroids play a role in
the biology of other cerebellar pediatric tumors (e.g., juvenile pilocytic astrocytomas and ependymomas). A recent
review indicates that astrocytomas are also hormonesensitive tumors (Hirtz etal. 2020).
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C. F. Valenzuela and S. Varela
37.3.2 Mature Cerebellum
Cerebellar neurosteroid levels were measured during normal
aging in wild-type mice and heterozygous staggerer mice,
which display precocious aging (Janmaat etal. 2011). Agingrelated decreases in 17β-estradiol, progesterone, and testosterone levels were correlated with Purkinje cell loss in these
mice; these effects occurred earlier in the staggerer mice.
Interestingly, locally produced cerebellar neurosteroids
(pregnenolone, 5α-dihydroprogesterone, and allopregnanolone) did not decline with age in either wild-type or staggerer
mice.
The cerebellum is also an important target of many abused
substances and plays an important role in the pathophysiology of substance use disorders (Moulton et al. 2014). A
recent study characterized neurosteroid pathways in human
male postmortem brains from alcohol-use disorder patients
and matching controls (Gatta etal. 2021). In samples from
patients with alcohol use disorder, cerebellar mRNA levels
for the 18-kDa translocator protein (involved in outer to
inner mitochondrial membrane transport of cholesterol),
3α-hydroxysteroid dehydrogenase (Fig. 37.1), and the
steroid- sensitive GABAA receptor δ subunit were signicantly reduced. The cerebellar 3α-hydroxysteroid dehydrogenase promoter exhibited elevated DNA methylation levels.
Cerebellar allopregnanolone and pregnanolone levels were
decreased. These ndings suggest that chronic alcohol exposure disrupts neurosteroid signaling in the cerebellum. It is
important to determine if other abused substances produce
similar effects.
37.4 Conclusions andFuture Directions
The cerebellum is an important target of neuroactive steroids
produced in peripheral glands, other brain regions (i.e., the
pineal gland), and the cerebellum itself. Developing PCs are
a major source of locally produced neurosteroids (i.e., progesterone and allopregnanolone), which contribute to the
maturation of dendrites, spines, and synapses in these neurons (Tsutsui and Haraguchi 2020). GABAA receptormodulating neurosteroids (e.g., allopregnanolone) are
produced in the mature cerebellum and regulate synaptic
transmission and excitability of PCs and GrCs. The function
of mature PCs and GrCs is modulated by estrogen receptors
that regulate synaptic transmission and plasticity, as well as
vestibulo-ocular reex adaptation that is mediated, in part,
by modulation of vestibulo-cerebellar function by estrogen.
Studies suggest that neuroactive steroids contribute to the
pathophysiology of several diseases that involve the cerebellum, including Niemann–Pick type C disease, gestational
dietary deciency of methyl donors (folate and vitamin
B12), prenatal stress, brain tumors, schizophrenia, autism,
mood disorders, and alcohol use disorder. Future studies
should examine if disruptions in cerebellar neuroactive steroid signaling are related to other conditions such as preterm birth, attention decit hyperactivity disorder, fetal
alcohol spectrum disorder, traumatic brain injury, stroke,
substance use disorders, sleep disorders, and multiple sclerosis (Dean and McCarthy 2008; Valenzuela et al. 2008;
Caldeira et al. 2004; Fanelli et al. 2013; Potts et al. 2009;
Mirzatoni et al. 2010; Caruso et al. 2014; Tsutsui and
Haraguchi 2020). It is also important to investigate the
potential utility of neuroactive steroids in the treatment of
diseases that affect the cerebellum (Ardeshiri et al. 2006;
Kelley etal. 2011; Jung etal. 2002; Murugan etal. 2019; Xu
etal. 2022; Yan etal. 2015). Another exciting area of research
is the regulation of the cerebellar actions of neuroactive steroids by the gut microbiota (Diviccaro etal. 2021).
Acknowledgements We dedicate this book chapter to the late Professor
Kazuyoshi Tsutsui (1952–2021) from the Department of Biology at
Waseda University in Japan for his groundbreaking work on cerebellar
neurosteroids. Dr. Valenzuela’s lab is supported by the National Institute
of Health grants R01 AA015614 and P50 AA022534.
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Role ofUnipolar Brush Cells
https://t.me/medicina_free
intheVestibulocerebellum
RachelN.Koops, CathrinB.Canto, BinWu,
MartijnSchonewille, BeerendH.J.Winkelman,
andChrisI.De Zeeuw
38
Abstract
In all species, unipolar brush cells (UBCs) are most abun-
dant in the vestibulocerebellum. Yet, the role of these
excitatory interneurons in the cerebellar input stage dur-
ing visual and vestibular stimulation remains elusive.
Here, we review the main morphological and electrophys-
iological properties of UBCs in the vestibulocerebellum,
and we highlight their potential role in the occulus dur-
ing the coordination of compensatory eye movements. We
advocate that they are well designed to contribute to
expansion coding in the temporal domain, while preserv-
ing the identity of sensory and/or oculomotor encoding,
so as to facilitate the optimal acquisition of all possible
components of movement kinematics.
Keywords
Glutamate entrapment · Signal delay lines · Neural
integration · Identity preservation · Expansion coding
Gain control · Phase control
Cathrin B. Canto, Bin Wu, Martijn Schonewille, Beerend H. J.
Winkelman and Chris I.De Zeeuw contributed equally with all other
contributors.
38.1 History
Altman and Bayer (1977) were one of the rst to identify
the cellular structure that is currently known as the
UBC.While conducting an experiment with 3H-thymidine
to elucidate the ontogeny of cerebellar cells, they noticed
a group of cells that contained cell bodies of which the
nuclei stained, whereas their cytoplasm did not; hence,
they called these cells pale cells. About a decade later
Hockeld (1987) referred to these cells as Rat-302 cells,
as they turned out to stain positive with the associated
monoclonal antibody. Similarly, Cozzi et al. (1989)
noticed a few years later that the same type of cells in the
granular cell layer of rats also expressed neuropeptide
secretogranin II, while, shortly after, Munoz (1990)
uncovered the monodendritic character of the cell when
he studied chromogranin A-like immunoreactivity in the
human cerebellum. However, it was not until the early
nineties that Mugnaini and colleagues (Harris etal. 1993;
Floris etal. 1994; Mugnaini and Floris 1994; Mugnaini
et al. 1994) revealed the full morphology, including the
brush-like structure at the end of the dendrite, with classical neuro- anatomical techniques such as Golgi staining
and electron microscopy, and coined the name unipolar
brush cell (UBC) (Fig.38.1a–c). It was also then that the
giant “synapse en maron”, as originally described at the
ultrastructural level by Chan-Palay and Palay (1971), was
R. N. Koops · C. B. Canto
Netherlands Institute for Neuroscience,
Amsterdam, The Netherlands
e-mail: r.koops@nin.knaw.nl; c.canto@nin.knaw.nl
B. Wu
Department of Neuroscience, Erasmus MC,
Rotterdam, The Netherlands
Department of Neurology and National Clinical Research Center
for Aging and Medicine, Huashan Hospital, Fudan University,
Shanghai, China
© 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_38
M. Schonewille
Department of Neuroscience, Erasmus MC,
Rotterdam, The Netherlands
e-mail: m.schonewille@erasmusmc.nl
B. H. J. Winkelman · C. I. De Zeeuw (
Netherlands Institute for Neuroscience,
Amsterdam, The Netherlands
Department of Neuroscience, Erasmus MC,
Rotterdam, The Netherlands
e-mail: b.winkelman@erasmusmc.nl; c.dezeeuw@erasmusmc.nl;
c.de.zeeuw@nin.knaw.nl
*)
243
244
a
b
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R. N. Koops et al.
c
d
e
Fig. 38.1 General anatomical properties of unipolar brush cells. (a)
Expression of Eomesodermin (EOMES), a specic marker for unipolar
brush cells (UBCs), in a coronal slice of the occulus (FL) and paraocculus (PFL) of the cerebellar cortex. (b) Expression of EOMES in a
sagittal plane of the vermis of the cerebellum, showing lobules II to X.
(c) Image of a UBC surrounded by granule cells, stained with the Golgi
method. The curved, thick and small arrows indicate the monodendrite,
brush and axon of the UBC, respectively. (d) Electron microscopic
image of a glomerulus with at the center a mossy ber (MF) rosette
(blue) surrounded by the soma and dendrite of a UBC (pink), as well as
a dendritic protrusion of a granule cell (GC) (yellow). A large part of the
UBC cytoplasm is occupied by the nucleus (N). Large arrows indicate
large asymmetric synapses formed by the MF with the soma and dendri-
ole (D1) of the UBC; small arrow indicates a lopodium originating from
the dendriole; and the circle indicates a small asymmetric synapse between
the MF and the GC dendritic protrusion. Another dendriole (D2) of the
same UBC forms an asymmetric dendrodendritic synapse with a GC (yellow) as shown in the rectangular box. Arrowheads indicate non-synaptic
appendages. (e) Another electron microscopic image of a UBC showing,
next to some of the same structures as in d, a thin unmyelinated axon
(purple), which emerges from the soma. The size of the UBC-soma is
similar to that of the UBC-soma in panel d. Panels A and B are modied
from Allen Mouse Brain Atlas, Allen Institute for Brain Science (2004);
https://mouse.brain- map.org/experiment/show/80516770 and https://
mouse.brain- map.org/experiment/show/100142505, respectively. Panels
c, d and e are adapted from Mugnaini etal. (1994, 1997)
38 Role ofUnipolar Brush Cells intheVestibulocerebellum
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245
recognized as being part of UBCs rather than Golgi cells.
Ever since many studies have been conducted to unravel
the specic functional properties of UBCs.
38.2 Cytology
UBCs located in the granule cell layer of the cerebellar cortex display typical characteristics. The size of their soma
measures between that of a granule cell and Golgi cell
(Altman and Bayer 1977), and their cytoplasm is noticeably rich in mitochondria, neurolaments, and dense core
vesicles (Harris etal. 1993; Floris et al. 1994; Mugnaini
et al. 1994; Rossi et al. 1995; McDonough et al. 2020)
(Fig. 38.1d, e). The generally sole dendrite of the UBC
ends with a brush of dendrioles emitting lopodia, which
receive multiple excitatory asymmetric synaptic inputs
from a single mossy ber (Floris etal. 1994; Morin etal.
2001; Sekerkova etal. 2005). The rosette of this mossy
ber is situated in a complex glomerulus, in which also
granule cell and Golgi cell dendrites participate (Mugnaini
etal. 1994, 1997; Jaarsma etal. 1996). Some of the UBC
dendrioles make asymmetric synapses with granule cell
dendrites, establishing dendrodendritic contacts (Mugnaini
etal. 1997). The proximal dendrite and soma of part of the
UBCs can also receive inhibitory inputs with presumptive
symmetric synapses from recurrent Purkinje cell collaterals
(Guo etal. 2021a) and/or the basal interstitial nucleus in the
white matter of the vestibulocerebellum (Jaarsma et al.
2018) (Fig.38.1e). The axon of UBCs is thin, unmyelinated
and long, which can split into several branches covering
long distances within a lobule, carrying boutons de passage
as well as mossy ber-like terminals at the end of its
branches (Nunzi and Mugnaini 2000) (Fig. 38.1d). The
axon terminals make synaptic connections with either granule cells or other UBCs (Berthie and Axelrad 1994; Dino
etal. 2000; Nunzi and Mugnaini 2000), and all these connections show the typical morphological features of excitatory synapses, including rounded vesicles and asymmetric
postsynaptic densities (Mugnaini etal. 1994; Nunzi etal.
2001). Notably, the UBC axon terminals of intrinsic mossy
bers can not only make a synaptic connection with the
brush but also with the cell body of postsynaptic UBCs
(Nunzi and Mugnaini 2000).
38.3 Ontogeny andDistribution
UBCs are born between E14.5 and E19.5in the rhombic lip
from where they migrate into the cerebellar granular layer
via the white matter (Hevner etal. 2006; Pibiri etal. 2017;
McDonough etal. 2020), following to some extent the route
of the Purkinje cells (Chung etal. 2009a, b; Sekerkova etal.
2014). The dispersion of the UBCs in the cerebellum takes a
relatively long time to be completed, often even into
adulthood (Takacs etal. 2000). Once postnatal development
is completed, UBCs are present in all lobules of the cerebellum, with the highest density in the vestibulocerebellum
(Munoz 1990; Braak and Braak 1993; Vig et al. 2005)
(Fig.38.1a, b). The relatively high number of UBCs in the
occulus and nodulus of the vestibulocerebellum has been
consistently found in a wide variety of species, ranging from
mammals like mouse, rat, rabbit, cat, guinea pig, opossum,
sheep, human, and non-human primates as well as sea mammals (Fortin etal. 1998; Dino etal. 1999; Takacs etal. 1999;
Alvarez et al. 2008) to sh (Kalinichenko and Pushchin
2008) and birds (Takacs etal. 1999).
38.4 Cell Physiology
The postsynaptic densities in the dendritic brush of UBCs are
rich in ionotropic glutamate receptors, including α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptors
(AMPARs) and N-methyl-D-aspartate receptors (NMDARs)
(Jaarsma etal. 1995), as well as metabotropic glutamate receptors (Jaarsma etal. 1998; Guo etal. 2021b). Accordingly, when
glutamate is released at the giant mossy ber to UBC synapse,
it will exert various effects mediated by these receptors
(Fig.38.2a, b). Glutamate will initially induce a fast AMPAR-
dependent excitatory postsynaptic current (EPSC), while ambient glutamate will subsequently also generate a slow
AMPAR-dependent EPSC (Rossi et al. 1995; Kinney et al.
1997). The slow AMPA-dependent EPSC appears when gluta-
mate is entrapped in the synaptic cleft, which elicits an enduring
process of desensitization and reactivation of AMPARs, ultimately taking hundreds of milliseconds for this component to
reach its peak amplitude and seconds to decay and reach baseline. In parallel, glutamate will also trigger another slower
response via activation of the NMDARs, the time constant of
which is independent of the membrane potential (Billups etal.
2002). Last but not least, glutamate will trigger a series of
metabotropic glutamate receptors, including mGluR1alpha and
mGluR2/3 (Jaarsma etal. 1998), which will exert diverse, longlasting and sequential, excitatory and inhibitory effects (Guo
etal. 2021b; see also below). Even though these metabotropic
glutamate receptors are predominantly concentrated on nonsynaptic appendages (Jaarsma etal. 1998), they play an important role in the integration of signals and they can elicit prominent
responses in the UBCs (Guo etal. 2021b).
The time course and amplitude of the synaptic currents are
furthermore affected by the rate at which excitatory amino
acid transporters (EAATs) remove glutamate from the synaptic cleft (Nunzi etal. 2003). As there is no spill-over of glutamate from nearby cells, the glutamate responsible for both the
fast and slow EPSCs originates exclusively from the presynap-
246
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R. N. Koops et al.
a
b
ce
d
Fig. 38.2 General cell physiological properties of unipolar brush cells.
(a) Schematic representation of an invitro current clamp (CC) and voltage clamp (VC) recording of a unipolar brush cell (UBC; pink) combined with presynaptic stimulation of a mossy ber (blue). (b) Examples
of a VC recording (left) and CC recording (right) of a UBC.The VC
recording shows a fast EPSC and a long-lasting, but smaller, slow
EPSC.These properties, which are rather unique to UBCs, result in a
burst of action potentials during CC recordings. (c) Schematic representation of a VC recording in a UBC that receives axonal input (purple; in text also referred to as intrinsic mossy ber) from another UBC
during stimulation of an extrinsic mossy ber (blue). (d) Electron
microscopic image of an axodendritic UBC-UBC connection. A glomerulus containing a gold–avidin-labelled axon terminal and unlabeled
tic mossy ber (Balmer etal. 2021). This will allow a UBC to
exclusively respond to the input from the single mossy ber
with which it is connected, and thereby to preserve the sensory
and/or motor identity of the signals that are carried forward by
the mossy ber Due to the delayed and sustained patterns of
activation generated at the dendritic brush, due to the fact that
there are both phasic and tonic responses, and due to the fact
that UBCs can also innervate other UBCs (Fig.38.2b–e), it
dendrioles of UBCs, with the presynaptic UBC axon in purple and the
postsynaptic UBC dendrite (d) in pink. The excitatory, asymmetric synaptic junctions between UBCs are indicated by black arrows, the nonsynaptic appendages by stars, and the dense core vesicles by open
arrows. (e) Excitatory postsynaptic currents (EPSCs) in different UBCs
postsynaptic to another UBC.A stimulus train of ve pulses at 200Hz
(red bars) shows a response in the postsynaptic UBC with an average
delay of the rst peak 97ms after the rst stimulation. The blue box on
the right shows the same EPSCs shown in the blue box on the left, but
at a different time scale. Panels a, c and e are adapted from Van Dorp
and De Zeeuw (2015); panel b is modied from Rossi etal. (1995) and
panel d from Dino etal. (2000)
comes as no surprise that UBCs show a wide range of action
potential discharge patterns. Indeed, the input of extracerebellar mossy bers combined with that of the intrinsic mossy
bers derived from UBCs can exert a large variety of excitatory responses downstream at the level of granule cells and
Purkinje cells, together establishing a rich temporal window of
response patterns (van Dorp and De Zeeuw 2014; Hensbroek
etal. 2015).
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