Development in the central nervous system: studies of activity-dependent plasticity and synapse refinement

The central nervous system (CNS) is a highly specified structure, involved in a large range of
function, from sensory processing to motor behavior to cognition. The CNS development is genetically
programmed but also heavily dependent on environmental cues. The CNS is a highly plastic structure,
most prominently at the synaptic level. Plasticity is a physiological process allowing a rapid change of
synaptic strength depending on experience, use and surrounding neuronal activity. It allows the integration
of neurons into neuronal networks and is also believed to be the mechanism underlying learning and
memory. During development, plasticity underlies the adaptation to the environment, via synapse
refinement, and experience-dependent plasticity. Synapse refinement, together with input competition, is
marked by synapse pruning and formation, to eliminate early-formed redundant synaptic contacts.
Located in the occipital part of the brain, the cerebellum is involved in motor control and
coordination, motor learning and memory, as well as cognition. Endowed with a very peculiar
cytoarchitecture, the cerebellar circuitry is centered around Purkinje Cells (PC). PCs integrate inputs
arising from the two main afferents to the cerebellum, with a direct connection for climbing fibers (CF),
with a relay of the parallel fibers (PF) for the mossy fibers. In the mature cerebellum, each PC is
innervated by an unique CF and this strong connection is the result of a very precise developmental
process. Early on, PCs are innervated by multiple CFs. This situation evolves to the mature connection
profile through a well-characterized four stages process, which is highly dependent on the proper
development of other connections to PCs, notably the PF-PC synapse. We studied this process in a model
for disturbed cerebellar maturation. Nogo-A is a major neurite outgrowth inhibitor of the CNS. It has been
principally studied in CNS injuries, where it restricts the capacity of axons to grow and regenerate. In the
cerebellum, the absence of Nogo alters the development of the PF-PC synapse, but does not alter the
elimination process of supernumerary CFs. At P14 as well as P28, the proportion of reminiscent
supernumerary CF is not affected by the lack of Nogo-A. However, it remains to test how the absence of
Nogo-A and its effect of the maturation of PF-PC synapse affect the cerebellar physiology.
Neurodevelopmental disorders have been linked to defects in cellular physiology in numerous
areas of the brain. Lately, several studies revealed that autism spectrum disorders (ASD) can be linked to
defects in several synaptic proteins, involved in maintaining the structure and anchoring of synaptic
contacts. Amongst others, it has been shown that proteins such as neuroligins exhibit genetic alterations in
ASD and are responsible for defects in cerebellar physiology. Neuroligin 3 is an adhesion molecule,
present at the postsynaptic site, forming a trans-synaptic complex with neurexins, present on the
presynaptic site. This complex is essential for synapse stabilization and function, but not for synapse
formation. Defects in cerebellar plasticity have been associated with particular deficits observed in ASD
patients. Plasticity in the cerebellum is a developmental process and is inducible by a wide range of
protocols. We studied the effect of the absence of neuroligin 3 on long-term depression (LTD) at PF – PC
synapses, a well-established model for cerebellar plasticity. In neuroligin 3 KO mice, our stimulation
protocol did not produce a decrease of the evoked response in the adult, while a clear reduction was
observed in young (P21-30) mice. In WT mice, our stimulation protocol induced a clear decrease of the
response in the adult, but not in young mice. Our results suggest that the occlusion of mGluR-LTD
observed in adult KO mice is a developmental process. Determining the subtleties underlying this
developmental process is a major importance for the development of new treatment strategies in ASD.
The visual cortex is a part of the brain that has been extensively studied, because of the ability to
record and image neuronal activation upon presentation of clearly defined sensory inputs, but also because
of a peculiar time-window for enhanced experience-dependent plasticity. This critical period is
characterized by the ability for monocular deprivation to induce the strengthening of the input from the
open eye, at the expense of those from the closed eye. Spike-timing dependent plasticity (STDP) is an
activity-dependent plastic process playing an important role in the adaptation of cortical connectivity to
the flow of inputs neurons receive. In STDP, the polarity and the amplitude of the response vary according
to the relative timing between the presynaptic input and the postsynaptic backpropagating action potential
(bAP). We tested if bAPs and STDP were subject to any modifications between several time-points of the
critical period. Our results revealed that when pairing a presynaptic spike with the postsynaptic train of
bAPs, at a positive timing, the amplitude of the response observed varied throughout the critical period.
Our results show that bAPs and STDP are mechanisms of premier importance for the cellular integration
of inputs. These two mechanisms participate in sensory input integration, as well as development and
refinement of cellular connections during the critical period, in V1 layer 2/3 pyramidal cells.
In summary, my thesis reveals important insights on neuronal physiology and factors implicated
in synapse refinement and activity-dependent plasticity, during development.