Naturally occurring neuronal death during the postnatal development of Purkinje cells and their precerebellar afferent projections

Abstract

Naturally occurring neuronal death plays a substantial developmental role in the building of the neural circuitries. The neuronal death caused by different cerebellar mutations is mostly of an apoptotic nature. Apart from the identity of the intrinsic mechanisms of the mutations, adult cerebellar mutants are a powerful tool to causally study the development of the cerebellar connectivity. Thus, studies on adult cerebellar neuronal cell death occurring in mouse mutants elucidate: (i) the dependence of the postsynaptic neurons on their partners, (ii) the ‘en cascade’ postsynaptic transneuronal degeneration after target-deprivation, and (iii) the close relationship between the molecular modular organization of the cerebellar cortex and dying Purkinje cells. Neuronal cell death has been extensively studied in developing olivocerebellar system. However, less data are available on the occurrence of naturally occurring neuronal death during the in vivo normal development of the Purkinje cells and the mossy fiber system neurons. The developmental role of neuronal death during the establishment and refinement of the olivocerebellar projection is currently discussed. Moreover, the occurrence of neuronal death during the development of the basilar pontine nuclei and its role in the acquisition of the adult pontocerebellar projection is still poorly understood. In the present review, we correlate the dates of Purkinje cells death with the inferior olivary and basilar pontine neuronal apoptosis, discussing their developmental relationships during the elaboration of the fine-grained maps of the cerebellar afferent connections.

Introduction

Naturally occurring cell death plays a crucial role in the development and homeostasis of pluricellular organisms. Since the pioneering analysis of Hamburger [50], naturally occurring neuronal cell death (NCD) has been correlated with the control of neuronal cell number during development (for a review, see Ref. [87]). NCD is involved in the withdrawal of aberrant axon projection or cell positions, the target-dependent matching of the sizes of both pre- and postsynaptic populations, and the refinement of the neural circuits [24], [34], [93]. These regressive phenomena depend of the competition between neurons for the trophic factors required for survival [22], [87], [94]. The decrease in or absence of appropriate trophic factors triggers an intrinsic genetic program—requiring specific protein synthesis [88]—which leads to cell death [87].

NCD is determined by the balance between the expressions of pro- and anti-apoptotic genes (for a review, see Refs. [65], [79], [87]). The breakdown of this balance elicits the activation of the caspases protein family [84] whose action results in DNA fragmentation and the formation of the apoptotic cell bodies. Among the caspases family members participating in programmed cell death, caspase-3 is the most frequently involved in the apoptosis of postmitotic neurons [92], [100], [121]. Caspase-3-independent apoptosis [125] and a neuroprotective role for caspase-3 against N-methyl-d-aspartate neurotoxicity [78] have also been recently suggested. Active caspase-3 immunocytochemistry is, however, a useful tool to detect neurons undergoing apoptosis during the nervous system development [47].

NCD occurs during the development of Purkinje cells (PCs) [47], [64] and their main primary afferents: the granule cells [60], [118] and the inferior olive (IO) neurons [12], [37]. The relationships of cerebellar and precerebellar NCD with: (i) the final organization of the highly precise pattern of adult cerebellar circuitry [6], [35], [46], [56], and (ii) the intrinsic cerebellar cortex molecular compartmentation, have been largely discussed [72], [103]. Moreover, the absence of NCD during the development of the basilar pontine nuclei (BPN) [8]—an important mossy fiber cerebellar afferent system—is an exception to the general observation of regressive phenomena taking place during nervous system development, in which NCD plays a key role in the refinement of neural circuitries [88].

This review explores the temporal relationships between NCD in PCs and in two major afferent sources—the IO and the BPN. Evidence is presented that NCD occurs in the BPN concurrently with the refinement of the adult cerebellar topography.