Maturation, Refinement, and Serotonergic Modulation of Cerebellar Cortical Circuits in Normal Development and in Murine Models of Autism

Abstract

The formation of the complex cerebellar cortical circuits follows different phases, with initial synaptogenesis and subsequent processes of refinement guided by a variety of mechanisms. The regularity of the cellular and synaptic organization of the cerebellar cortex allowed detailed studies of the structural plasticity mechanisms underlying the formation of new synapses and retraction of redundant ones. For the attainment of the monoinnervation of the Purkinje cell by a single climbing fiber, several signals are involved, including electrical activity, contact signals, homosynaptic and heterosynaptic interaction, calcium transients, postsynaptic receptors, and transduction pathways. An important role in this developmental program is played by serotonergic projections that, acting on temporally and spatially regulated postsynaptic receptors, induce and modulate the phases of synaptic formation and maturation. In the adult cerebellar cortex, many developmental mechanisms persist but play different roles, such as supporting synaptic plasticity during learning and formation of cerebellar memory traces. A dysfunction at any stage of this process can lead to disorders of cerebellar origin, which include autism spectrum disorders but are not limited to motor deficits. Recent evidence in animal models links impairment of Purkinje cell function with autism-like symptoms including sociability deficits, stereotyped movements, and interspecific communication by vocalization.

Age-dependent dormant resident progenitors are stimulated by injury to regenerate Purkinje neurons

“…A second possibility is that the differentiation of iPCs is dictated by the timing of the establishment of the cerebellar circuitry. We speculate that efficient regeneration is possible at P1 because PCs still have an immature morphology and integration into the cerebellar circuitry, whereas at later stages the parallel fibers (axons of granule cells) synapse with PCs and climbing fibers (axons of the inferior olive neurons) refine their synapses and both cells promote PC maturation ( Good et al, 2017 ; Hoxha et al, 2017 ). Thus, maturation and integration of a newly generated PC into the cerebellar circuitry might not be efficient or possible after P5.…”

Role of β3‐adrenergic receptor in the modulation of synaptic transmission and plasticity in mouse cerebellar cortex

“…The involvement of PI3K in PCs was confirmed by the finding that wortmannin prevented the inhibitory action of CL on the PF‐EPSCs. Signaling pathways such as PI3K/AKT and its downstream targets, including the mammalian target of rapamycin (mTOR) have been reported to be essential for spinogenesis and synaptogenesis upon growth factor stimulation, including insulin growth factor‐1 (Cuesto et al., 2011; Hoxha et al., 2017; Hoxha, Lippiello, et al., 2018). Given the high density of β3‐AR on PCs, it would be interesting to examine how and whether this receptor contributes to neuronal remodeling during cerebellar development.…”

Purkinje Cell Signaling Deficits in Animal Models of Ataxia

“…The elimination of supernumerary CF synapses is significantly correlated with the development of PF synapses through a heterosynaptic competition (Scelfo and Strata, 2005 ; Hoxha et al, 2017 ). Indeed, in mutant mice that lack granule cells or functional PFs, such as weaver , reeler and staggerer as well as X-irradiated mice, the transition from multiple to single CF innervation is defective so that multiple innervation of PCs by CFs persists into the adult stage and is associated with ataxia and loss of motor coordination (Crepel et al, 1980 ; Crepel, 1982 ; Hashimoto and Kano, 2013 ).…”