Download Development of glutamatergic and GABAergic synapses

Development of glutamatergic and GABAergic synapses
Marco Sassoè-Pognetto
Department of Neuroscience, C.so Massimo d’Azeglio, 52, I-10126 Turin, Italy
Correspondence:
Prof. Marco Sassoe
Dip. di Neuroscienze
C.so Massimo d’Azeglio, 52
10126 Torino, Italy
Tel: +39-011-6707778
E-mail: [email protected]
Introduction
The cerebellum has a prolonged course of development, that largely extends into
postnatal life (Wang and Zoghby 2001). This feature, together with the availability
of several natural mutants and of cell-specific genetic tools (Sotelo 2004, Sajan et al.
2010), makes the cerebellum one of the most accessible brain regions for studying
synaptogenesis in situ. In the cerebellar cortex, synaptogenesis is entirely postnatal,
although it occurs at rather different rates in different lobules (Altman, 1972a-c). In
both mice and rats, synapses start to form in the first postnatal week, and reach
adult densities at the end of the third week (Fig. 1; Sassoè-Pognetto and Patrizi,
2013). The entire period of synaptogenesis is characterized by a progressive growth
of the granular and molecular layers, and a proliferation of synapses from the
bottom upward. Only a few studies have specifically investigated the development
of synaptic connectivity in the deep cerebellar nuclei (Eisenman et al. 1991, Garin
and Escher, 2001). These investigations have suggested that synaptogenesis may
start in the nuclei well before the emergence of the first synapses in the cerebellar
cortex, but the precise pattern remains to be determined.
Development of glutamate synapses
The main types of glutamate synapses in the cerebellum are those established by
mossy fibers (MFs), parallel fibers (PFs) and climbing fibers (CFs). In rodents, MFs
invade the gray matter at P3-P5 and start establishing the first synapses onto granule
cells at the end of the first postnatal week. However it is only during the second
postnatal week that synapse number increases considerably, reaching a peak at P15
(Altman 1972c, Hamóri and Somogyi 1983). During development, MF synapses
undergo an extensive structural remodeling, that is accompanied by changes of their
electrophysiological properties (Larramendi 1969, Cathala et al. 2005). The
formation of MF synapses and their developmental maturation depend on
synaptogenic factors released by granule cells, such as Wnt7a and fibroblast growth
factor 22 (Hall et al. 2000, Umemori et al., 2004).
PFs establish the first synapses as soon as their target neurons, the Purkinje cells
(PCs), start growing their dendrites in the developing molecular layer at the end of
the first postnatal week (Altman, 1972a,b). The formation of PF synapses depends
on trans-synaptic interactions between the 2 glutamate receptor (GluD2), that is
expressed selectively by PCs, 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 et al. 2010, Uemura et al.
2010).
CFs provide the earliest synaptic inputs to PCs in the developing cerebellar cortex
(Fig. 1). CF synapses undergo a remarkable structural remodelling throughout
development. During the first postnatal week, these afferents establish a dense
plexus around the cell body of PCs (Cajal, 1890). 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 et al., 2009). The remodeling of CFs involves also heterosynaptic
competition with PFs. Thus, a decrease in PF innervation (e.g. in mutant mice with
reduced numbers of granule cells or in mice lacking GluD2) results in retention of
multiple CFs and an expansion of the CF innervation territory on PC distal
dendrites (Cesa and Strata 2009 and references therein). By contrast, a selective
silencing of CFs (e.g. after lesioning the inferior olive) causes the emergence of
supernumerary spines in the proximal dendrites of PCs, which become innervated
by PFs. Interfering with GABAergic inhibition also impairs CF synapse elimination
(Nakayama et al., 2012). Therefore, synapse refinement in PCs requires appropriate
levels of electrical activity evoked by CFs, PFs and GABAergic inputs.
Development of GABA synapses
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 et al., 2010).
Basket cells start innervating the cell body of PCs at the end of the first postnatal
week (Sotelo 2008, Viltono 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).
Formation of the pinceau involves a displacement of basket cell axons from the cell
body of PCs to the AIS (Sotelo, 2008). The targeting of basket axons to the AIS
depends a subcellular gradient of neurofascin 186, a cell adhesion molecule of the
L1 immunoglobulin family, along the PC soma-AIS axis, and such gradient requires
ankyrinG, a membrane adaptor protein that recruits neurofascin (Ango et al. 2004).
Interestingly, another member of the same family of adhesion molecules, CHL1, is
localized along Bergmann glia fibers 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 et al. 2008). Thus different members of the L1 family contribute to axon
patterning and subcellular synapse organization in different types of interneurons.
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).
According to a recent study, PC-PC synapses are established early during postnatal
development (from P4). These synapses are believed to represent a substrate for
waves of activity that propagate along chains of connected PCs (Watt et al. 2009).
These travelling waves are absent in adult mice, therefore it has been proposed that
they may have a developmental role in wiring cerebellar networks.
Golgi cells mediate synaptic inhibition in the granular layer. Their axon terminals
surround the glomeruli and make synapses with the dendrites of granule cells (Palay
and Chan-Palay, 1974). 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 matures
with a time course similar to that of MF synapses (McLaughlin et al. 1975). 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 granule cell layer 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 molecular layer.
Knowledge of the connectivity and physiology of these cerebellar neurons is
fragmentary, and very little is known about their development.
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Figure legend
Fig. 1. Graphic representation of the development of synapses made by different
types of cerebellar neurons and by cerebellar cortical afferents. The diagram is
based on studies of the mouse and rat cerebellum. There is still a lot of uncertainty
about the precise dates of the onset and the conclusion of the synaptogenic period,
as symbolized by the grading colors. Significant phases of the development of
specific types of synapses are indicated. (After Sassoè-Pognetto and Patrizi, 2013).