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M. Sassoè-Pognetto
Fig. 17.1 Neuronal elements and basic circuitry of the cerebellar cortex. Two major afferent systems reach the cerebellar cortex: climbing
bers (CF) provide direct excitatory contacts to Purkinje cells (PC) and
mossy bers (MF) terminate in glomerular structures in the granule cell
layer (GCL), in which they establish excitatory synapses (+) with the
dendrites of granule cells (GC). A glomerulus is a complex of synapses,
consisting of mossy ber terminals (rosettes), surrounded by granule
cell dendrites and Golgi cell axon terminals (gray circle). The ascending axons of granule cells reach the molecular layer (ML) and form
parallel bers (PF), which make glutamatergic synapses with Purkinje,
stellate (SC), basket (BC), and Golgi (GO) cells. With the exception of
granule cells, all cerebellar cortical neurons, including Purkinje cells,
make inhibitory synaptic connections (−). A peculiar assembly of
GABAergic axons is the pinceau, which is formed as basket cell axons
surround the axon initial segment of Purkinje cells. The recently
described Golgi-to-Golgi inhibitory synapses are not indicated in the
diagram. Unipolar brush cells, globular cells, and candelabrum cells are
also not represented. DCN deep cerebellar nuclei, LU Lugaro cell, PCL
Purkinje cell layer
17 Development ofGlutamatergic andGABAergic Synapses
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development of the pinceau
primary growth stage
117
STELLATE CELLS
BASKET CELLS
PARALLEL FIBERS
GOLGI CELLS
synaptic waning
MOSSY FIBERS
pericellular nest
CLIMBING FIBERS
E19 P0 P5 P7 P9 P12 P15 P21 P30
Fig. 17.2 Graphic representation of the development of synapses
made by different types of cerebellar neurons and by cerebellar cortical
afferents. The diagram is based on the studies of the mouse and rat
cerebellum. There is still uncertainty about the precise dates of the
17.1 Development ofGlutamate Synapses
somato-dendritic translocation
onset and the conclusion of the synaptogenic period, as symbolized by
the grading colors. Signicant phases of the development of specic
types of synapses are indicated
and repulsive factors that prevent the invasion of MFs into
the external granular layer and promote the removal of tran-
17.1.1 Mossy Fiber Synapses
sient synapses with PCs. Synaptogenic factors that stimulate
the formation of synapses between MFs and granule cells
The main types of glutamate synapses in the cerebellum are
those established by MFs, PFs, and CFs. MFs arise from a
variety of different sources in the brainstem and spinal cord,
and terminate forming characteristic “rosettes” within glomeruli in the GCL, where they make glutamatergic synaptic
contacts with the dendrites of granule cells (Palay and Chan-
comprise Wnt7a, broblast growth factor 22 and cadherin-7
(Hall etal. 2000; Umemori etal. 2004). Notably, in agranular cerebella (e.g., in weaver and reeler mice), aberrant
MF-PC synapses are maintained, suggesting that the absence
of the correct target neurons can result in a stabilization of
mismatched synapses (Sotelo 1990).
Palay 1974). In rodents, MFs invade the gray matter at P3–
P5 and start establishing the rst synapses onto granule cells
at the end of the rst postnatal week. However, it is only
17.1.2 Parallel Fiber Synapses
during the second postnatal week that synapse number
increases considerably, reaching a peak at P15 (Altman
1972c; Hámori and Somogyi 1983). During development,
MF synapses undergo an extensive structural remodeling,
that is accompanied by changes of their electrophysiological
properties (Larramendi 1969; Cathala etal. 2005). This maturation comprises the elimination of surplus synapses and
the segregation of long synaptic appositions into smaller
active zones (synaptic “waning”). Several investigations
have demonstrated that the specicity of MF connectivity
depends on the interplay of positive signals that mediate synapse formation with the appropriate targets (granule cells),
PFs are oriented perpendicularly to the plane of PC dendrites
and establish excitatory synapses with spines located on the
distal dendrites (the so-called spiny branchlets), causing the
PCs to discharge single action potentials, named “simple
spikes.” PF synapses are distinguished by the presence of the
postsynaptic δ2 glutamate receptor (GluD2), which is not
present at synapses made by CFs (see below). Rather than
acting as a glutamate receptor, GluD2 has a fundamental role
in mediating synaptic adhesion (Yuzaki 2003).
PFs establish the rst synapses as soon as PCs start growing their dendrites in the developing ML at the end of the rst
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M. Sassoè-Pognetto
postnatal week (Altman 1972a, b). The progressive proliferation of synapses from the bottom upward results initially in
a gradient in the density of synaptic contacts between the
deep regions and the cerebellar surface. This gradient is no
longer seen after P21, when synapse density becomes relatively uniform throughout the ML (Larramendi 1969).
Interestingly, this developmental sequence is accompanied
by a progressive switch of the vesicular glutamate transporters, VGlut1 and VGlut2, in PF terminals (Miyazaki et al.
2003). Thus, early PF terminals express VGlut2, which is
gradually replaced by VGlut1 following an inside-out gradient. This replacement is accomplished by P30, after which
PFs and CFs express differentially VGlut1 and VGlut2
(Ichikawa etal. 2002). The formation and maintenance of PF
synapses depends on trans-synaptic interactions between
postsynaptic GluD2 and cerebellin 1 (Cbln1), a C1q family
member secreted from granule cell axons (Yuzaki 2010).
Cbln1 binds GluD2 and also interacts with presynaptic
neurexins, establishing a trimeric trans-synaptic complex
that links pre- and postsynaptic specializations (Matsuda
etal. 2010; Uemura etal. 2010).
17.1.3 Climbing Fiber Synapses
CFs provide the earliest synaptic inputs to PCs in the
developing cerebellar cortex (Fig.17.2) and their synapses
undergo a remarkable structural remodeling throughout
development. During the rst postnatal week, these afferents
establish a dense plexus around the cell body of PCs, making
asymmetric synapses with somatic spine-like protrusions
(Cajal 1890; Sotelo 2008; Ichikawa etal. 2011). Subsequently,
activity-dependent competition among CFs results in regression of multiple innervation and dendritic translocation of a
single “winner” CF from the soma to the proximal dendrites
(Hashimoto etal. 2009). The translocation of CFs from the
soma to the proximal dendrites starts at P9 and is almost
completed by P15. The elimination of CFs critically depends
on neuronal activity and involves competition among afferent CFs, as well as heterosynaptic competition with PFs.
Several molecules and signaling pathways that mediate CF
elimination have been identied (for a detailed review of the
mechanisms involved in CF synapse renement, see Chap.
14 by Kano and Watanabe in this Volume).
17.2 Development ofGABA Synapses
17.2.1 Stellate/Basket Cell Synapses
CFs make synapses on spines located on the proximal dendritic domain of PCs, and normally do not invade the distal
dendrites innervated by PFs. In the mature cerebellum, inferior olivary neurons contact on average seven PCs, while an
individual PC is innervated by a single CF; this one-to-one
relationship is the result of the postnatal elimination of
supernumerary CFs, which occurs during the second and
third postnatal weeks (see below). Synapses made by CFs
are so strong that they generate massive bursts of action
potentials known as “complex spikes.” CFs are crucial for
cerebellar function as they convey signals regarding errors in
motor control and they induce long-term depression (LTD)
in co-activated PF synapses. As a fact, deprivation of CF
input causes severe movement disorders that are similar to
the defects observed after cerebellum damage (Apps and
Garwicz 2005).
CF synapses differ from those made by PFs in that they do
not contain the GluD2 receptor (Landsend et al. 1997).
Interestingly, another member of the C1q family, the C1qlike family protein C1ql1, has been implicated in CF synaptogenesis. C1ql1 is expressed in inferior olive neurons, is
secreted by CFs, and interacts in PCs with the cell-adhesion
G-protein coupled receptor 3BAI3 (brain angiogenesis
inhibitor; Sigoillot etal. 2015). Experimental analyses have
shown that the C1ql1/3BAI3 interaction contributes to regulate the formation and maintenance of CF synapses and the
extent of CF synaptic territory in PCs (Kakegawa etal. 2015;
Sigoillot etal. 2015).
Synaptic inhibition in the supragranular layers is mediated
mainly by basket and stellate cells. Basket cells make synapses with the cell body and the proximal dendrites of PCs,
and also form a unique plexus around the axon initial segment
(AIS), called a pinceau (Cajal 1911). In contrast, stellate cells
establish contacts with the dendrites of PCs and of other cerebellar interneurons (Briatore etal. 2010). Basket cells start
innervating the cell body of PCs at the end of the rst postnatal week (Sotelo 2008; Viltono etal. 2008). The number of
perisomatic synapses then increases, together with a strong
decrease in the number of somatic spines innervated by CFs.
In the same period, basket cell synapses undergo a process of
“waning” (Larramendi 1969), consisting in a fragmentation
of long synaptic appositions into multiple shorter active
zones. These morphological rearrangements are accompanied by a gradual loss of the scaffolding molecule gephyrin
from postsynaptic specializations (Viltono et al. 2008), as
well as a decrease in the amplitude of IPSCs recorded from
PCs (Pouzat and Hestrin 1997). The period of inhibitory synapse development terminates in the fourth postnatal week,
when synapse density becomes uniform throughout the ML
(Patrizi etal. 2008; Viltono etal. 2008).
The formation and maturation of the pinceau is a prolonged process that begins in the second postnatal week and
extends well after P21 by a progressive recruitment of basket
terminals (Sotelo 2008). The descending branches of basket
axons rst enwrap the cell body of PCs, making perisomatic
synapses (P7), and then reach the AIS by P9. The targeting of
17 Development ofGlutamatergic andGABAergic Synapses
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119
basket axons to the AIS depends on Semaphorin3A (Sema3A)
and its receptor neuropilin-1 (NRP1; Telley et al. 2016).
Sema3A secreted by PCs attracts basket cell axons expressing NRP1 toward the AIS.Moreover, it appears that NRP1
also mediates subcellular target recognition through trans-
synaptic interaction with neurofascin 186 (NF 186), a cell
adhesion molecule of the L1 immunoglobulin family which
is required for the formation and maintenance of the pinceau
(Ango etal. 2004; Zonta etal. 2011). Interestingly, another
member of the same family of adhesion molecules, CHL1,
localizes along Bergmann glia bers and stellate cells during
the formation of stellate axon arbors. In the absence of
CHL1, stellate axons show aberrant branching and orientation, and synapse formation with PC dendrites is impaired
(Ango etal. 2008). Thus, different members of the L1 family
contribute to axon patterning and subcellular synapse organization in different types of interneurons.
17.2.2 PC Axon Collaterals
The axon collaterals of PCs also establish GABA synapses
with different types of cerebellar neurons, including other
PCs (Cajal 1911; Palay and Chan-Palay 1974). The synaptic
targets of PC collaterals have been the subject of controversy, although there is substantial consensus that PC axons
connect with other PCs and distinct types of interneurons
(Witter etal. 2016 and references therein). A recent study
based on a combination of anatomical, optogenetic, and
electrophysiological approaches revealed that both in juveniles and adult mice the axon collaterals make synapses with
other PCs in such a way that essentially all PCs are inhibited
by other PCs (Witter etal. 2016). In the same study, PC collaterals were found to make synapses also with interneurons.
It has also been reported that PC collaterals directly inhibit
granule cells regulating their excitability on multiple timescales (Guo etal. 2016). Interestingly, these connections are
region-specic, as they are mostly found in cerebellar lobules involved in processing vestibular information and regulating eye movements.
17.2.3 Golgi Cell Synapses
Golgi cells are interneurons that provide inhibition to the
granule cells (Ito 2006; Schilling etal. 2008; Galliano etal.
2010). It has been suggested that Golgi cells act as an adapt-
able spatiotemporal lter that controls information ow
through the cerebellar cortex (D’Angelo 2008). Ablation of
Golgi cells by immunotoxin-mediated cell targeting impairs
motor coordination, revealing a crucial role for cerebellar
function (Watanabe et al. 1998). Golgi cell axons are
restricted to the GCL and surround the glomeruli, making
inhibitory synapses with the dendrites of granule cells. Most
Golgi cells contain both GABA and glycine and can mediate
GABAergic or glycinergic inhibition based on differential
expression of either GABAA or glycine receptors in the target neurons (Dugué et al. 2005). Immunohistochemical
investigations have revealed that Golgi cell synapses mature
with a time course similar to that of MF synapses. The axon
terminals of Golgi cells develop rapidly during the second
postnatal week, forming ring-like arrangements at the
periphery of the glomeruli (McLaughlin etal. 1975). During
this period, granule cells undergo a marked acceleration of
inhibitory postsynaptic currents, which may be due to
changes in the subunit composition of GABAA receptors
(Brickley et al. 1999). It has been demonstrated that the
BDNF receptor TrkB controls the formation and maintenance of synapses between Golgi cells and granule cells
(Rico etal. 2002), primarily by regulating the assembly of
pre- and postsynaptic adhesion molecules (Chen etal. 2011).
Other types of interneurons that mediate synaptic inhibition in the cerebellar cortex include Lugaro, globular, and
candelabrum cells (Schilling et al. 2008). Like Golgi cells,
these neurons are situated in the GCL and have a dual
GABAergic/glycinergic phenotype. However, unlike Golgi
cells, their axons are not restricted to the granule cell layer,
but they distribute throughout the ML.Knowledge of the connectivity and physiology of these cerebellar neurons is incomplete, and very little is known about their development.
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Synaptogenesis andSynapse
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Elimination inDeveloping Cerebellum
KouichiHashimoto, MasahikoWatanabe,
andMasanobuKano
18
Abstract
Purkinje cells (PCs) are the sole output neurons of the
cerebellar cortex and play pivotal roles in the coordination, control, and learning of movements. In adult cerebellum, they receive two distinctive excitatory synaptic
inputs from parallel bers (PFs), the axons of granule
cells (GCs), and climbing bers (CFs) arising from the
inferior olivary nucleus in the medulla oblongata. Each
PC receives functionally weak but numerous (c.a.
100,000 in mice) PF synapses, on spines of distal dendrites. In contrast, most PCs are innervated by single but
functionally very strong CFs on stubby spines of proximal dendrites. PCs receive GABAergic inhibitory synaptic inputs from basket and stellate cells (BCs and SCs) in
the molecular layer. These synaptic organizations are
established mostly during the rst 3 weeks of a rodent’s
life. In this chapter, we briey review how these microcircuits around PCs are organized, maintained, and modied
during postnatal development.
Keywords
Purkinje cell · Basket cell · Stellate cell · Granule cell
Parallel ber · Climbing ber · Synaptogenesis · Synapse
elimination · Cerebellum
K. Hashimoto
Department of Neurophysiology, Graduate School of Biomedical
and Health Sciences, Hiroshima University, Hiroshima, Japan
e-mail: hashik@hiroshima-u.ac.jp
M. Watanabe
Department of Anatomy, Hokkaido University Graduate School of
Medicine, Sapporo, Japan
e-mail: watamasa@med.hokudai.ac.jp
M. Kano (*)
Department of Neurophysiology, Graduate School of Medicine,
The University of Tokyo, Tokyo, Japan
e-mail: mkano-tky@m.u-tokyo.ac.jp
18.1 Synaptogenesis andRenement ofCF
toPC Synapses
18.1.1 Synaptogenesis ofCFs toImmature PCs
Olivocerebellar axons reach the immature cerebellum
around embryonic day (E) 18 in rodent. They start to form
synapses just after their arrival but do not have a typical
“climbing” morphology at this stage. Immature olivocerebellar axons extensively ramify in the white matter and the
GC layer and give rise to many collaterals around PCs
(creeper stage) (Chedotal and Sotelo 1993). Since immature PCs are devoid of large primary dendrites, CFs mainly
form terminals on abundant perisomatic protrusions and
thorns emerging from the PC somata.
18.1.2 Postnatal Renement ofCF toPC
Synapses
While most PCs are innervated by single CFs in the adult
cerebellum, each PC receives synaptic inputs from multiple
CFs at birth. Adult-like mono innervation is gradually established during postnatal development by the elimination of
surplus CFs (Crepel 1982), which proceeds in at least four
distinct phases (Kano etal. 2018).
Around P2–P3, individual CFs of each multiplyinnervated PC form synapses with relatively similar synaptic
strength (Fig.18.1). During the rst postnatal week, a single
CF is selectively strengthened on the soma of each PC both
functionally and morphologically (termed “functional differentiation”). Mice with PC-specic deletion of Cav2.1, the
α-subunit of the P/Q-type voltage-dependent Ca2+ channel
(VDCC), show impairment in the selective strengthening of
a single CF (Hashimoto etal. 2011), suggesting that activitydependent Ca2+ inux through P/Q-type VDCCs is crucial
for establishing a single “winner” CF in each PC (Hashimoto
etal. 2011; Kawamura etal. 2013).
© 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_18
121
122
P3
P7
MF
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P21P12
PF
SC
GC
Fig. 18.1 Synaptogenesis and synapse elimination around PCs during
postnatal development. PC Purkinje cell, CF climbing ber, PF parallel
ber, BC basket cell, SC stellate cell, GC granule cell, MF mossy ber.
Note that PF synapses onto BCs and SCs are not illustrated for
simplicity
BC
PC
Several molecules have been shown to be involved in
strengthening of CF synaptic inputs. These include: (1)
Semaphorin 3A (Sema3A), a secreted form of semaphorin,
which is secreted from PCs and acting retrogradely on
Plexin A4 (PlxnA4) on CF terminals (Uesaka and Kano
2018; Uesaka et al. 2014), (2) C1ql1, a member of C1q
family proteins, which derives from CFs and anterogradely
acts on brain-specic angiogenesis inhibitor 3 (Bai3) in
PCs (Kakegawa etal. 2015; Sigoillot etal. 2015), and (3)
progranulin, a growth factor, which derives from PCs and
acts retrogradely on Sort1 on CF terminals (Uesaka etal.
2018).
Then, the strongest CF extends its innervation territory
from the soma to dendrites, which is known as “CF translocation” (Fig.18.1). As mentioned above, CFs initially establish synaptic contacts on the ne process emerging from the
soma, and form a plexus on the lower part of the PC somata
(“pericellular nest” stage) (Cajal 1911). While the stem dendrite of PCs starts to grow into the molecular layer from
around P6, multiple CFs continue to innervate PC somata
until around P9. After the functional differentiation of CFs,
only the strongest (winner) CF extends its innervation territory from the soma to stem dendrites from P9 (“capuchin”
stage) (Cajal 1911). Translocation of a single “winner” CF to
PC dendrite has been shown to require the P/Q-type VDCC
in PCs (Hashimoto etal. 2011), the C1ql1 to Bai3 anterograde signaling (Kakegawa etal. 2015; Sigoillot etal. 2015),
and the progranulin to Sort1 retrograde signaling (Uesaka
etal. 2018).
K. Hashimoto et al.
In the “dendritic” stage (Cajal 1911), CF synapses progressively translocate to growing PC dendrites. On the other
hand, weaker (loser) CFs remain around the soma, and are
then eventually eliminated in two distinct phases (the “early
and late phases of CF elimination”) (Kano and Watanabe
2019; Kano etal. 2018). The early phase of CF synapse elim-
ination starts at around P7 just after the functional differentiation. Unlike the late phase of CF synapse elimination, the
early phase is not dependent on proper formation of PF–PC
synapses. Several lines of evidence suggest that neuronal
activity is crucial for this event (Kano and Watanabe 2019;
Kano etal. 2018). The P/Q-type VDCC in PCs is crucial for
the early phase of CF synapse elimination (Hashimoto etal.
2011; Miyazaki etal. 2012) but it is currently unknown how
Ca2+ inux through the P/Q-type VDCC into PCs leads to
elimination of weaker CF synapses from the soma.
The late phase of CF synapse elimination starts at around
CF
P12 (Kano and Watanabe 2019; Kano etal. 2018). This process is critically dependent on proper formation of excitatory
PF synapses (Hashimoto etal. 2009) and inhibitory BC synapses on PCs (Nakayama etal. 2012). In mice decient in the
type 1 metabotropic glutamate receptor (mGluR1) or any of its
downstream signaling molecules (Gαq, PLCβ3, PLCβ4, and
PKCγ), the late phase of CF elimination is severely impaired
(Kano and Watanabe 2019; Rai etal. 2021). The impaired CF
elimination is rescued by introducing PC’s major mGluR1
splice variant, mGluR1a, but not another mGluR1 splice variant, mGluR1b, into PCs of mGluR1 knockout mice (Ichise
et al. 2000; Ohtani etal. 2014). These results indicate that
mGluR1a and its downstream signaling to PKCγ in PCs are
crucial for the late phase of CF elimination. In the cascade
downstream of mGluR1, Sema7A, a GPI linked subtype of
semaphorin, in postsynaptic PCs and its receptors (ItgB1 and
PlxnC1) on CFs are demonstrated to be involved (Uesaka and
Kano 2018; Uesaka etal. 2014). Moreover, at the downstream
of mGluR1, brain-derived neurotrophic factor (BDNF) derived
from postsynaptic PCs is demonstrated to act retrogradely on
its high afnity receptor TrkB in CFs to promote the late phase
of CF synapse elimination (Choo etal. 2017). Besides mGluR1
signaling cascade, the immediate early gene Arc/Arg3.1 acti-
vated by Ca2+ inux through the P/Q-type VDCC into PCs is
found to be involved in the late phase of CF synapse elimination (Mikuni etal. 2013).
18.2 Synaptogenesis andRenement ofPF
toPC Synapses
18.2.1 Synaptogenesis ofPFs toImmature PCs
During the prenatal period, GC precursors migrate to the cerebellar surface and form the external granular layer. After
birth, they proliferate and descend in the molecular and PC
18 Synaptogenesis andSynapse Elimination inDeveloping Cerebellum
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layers to form the internal granular layer (Altman and Bayer
1997). In the premigratory zone of the external granular layer,
postmitotic spindle-shaped GCs extend future PFs to both
directions in the transverse plane parallel to the cortical surface (Fig.18.1). Then, GCs start to migrate along radial bers
of the Bergmann glia (Bergmann bers) in the molecular layer
by extending downward bers. As consequence, T-shaped
axon of GCs is constructed. Because horizontal beams of
newly generated PFs pile up on previously formed PFs in the
supercial or upper zone of the molecular layer, formation and
maturation of PFs proceed in an orderly “inside-out” manner.
This sequential development of PFs and synaptic transmission
is shown to be crucial for proper network formation and motor
function in the cerebellum (Park etal. 2019).
During the rst 10 days of a rodent’s life, proliferation
and migration of GCs are slow in rate (Altman and Bayer
1997). Moreover, PC dendrites are immature, particularly, in
the upper zone of the molecular layer, where dendrites extend
lopodium-like protrusions, PF–PC synapses are few in
number, PC spines are often free of innervation, and synaptic
coverage by lamellate processes of Bergmann glia is incomplete (Kurihara etal. 1997; Yamada etal. 2000). In the next
10 days, PC dendrites grow dynamically, the bulk of GCs
come into existence, and PF–PC synapses explosively
increase in number (Takacs and Hamori 1994). Moreover,
almost all spines form synaptic contact with PF terminals,
and PF–PC synapses are equipped with well-developed postsynaptic density and complete coverage by Bergmann glia
(Kurihara et al. 1997; Spacek 1985; Yamada et al. 2000).
Analyses of agranular and hypogranular animal models have
demonstrated that PF synapse formation in PCs plays a critical role in the elongation, branching, and planer development of PC dendritic trees (Sotelo 2004).
GluD2 and Cbln1 play an important role in PF–PC synapse formation (Mishina etal. 2012; Yuzaki 2011). GluD2 is
a member of ionotropic glutamate receptors but does not
function as a glutamate-gated ion channel. GluD2 is expressed
predominantly in PCs and selectively localized at PF but not
CF synapses (Mishina etal. 2012). Cbln1, which was originally identied as a precursor of the PC-specic peptide cerebellin, belongs to the C1q/tumor necrosis factor superfamily
and is released into culture medium as a hexamer (Yuzaki
2011). Cbln1 is highly expressed in GCs, and accumulated in
the synaptic cleft at PF–PC synapses (Yuzaki 2011).
In GluD2 or Cbln1 knockout mice, the density of PF synapses is signicantly reduced. Moreover, many free spines
and frequent mismatching of pre- and post-synaptic specialization at PF synapses are conspicuous and unique to these
mutants (Hirai et al. 2005; Kashiwabuchi et al. 1995;
Kurihara etal. 1997). Tripartite molecular complex formed
by GluD2 on PC dendritic spines, Cbln1 released from GCs,
and specic neurexin variant (S4+-neurexin) on PF terminals
act as a bidirectional synaptic organizer that strengthens and
stabilizes the connectivity of PF–PC synapses (Matsuda
etal. 2010; Uemura etal. 2010). This trans-synaptic molecular bridge is also functional in adult brains, as defects of PF–
PC synapses are induced after drug-induced GluD2 ablation
in adult mice (Takeuchi etal. 2005).
18.2.2 Postnatal Renement ofPF toPC
Synapses
In addition to mono-innervation by CFs, segregation of the
PF and CF territories on PC dendrites is another distinguished feature in excitatory synaptic organization of
PC.Until P9, CF and PF territories are separated, because
CFs innervate the soma and PFs form synaptic contacts only
on the dendrite. Then, these two territories become overlapped by commencement of dendritic translocation of a
single “winner” CF from P9 to P15, when PFs remain to
innervate the whole extent of PC dendritic tree (Ichikawa
etal. 2016). From P15 to P20, the territories segregate again
by massive elimination of PF synapses from the proximal
compartment of PC dendrites (Ichikawa etal. 2016). This
developmental process of PF synapse elimination is impaired
in mutant mouse strains lacking mGluR1, PKCγ, or P/Q- type VDCC, leading to sustained overlapping territories of
CF and PF innervation at the proximal compartment of PC
dendrites (Ichikawa etal. 2016; Miyazaki etal. 2004, 2012).
18.3 Synaptogenesis ofBCs and SCs toPCs
The basket cell (BC) and stellate cell (SC) are GABAergic
interneurons in the molecular layer, which receive excitatory
inputs from PFs and send feed-forward inhibition to PCs.
Both types of interneurons are derived from dividing progenitors in the white matter of postnatal cerebellum, and
later migrate into the molecular layer (Zhang and Goldman
1996). They also share similar molecular expression and r-
ing proles and are often called molecular layer interneurons
(MLIs) collectively. Nevertheless, they are distinct in innervation domains of target PCs (also see Chap. 23 “Basket
cells”). In the mature cerebellum, BCs innervate the soma
and construct the pinceau formation around the axon initial
segment (AIS) of PCs, while SCs form synapses on PC dendrites (Fig.18.1).
18.3.1 Synaptogenesis ofBC Axon
toImmature PCs
The BC migrates across the PC layer to the molecular layer
and starts to form synapses on the PC soma at the end of the
rst postnatal week (Ango etal. 2004). Around P9, most of
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K. Hashimoto et al.
the perisomatic synapses are formed by CFs. Thereafter until
P20, BC axons take over somatic synaptic sites, concomitant
with the progressive elimination of somatic CF synapses
(Ichikawa etal. 2011). From around P9, BC axons reach the
AIS and begin to form the pinceau.
Targeting of BS axons to the AIS is mediated by several
molecules including membrane-associated adaptor protein
ankyrin-G and one of its binding partner, neurofascin 186
(NF186), a PC-specic splice variant of neurofascin of the
L1 family immunoglobulin cell adhesion molecule (L1CAM)
(Ango etal. 2004; Brummendorf etal. 1998; Huang et al.
2007; Williams etal. 2010). NF186 exhibits a sharp concen-
tration gradient from the AIS toward the soma and dendrites
of PCs, being highest at the AIS (Ango etal. 2004). This
gradient is already formed at the end of the rst postnatal
week when BC axons rst contact the somata of PCs.
Ankyrin-G is expressed exclusively at AISs in PCs. AnkyrinG- decient mice show a defect in distribution of NF186 and
abnormal widespread coverage of AISs with BC axons
instead of the focal ensheathment of AIS in wild-type mice
(Ango etal. 2004; Huang etal. 2007; Williams etal. 2010).
Conditional deletion of NF186 from PCs of developing mice
also prevents maturation of the AIS and causes disorganization of the pinceau (Buttermore etal. 2012).
Besides NF186, Sema3A and its cognate receptor neuropilin- 1 (NRP1) are essential for establishment of BC–PC
wiring during postnatal development (Cioni et al. 2013;
Telley etal. 2016). It is suggested that NRP1in BCs contributes to axon collateral guidance to the PC soma (Telley etal.
2016), collateral contact and recognition of the PC soma/AIS
(Telley etal. 2016), and terminal branching of BC axons at
the PC’s AIS (Cioni etal. 2013).
18.3.2 Synaptogenesis ofSC Axon
toImmature PCs
SC precursors migrate into the molecular layer a few days
after migration of BC precursors, which continue until
around P14 (Yamanaka etal. 2004). Between P12 and P16,
SCs become bipolar and extend neurites in horizontal orientation (Ango etal. 2008). Then, at P16–P18, SC axons extend
ascending and descending collaterals, which are further elaborated with appearance of plexus of ner branches up to P40
(Ango etal. 2008). Importantly, both ascending and descending collaterals of SC axons are strictly associated with
Bergmann bers (Ango etal. 2008). During the second to
fourth postnatal weeks, Bergmann bers are transformed
into a highly elaborate meshwork by extending numerous
ne lamellate processes that enwrap PC synapses (Yamada
etal. 2000). SC axons appear to be guided toward PC dendrites by using Bergmann bers as an intermediate scaffold,
and terminals are formed at the intersection between
Bergmann bers and PC dendrites. Thus, Bergmann bers
may function as an intermediate scaffold to guide SC axons
along the characteristic trajectories toward multiple PC dendrites and to form synaptic contacts.
Close homologue of L1 (CHL1) is another member of
L1CAM, and localized to apical Bergmann bers and SCs
during development. In CHL1 knockout mice, SC axons
exhibit abnormal branching and orientation, and SC–PC synapses are reduced and cannot be maintained, leading to progressive atrophy of axon terminals, whereas the formation of
the pinceau by BC axons is intact (Ango etal. 2008). These
abnormalities in SC axons are also observed in Bergmann
glia-specic CHL1-deleted mice. These lines of evidence
demonstrate that CHL1 expressed in the Bergmann glia
works as guiding scaffolds to organize SC axon arbors and
formation of SC–PC synapses (Ango etal. 2008; Williams
etal. 2010).
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