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M. Martina and G. Sekerková
with that of afferent bers from the vestibular nerve end of
the vestibular nuclei (Büttner-Ennever 1999; Diño et al.
1999), it was originally suggested that UBCs provide feed-
forward amplication of individual vestibular afferent signals. Accordingly, c-Fos expression can be elicited in type I
UBCs following vestibular stimulation (Sekerková et al.
2005). Type I, calretinin-positive, UBCs (functionally equiv-
alent to the “OFF” cells) are innervated by primary vestibular bers originating in macular and canal vestibular
end-organs (Diño etal. 2001) as well as by bers from the
medial vestibular nucleus and the nucleus prepositus hypoglossi (Barmack etal. 1992). Similar to type I UBCs, type II
UBCs are also targeted by primary vestibular inputs, mostly
originating in the semicircular canals (Balmer and Trussell
2019), although it is possible that they also receive non-ves-
tibular afferents, particularly considering that type II UBCs
are present in all cerebellar lobules. Additionally, tract-tracing experiments show that the cerebellar regions that are
enriched in UBCs also receive afferent inputs from some
brainstem nuclei, especially those related to eye movements
(Mugnaini etal. 2011); therefore, it is likely that UBCs are
contacted by these afferents. Finally, intrinsic mossy bers
(the UBCs’ axons) may contribute up to 50% of the mossy
ber terminals in some cerebellar areas such as lobule X
(Nunzi and Mugnaini 2000). Accordingly, acute slice recordings suggest the existence of higher order UBCs that receive
inputs from other UBCs (van Dorp and De Zeeuw 2015). A
further difference in the connectivity of the two UBC populations concerns the inhibitory input. While both types are
inhibited by Golgi cells (Rousseau etal. 2015), type II, but
not type I, UBCs also receive inhibitory input through
Purkinje cell axon collaterals (Guo etal. 2021).
type II UBCs generate an extended action potential burst
that is believed to cause long-lasting activation of downstream granule cells (Diño etal. 2000). In type II UBCs, the
prolonged response to synaptic stimulation is further
enhanced by activation of type I mGluR receptors (BorgesMerjane and Trussell 2015). The effect of synaptic activation on type I UBC, on the other hand, may depend on their
baseline activity. Type I UBCs are capable of spontaneous
ring (Russo etal. 2007; Kim etal. 2012), which is downregulated by group II mGluRs (Russo etal. 2008). Thus,
glutamate entrapment in the synaptic space would rst
increase UBC ring frequency, but then induce prolonged
silencing, which has been suggested to mimic the behavior
of “OFF” retinal ganglion cells (Borges-Merjane and
Trussell 2015). Both UBC subtypes, however, seem tuned
to respond to synaptic stimulation by generating highly
spaced signals that introduce temporal delays in the circuitry. This prediction nicely matches experimental data
showing that the slow synaptic currents of UBCs are ideally suited for the generation of responses with delays varying from zero up to hundreds of milliseconds depending on
the stimulus frequency (van Dorp and De Zeeuw 2014).
Thus, UBCs represent a circuit element capable of generating transmission delays that extend beyond the neuronal
membrane time constants. Considering that the intrinsic
mossy bers may contribute up to 50% of the mossy ber
terminals in lobule X, it is likely that multiple UBCs may
be situated within an individual circuit, thus having the
capability to insert a wide range of temporal patterns in signal transmission.
27.5 Cerebellar UBCs andDisease
27.4 Function
The highest UBC density occurs in the median cerebellar
cortex and part of the occulus/paraocculus complex; this
mode of distribution, together with studies of afferent connectivity, suggests that UBCs play a major role in the regulation of body posture, head position, and eye movements
(reviewed in Mugnaini etal. 2011). This conclusion is supported by the strong in-vivo activation of UBCs by head
movements (Hensbroek etal. 2015).
The UBC brush forms extensive one-to-one contact with
an individual mossy ber terminal. As a consequence of the
extensive (12–40μm2; Rossi etal. 1995) apposition surface
of the MF-UBC synapse, the UBC synaptic response is
unusually long-lasting (~3 s; Rossi et al. 1995). Because
UBCs are GAD-, GABA- and glycine-immunonegative,
but stain intensely for glutamate (Mugnaini and Floris
1994; Nunzi and Mugnaini 2000), they are considered
excitatory interneurons. In response to synaptic excitation,
In parallel with the increasing amount of information concerning the physiological role of UBCs, recent studies have
begun proposing potential roles of these cells in disease. In
particular, UBCs seem to have important roles in ataxia and
tinnitus.
27.5.1 Tinnitus
While tinnitus (phantom perception of sound in the absence
of an external acoustic stimulus) is associated with several
known conditions, the most common being noise-induced
hearing loss, the cellular mechanisms of tinnitus are still
unknown. It has been suggested that cerebellar UBCs play a
role in the generation of tinnitus (Baizer etal. 2012; Bauer
etal. 2013). In this context, type I UBCs appear particularly
intriguing. First, they are highly enriched in the cerebellar
areas associated with tinnitus generation, such as the paraocculus, which, via the pons, receives input from secondary
27 Unipolar Brush Cells
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185
auditory cortex (Azizi etal. 1985). Second, they are capable
of autonomous ring (Russo et al. 2007, 2008; Kim et al.
2012). Third, after deafferentation UBCs not only survive,
but they extend a mesh of newly formed intrinsic mossy
bers (Nunzi et al. 2001) that take over areas deprived of
extrinsic mossy ber inputs. Therefore, we may hypothesize
that following acoustic deafferentation, intrinsic mossy
bers originating from type I UBCs take over the synapses
orphan of the peripheral inputs and excite the postsynaptic
cells through their intrinsic activity.
27.5.2 Ataxia
The moonwalker (Mwk) mouse is a model of human ataxia
originally attributed to Purkinje cell loss (Becker etal. 2009).
However, the phenotype is fully expressed at 1month of age,
when Purkinje cell loss is still absent, but UBC loss is massive (Sekerková etal. 2013). This nding suggests that the
phenotype may be attributable, at least in part, to the UBC
loss. In the Mwk mice, type II UBCs are completely ablated,
while type I UBCs are still present, but their number is dramatically decreased. The potential involvement of type II
UBCs in ataxia matches the observation that, contrary to
type I UBCs that are limited to the vestibule-cerebellum,
type II UBCs are present in every cerebellar lobule, including the spino-cerebellum. This suggests that UBC-dependent
transmission delays may have an important role in motor
coordination. In support of these conclusions and of the role
of UBC dysfunction in ataxia, it was recently reported that
knock out of the ASIC5 ion channel, which is selectively
expressed in type II UBCs (Boiko et al. 2014), causes
impaired excitability of these cells and an ataxic phenotype
(Kreko-Pierce etal. 2020).
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sion of acid-sensing ion channel 5 (asic5) in unipolar brush cells of
the vestibulocerebellum. PLoS One 9(3):e91326
Borges-Merjane C, Trussell LO (2015) ON and OFF unipolar brush
cells transform multisensory inputs to the auditory system. Neuron
85(5):1029–1042
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and cerebellum. Ann N Y Acad Sci 871:51–64
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Diño MR, Perachio AA, Mugnaini E (2001) Cerebellar unipolar brush
cells are targets of primary vestibular afferents: an experimental
study in the gerbil. Exp Brain Res 140:162–170
Guo C, Rudolph S, Neuwirth ME, Regehr WG (2021) Purkinje cell out-
puts selectively inhibit a subset of unipolar brush cells in the input
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Hensbroek RA, Ruigrok TJ, van Beugen BJ, Maruta J, Simpson JI
(2015) Visuo-vestibular information processing by unipolar brush
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Kim J-A, Sekerková G, Mugnaini E, Martina M (2012)
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Glial Cells
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KatharineL.Dobson andTomasC.Bellamy
28
Abstract
Glia are the non-neuronal, electrically passive cells of the
nervous system. They were rst dened as a distinct cell type
by Rudolph Virchow in 1856 and derived their name from
the Greek for “glue” due to their presumed primary function
as connective tissue. The term is misleading, however, as it
implies a single cell type when it in fact encompasses several
distinct cell classes, most notably: oligodendrocytes, astro-
cytes, and microglia. The origins and roles of these different
glial classes are markedly different, but they have collec-
tively been viewed as supportive cells that play structural and
protective roles throughout development and maintain a
healthy microenvironment favorable to neuronal function.
This traditional conception is now giving way to an apprecia-
tion that glial cells play an active and dynamic role in neuro-
physiology, in addition to providing passive support. This
chapter outlines the origins, anatomy, and primary roles of
the major glial cells in the cerebellum.
Keywords
Astrocyte · Oligodendrocyte · Microglia · Bergmann
glial cell · Calcium signaling
28.1 Gliogenesis andGlial Lineages
Gliogenesis is the developmental process by which all glial
cell types are generated; both the production of glial progenitor cells and their differentiation into mature glia. There are
K. L. Dobson
Centre for Discovery Brain Sciences, University of Edinburgh,
Edinburgh, UK
e-mail: Katharine.Dobson@ed.ec.uk
T. C. Bellamy (*)
School of Life Sciences, University of Nottingham,
Nottingham, UK
e-mail: tomas.bellamy@nottingham.ac.uk
two routes through which cerebellar glia develop, with macroglia (astrocytes and oligodendrocytes) deriving from the
neuroepithelium (along with neurons), and microglia originating from the mesodermal hematopoietic lineage.
Neuroepithelial cells, which are embryonic stem cells
capable of both neuronal and glial fates, undergo morphological and epigenetic modication such that by midgestation they have differentiated to become radial glial
cells. It is from these progenitor cells that astrocytes and oligodendrocytes arise (Rowitch and Kriegstein 2010). Radial
glia undergo either direct differentiation into astrocytes, or
form oligodendrocyte precursor cells which are subsequently
capable of further specialization into oligodendrocytes.
Microglia enter the cerebellum early in embryogenesis as
circulating fetal macrophages and are thought to colonize the
developing brain (Menassa and Gomez-Nicola 2018).
Further transformation results in embryonic microglia that
mature in early post-natal life.
28.2 Oligodendrocytes andMicroglia
Oligodendrocytes are the myelinating cells of the central
nervous system. In the cerebellar cortex, they myelinate the
mossy and climbing ber inputs, and the Purkinje neuron
axons that are the sole output. Accordingly, oligodendrocytes are most commonly located in the lower granular layer
and the white matter (Fig. 28.1). In the rat cerebellum,
approximately seven axons are myelinated by each mature
oligodendrocyte (Bakiri etal. 2011).
In addition to the classic myelinating oligodendrocytes,
another class of non-myelinating cells also originates from
oligodendrocyte precursors but do not lose expression of the
proteoglycan NG2 during differentiation. These cells are
therefore referred to as NG2 cells (or polydendrocytes) and
could potentially represent an additional major class of central nervous system glial cells (Nishiyama etal. 2009). NG2
cells are found throughout the cortex and have been shown to
© 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_28
187
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K. L. Dobson and T. C. Bellamy
Fig. 28.1 Diagram of the cerebellar cortical layers with the most abundant macroglial cells present in each layer illustrated in black. PN Purkinje
neuron, GN granule neuron, ML molecular layer, PCL Purkinje cell layer, GL granular layer, WM white matter
receive synaptic input from parallel and climbing bers
(Fig.28.1). Their role and function are currently a matter of
active debate, with recent evidence indicating that NG2 cells
are activated to remyelinate demyelinated regions following
injury (Baaklini etal. 2019).
The microglia of the cerebellum function in much the
same way as elsewhere in the central nervous system. Under
physiological conditions, microglia exist in a resting state,
with each cell body possessing several ne ramied processes that encompass an individual domain or territory.
Under pathophysiological conditions, such as following
injury or disease, the cell retracts these processes and enters
an activated state. Activated microglia are highly mobile,
thus they are able to rapidly translocate to the site of injury
and, if required, perform phagocytic duties. Recent evidence
suggests that, while these basic functions are shared by all
microglia, cerebellar microglia differ from cortical microglia
in their morphology, relative density, and the extent to which
the somata are motile under healthy conditions (Stoessel and
Majewska 2021). This nding suggests that some regional
specialization of microglia phenotype adapts the maturing
cells to local functional needs.
In addition to their immune response function, microglia
also play an important role during development by engulng
and eliminating synapses to rene network connectivity in
the maturing brain. In the cerebellum, microglia direct the
apoptosis of Purkinje neurons during a critical thinning
period of development when up to 60% of these neurons are
lost (Marín-Teva etal. 2004). Microglia also appear essential
for the elimination of excess climbing ber inputs during
cerebellar cortical development. Loss of microglia leads to
widespread abnormalities in cerebellar cortical development,
conrming their central role in the renement and specication of the cerebellar microcircuit.
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28.3 Astrocytes
Astrocytes are a heterogeneous population of cerebellar glia,
comprising brous astrocytes of the white matter tracts and
protoplasmic astrocytes of the gray matter (Fig. 28.1). In
addition to anatomical location, these two classes of astroglia are also distinguished on a morphological basis– protoplasmic astrocytes have more heavily branched processes
than brous astrocytes. The astrocyte population of the cerebellum functions as an interconnected network known as a
syncytium, with individual cells connected via gap junctions
that allow the controlled diffusion of small molecules
between neighboring cells.
Fibrous astrocyte somata within regions of white matter
are arranged in rows between axonal bundles, with their processes forming perivascular endfeet and perinodal contacts.
The protoplasmic astrocytes found in the granular layer are
termed “velate” astrocytes, due to the sheet-like projections
that spread through the neuropil, enclosing the mossy ber
glomeruli and so limiting diffusion of transmitter away from
sites of release. The velate astrocytes are therefore thought to
demarcate glomeruli and associated granule neurons into
anatomical compartments, with the hypothesized function of
segregating specic mossy ber inputs (Hoogland and Kuhn
2010).
28.4 Bergmann Glia
In the molecular layer, the predominant astroglial cell is a
type unique to the cerebellum: the Bergmann glial cell.
Bergmann glia (sometimes termed Golgi epithelial cells) are
classed as protoplasmic astrocytes, but retain much in common with the radial glia from which they are derived
(Fig.28.1). Protoplasmic astrocyte identity is dependent on
neuron-derived sonic hedgehog signaling, with Bergmann
glia formed in its presence and velate astrocytes in its absence
(Farmer etal. 2016).
Bergmann glial somata align with Purkinje neuron somata
between the granular and molecular layers, and extend two
or more long radial processes through the molecular layer to
the pial surface, where they terminate in bulbous endfeet.
After maturation, each of these primary Bergmann bers
becomes decorated with multiple elaborate membrane protrusions known as microdomains, which sprout from the
ber and project into the neuropil of the molecular layer as
complex leaf-like structures with high surface area to volume ratios. These processes enclose all of the synapses
within the molecular layer, both excitatory and inhibitory,
thus restricting diffusion of neurotransmitter away from
active synapses. In the rat cerebellum, there are approximately eight Bergmann glia to every Purkinje neuron, with
each glial cell providing coverage of up to 6000 synapses.
This ensheathment of neuronal synapses by Bergmann glia
remains plastic in the period following neurodevelopment–
indeed experience-dependent remodeling has been observed
following stress exposure in mice (Bender etal. 2020), indicating the potential for continuous adaptation of this close
anatomical association between neuron and glial cell.
In recent years, an old controversy has been revisited
regarding the existence of an additional glial cell type in the
molecular layer that closely resembles Bergmann glia; the
Fañanas cell (Goertzen and Veh 2018). Although similar in
appearance, the somata of these cells do not align so closely
to the Purkinje cell layer, and they express markers that
appear to be absent from classical Bergmann glia. This
uncertainty is a good case study for the challenge of denitively classifying a cell family that has a large variety of cell
shapes, sizes, and gene expression proles.
28.5 Astroglial Functions
intheCerebellum
Cerebellar astroglia carry out the same core roles as astrocytes elsewhere in the central nervous system. Many of these
roles are supportive, and only key roles are covered here for
brevity; see Kettenmann and Ransom (1995) for more
details.
K+ buffering is a major homeostatic mechanism by which
increased extracellular K+ released during action potential
propagation is rapidly taken up by astrocytes (by virtue of
their characteristically high K+ membrane permeability at
rest), and redistributed through the astrocyte syncytium to
sites of lower concentration. Another key role is the recycling of neurotransmitters: astroglia express transporters for
both glutamate and GABA positioned near sites of release
that rapidly clear the transmitters from the extrasynaptic
space. Within the cytosol, the transmitters are metabolized to
glutamine, which is released back into the extracellular space
for reuptake by neurons. Finally, astrocytes can undergo a
phenotypic change in response to noxious stimuli, adopting
a quasi-immune cell state; a process known as reactive gliosis. This “activation” of astrocytes accompanies neuropathology and can be both benecial and detrimental to
resolution of the injury or infection.
In addition to these general functions of astrocytes,
Bergmann glia also play a crucial role in directing neuronal
migration during development. Granule neuron precursor
cells in the immature cerebellum are initially positioned as
an external layer, but migrate along the radial Bergmann
glial bers (at that stage, lacking microdomain protrusions), to reach the internal granular layer in the adult
cerebellum.
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K. L. Dobson and T. C. Bellamy
Finally, a major development in our understanding of
astroglia that has emerged over the last few decades is the
realization that these cells also play an active role in modulating neuronal function. In addition to expression of neurotransmitter transporters, astroglial processes also express
both ionotropic and metabotropic receptors. These receptors
are commonly linked to calcium signaling pathways, and so
enable the astrocytes to detect and respond to synaptic
transmission.
Calcium elevation can lead to release of neuromodulators
from astrocytes that feed back to the neuronal network, modifying activity– a process termed “gliotransmission”– which
has been implicated in a wide range of neuronal processes,
including synaptogenesis, neurovascular coupling, synchronization of network activity, and synaptic plasticity (Haydon
2001). In Bergmann glia, disruption of glutamate-evoked
calcium signaling causes dysregulation of synaptic transmission to Purkinje neurons and motor defects, conrming the
active role that neuron-glial signaling has in establishing
proper connectivity and regulation of the cortical microcircuit. It is becoming increasingly clear that such bidirectional
communication between neurons and glia is essential for
proper cerebellar function, throughout development.
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GABA Pathways andReceptors
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TomooHirano andShin-yaKawaguchi
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Abstract
GABAergic neurons including Purkinje cells play critical
roles in cerebellar neuronal circuits. In the cerebellar cor-
tex, molecular layer interneurons (stellate and basket
cells) provide feedforward inhibitory loops between par-
allel bers and Purkinje cells, and granular layer interneu-
rons (Golgi cells) form feedback inhibition loops with
granule cells. Some GABAergic neurons in the cerebellar
nuclei inhibit inferior olive neurons, which send excit-
atory climbing bers to the cerebellum. These cerebellar
nuclei neurons and Purkinje cells are rare examples of
projection neurons, which exert inhibition by releasing
GABA as a transmitter. Cerebellar neurons express vari-
ous types of ionotropic and metabotropic GABA recep-
tors, which mediate the effects of GABA, and granule
cells express extrasynaptic ionotropic GABA receptors
that play a role in tonic inhibition. Both excitatory and
inhibitory synapses on GABAergic neurons show neuro-
nal activity-dependent plasticity, which contributes to
motor learning. Several types of mutant mice defective in
GABAergic neurons or synaptic functions have been
found or generated, and they show failures in motor coor-
dination and/or motor learning. Dysfunctions of cerebel-
lar GABAergic system have been suggested to be causes
of ataxia, and a GABA-mimetic drug improves motor
coordination in some ataxic patients.
Keywords
Purkinje cell · Basket cell · Stellate cell · Golgi cell ·
GABA receptor · Synaptic plasticity · Ataxia
T. Hirano (*) · S.-y. Kawaguchi
Department of Biophysics, Graduate School of Science, Kyoto
University, Kyoto, Japan
e-mail: hirano.tomoo.36r@st.kyoto-u.ac.jp;
kawaguchi.shinya.7m@kyoto-u.ac.jp
29.1 GABA Pathways intheCerebellum
There are several types of GABAergic inhibitory neurons in
the cerebellum (Fig.29.1) (Ito 2006; Hirano 2021). Among
them, Purkinje cells are the sole output neurons of the cortex
and send output to the deep cerebellar nuclei or vestibular
nuclei. Other GABAergic neurons are the interneurons: stellate and basket cells in the molecular layer, and Golgi cells in
the granular layer. Major inputs to the cerebellum are
glutamatergic and come through the excitatory mossy and
climbing bers. Mossy bers form synapses on granule cells
in the cortical granular layer and also on neurons in the cerebellar nuclei. A granule cell extends an axon to the molecular layer, where it forms parallel bers that send excitatory
glutamatergic output to Purkinje cells and also to two types
of GABAergic interneurons, stellate and basket cells, which
in turn send inhibitory output to Purkinje cells. All parallel
bers run orthogonally to Purkinje cell dendrites which
extend branches on a sagittal plane. A basket cell forms synapses on the axon hillocks of Purkinje cells and effectively
suppresses action potential generation. On the other hand, a
stellate cell forms synapses on the dendrites of Purkinje cells
and might selectively suppress the effect of nearby parallel
ber synapses. Stellate and basket cells form feed-forward
inhibitory loops between parallel bers and Purkinje cells
and may also play roles in lateral inhibition, as their axons
tend to run orthogonally to parallel bers (Kim and Augustine
2021). Golgi cells receive parallel ber input and inhibit
granule cells, thus forming an inhibitory feedback loop.
Golgi cells also receive direct mossy ber input, forming a
feed-forward inhibitory pathway as well.
There are glutamatergic and GABAergic neurons in the
deep cerebellar nuclei, and some of them are regulated by the
GABAergic output of Purkinje cells. Actually, GABAergic
synapses formed by Purkinje cells outnumber synapses
formed by local cerebellar nuclei neurons. One type of
GABAergic neuron in the nuclei sends output to the inferior
olive nuclei in the medulla oblongata, from where strong
© 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_29
191
192
CN
https://t.me/medicina_free
T. Hirano and S.-y. Kawaguchi
ML
PL
GL
Cortex
CF
PC
BC
Sole output
from the cortex
SC
Feedforward
inhibition
PF
GC
GoC
Feedback
inhibition
MF
IO
Fig. 29.1 Cerebellar neuronal circuits. Filled and open symbols represent GABAergic and glutamatergic neurons, respectively, and solid and
broken lines indicate GABAergic and glutamatergic axons, respectively. ML molecular layer, PL Purkinje cell layer, GL granular layer, IO
excitatory climbing bers are sent to the cerebellum. Purkinje
cells and GABAergic nuclei neurons innervating the inferior
olive are rare examples of inhibitory projection neurons in
the central nervous system.
29.2 GABA Receptors intheCerebellum
GABA receptors, which mediate the effects of GABA, are
classied into ionotropic GABAA and GABAC receptors, and
metabotropic GABAB receptors. An ionotropic GABA receptor is composed of ve subunits, forming a Cl− conducting
channel which mediates inhibition of neuronal activity by
hyperpolarization and/or producing a shunting effect on current ow through the plasma membrane. There are 19 genes
for ionotropic GABA receptor subunits. They are α1–6,
β1–3, γ1–3, δ, ε, θ, π, and 3 types of ρ subunits. GABAC
receptors are exclusively composed of ρ subunits, which provide distinct pharmacological sensitivity to allosteric modu-
inferior olive nuclei, CN cerebellar nuclei, CF climbing ber, MF
mossy ber, PF parallel ber, PC Purkinje cell, SC stellate cell, BC
basket cell, GC granule cell, and GoC Golgi cell
lators such as benzodiazepines and barbiturates. On the other
hand, the subunits other than ρ are constituents of various
types of GABAA receptors (Olsen and Sieghart 2009).
Among them, a majority of GABAA receptors are composed
of α, β, and γ subunits. GABAA receptors consisting of different subunits contribute to differential effects of GABA in
the cerebellum (Wisden etal. 1996). A Purkinje cell expresses
α1, β2, β3, and γ2 subunits; basket and stellate cells express
α1, β2, and γ2 subunits; a granule cell expresses α1, α6, β2,
β3, γ2, and δ subunits. In a granule cell, α1, α6, β2, and γ2
subunits are found in synapses formed by a Golgi cell and
also on extrasynaptic membrane at low levels. The δ subunits
and granule-cell-specic α6 subunits form a heteropentameric GABA receptor with a high afnity to GABA (Saxena
and Macdonald 1996). These receptors are found only on
extrasynaptic membrane and show single-channel currents
with small conductance, long open time, and little desensitization, contributing to tonic inhibition of a granule cell
(Brickley et al. 2001; Olsen and Sieghart 2009). GABAA
29 GABA Pathways andReceptors
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193
receptors are also found in Purkinje cell axons, and their activation rather depolarizes axon terminals due to a high intraaxonal concentration of Cl−, and thereby enhances GABA
release (de San Martin etal. 2017).
The metabotropic GABAB receptors are heterodimers
composed of GABAB1 and GABAB2 subunits and coupled
with Gi proteins to suppress the activity of adenylyl cyclase.
As a result, diverse changes of ion channels and/or signaling
cascades are induced: a decrease in cytoplasmic cAMP concentration, increased K+ conductance via activation of GIRK
channels, negative regulation of voltage-gated Ca2+ channels,
etc. (Chalifoux and Carter 2011). Both GABAB1 and GABAB2
subunits of GABAB receptors show high level expression
around glutamatergic synapses between parallel bers and a
Purkinje cell. Presynaptically, GABAB receptors are found
on extrasynaptic membrane of parallel bers, and postsynaptically both on postsynaptic and extrasynaptic membrane of
a Purkinje cell (Lujan and Shigemoto 2006). These GABAB
receptors around glutamatergic synapses seem to be activated by ambient GABA, which is released from not only
neurons but also glial cells. It was reported that channelmediated release of GABA from glial cells is critical for
tonic GABAergic inhibition of granule cells (Lee et al.
2010). All of granule, basket, stellate, and Golgi cells also
express GABAB receptors. Functional consequence of
GABAB receptor activation is, in principle, the negative regulation of transmitter release at presynaptic compartments
(Dittman and Regehr 1996) and the modulation of neuronal
activity and/or plasticity at postsynaptic compartments
(Chalifoux and Carter 2011).
29.3 Regulation ofGABAergic Neurons
andSynapses
Firing patterns of cerebellar GABAergic neurons are modulated by neuronal activities. Coupled activation of parallel
bers and a climbing ber produces long-term depression of
excitatory synaptic transmission between parallel bers and
a Purkinje cell, and uncoupled activation of parallel bers
induces long-term potentiation (Ito 2001; Hirano 2013).
Long-term depression has been considered as a primary cellular mechanism for motor learning. GABAergic inputs to
Purkinje cells from molecular layer interneurons potently
suppress the Ca2+ increase normally produced in the Purkinje
neurons in response to the climbing ber input, thereby controlling long-term depression and motor learning (Rowan
etal. 2018). Parallel ber input to a stellate cell is also modu-
lated by activities of parallel and climbing bers (Dean etal.
2010), and the activity of interneurons is shown to change
during associative learning in mice (Ma etal. 2020).
GABAergic synapses in the cerebellum also show plasticity. Synaptic transmission between a stellate cell and a
Purkinje cell undergoes short-term and long-term plasticity
depending on neuronal activities such as depolarizationinduced suppression of inhibition, depolarization-induced
potentiation of inhibition, and rebound potentiation (Kano
etal. 1992; Duguid and Smart 2004; Yoshida etal. 2002, also
see Hirano and Kawaguchi 2014). Among them, rebound
potentiation is long-lasting potentiation of the GABAergic
transmission (Kano etal. 1992). The potentiation is induced
by climbing ber activity that elicits an increase in intracellular Ca2+ concentration of a Purkinje cell. Both rebound
potentiation at GABAergic synapses and long-term depression at excitatory synapses work to depress the activity of a
Purkinje cell depending on the climbing ber input, which
suggests a possible cooperation of the two types of synaptic
plasticity in the cortical information processing. Indeed, suppression of rebound potentiation affects motor learning
(Tanaka et al. 2013). Synaptic plasticity has also been
reported at GABAergic and glutamatergic synapses in the
cerebellar nuclei, and GABAergic Purkinje cell output is
involved in regulation of synaptic plasticity at those synapses
(Zeng and Raman 2010).
Molecular layer interneurons (stellate and basket cells)
and Golgi cells are electrically coupled in each group through
gap junctions (Mann-Metzer and Yarom 1999; Dugue etal.
2009), and their activity tends to synchronize activity in each
neuronal type to a certain extent. In vivo ring patterns of
cerebellar cortical inhibitory interneurons were studied in
the uvula and nodulus regions (Barmack and Yakhnitsa
2008). Recently, differential effects of selective depletion of
inhibitory synaptic output from basket or stellate cells on
action potential ring in Purkinje cells were studied using an
inducible conditional genetic technique, which allowed deletion of the vesicular GABA transporter in either cell types
(Brown etal. 2019). Depletion of basket cell output increases
the frequency of continuous action potential ring (simple
spikes) in a Purkinje cell, and decreases the frequency of
complex spikes, which are characteristic multi-peaks action
potentials and are caused by the climbing ber input. On the
other hand, depletion of stellate cell output increases the
regularity of simple spike ring and the frequency of complex spikes. It should be noted that Purkinje cells are capable
of autonomously generating simple spikes without synaptic
inputs (Hausser and Clark 1997). The properties of basket
and stellate cells were described in a recent review article
(Kim and Augustine 2021).
29.4 Mutant Mice Aected inGABAergic
Neurons or GABA Receptors
There are some mutant mouse lines affected in GABAergic
neurons or synapses in the cerebellum. Lurcher mice and
Purkinje cell degeneration (PCD) mice lose most of
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