The intellectual disability protein PAK3 regulates oligodendrocyte precursor cell differentiation.

Oligodendrocyte and myelin deficits have been reported in mental/psychiatric diseases. The p21-activated kinase 3 (PAK3), a serine/threonine kinase, whose activity is stimulated by the binding of active Rac and Cdc42 GTPases is affected in these pathologies. Indeed, many mutations of Pak3 gene have been described in non-syndromic intellectual disability diseases.

The RhoGEF DOCK10 is essential for dendritic spine morphogenesis.

By regulating actin cytoskeleton dynamics, Rho GTPases and their activators RhoGEFs are implicated in various aspects of neuronal differentiation, including dendritogenesis and synaptogenesis. Purkinje cells (PCs) of the cerebellum, by developing spectacular dendrites covered with spines, represent an attractive model system in which to decipher the molecular signaling underlying these processes. To identify novel regulators of dendritic spine morphogenesis among members of the poorly characterized DOCK family of RhoGEFs, we performed gene expression profiling of fluorescence-activated cell sorting (FACS)-purified murine PCs at various stages of their postnatal differentiation.

Mature Purkinje cells require the retinoic acid-related orphan receptor-α (RORα) to maintain climbing fiber mono-innervation and other adult characteristics.

Neuronal maturation during development is a multistep process regulated by transcription factors. The transcription factor RORα (retinoic acid-related orphan receptor α) is necessary for early Purkinje cell (PC) maturation but is also expressed throughout adulthood. To identify the role of RORα in mature PCs, we used Cre-lox mouse genetic tools in vivo that delete it specifically from PCs between postnatal days 10-21.

Thyroid hormone triggers the developmental loss of axonal regenerative capacity via thyroid hormone receptor α1 and krüppel-like factor 9 in Purkinje cells.

Neurons in the CNS of higher vertebrates lose their ability to regenerate their axons at a stage of development that coincides with peak circulating thyroid hormone (T(3)) levels. Here, we examined whether this peak in T(3) is involved in the loss of axonal regenerative capacity in Purkinje cells (PCs). This event occurs at the end of the first postnatal week in mice.

c-Jun N-terminal kinase (JNK) and p38 play different roles in age-related Purkinje cell death in murine organotypic culture.

Several studies have shown that Purkinje cells die by apoptosis in organotypic slice cultures from postnatal 3-day-old (P3) mice. This cell death is age-dependent and has been proposed as indirect evidence for the programmed Purkinje cell death occurring in in vivo cerebellum. Here, we studied whether c-jun N-terminal kinase (JNK) and p38 kinase pathways contribute to the Purkinje cell death observed in cerebellar slice cultures obtained from P3 mice.

Induction of early Purkinje cell dendritic differentiation by thyroid hormone requires RORα.

Background: The active form (T3) of thyroid hormone (TH) controls critical aspects of cerebellar development, such as migration of postmitotic neurons and terminal dendritic differentiation of Purkinje cells. The effects of T3 on early dendritic differentiation are poorly understood.

Results: In this study, we have analyzed the influence of T3 on the progression of the early steps of Purkinje cell dendritic differentiation in postnatal day 0 organotypic cerebellar cultures.

Synapse elimination in olivo-cerebellar explants occurs during a critical period and leaves an indelible trace in Purkinje cells.

During developmental synaptogenesis, the pre- and postsynaptic cells undergo specific interactions that lead to the establishment of the mature circuit. We have studied the roles of the pre- and postsynaptic cells in establishing this mature innervation by using an in vitro model of synaptic development. We describe climbing fiber (CF)-Purkinje cell (PC) synaptogenesis in cultured mouse hindbrain explants and show that synaptic competition occurs during early development in vitro.

Gene expression signature of cerebellar hypoplasia in a mouse model of Down syndrome during postnatal development.

Background: Down syndrome is a chromosomal disorder caused by the presence of three copies of chromosome 21. The mechanisms by which this aneuploidy produces the complex and variable phenotype observed in people with Down syndrome are still under discussion. Recent studies have demonstrated an increased transcript level of the three-copy genes with some dosage compensation or amplification for a subset of them.

SCLIP is crucial for the formation and development of the Purkinje cell dendritic arbor.

Cerebellar Purkinje cells elaborate one of the most complex dendritic arbors among neurons to integrate the numerous signals they receive from the cerebellum circuitry. Their dendritic differentiation undergoes successive, tightly regulated phases of development involving both regressive and growth events. Although many players regulating the late phases of Purkinje cell dendritogenesis have been identified, intracellular factors controlling earlier phases of dendritic development remain mostly unknown.

Expression of netrin-1, slit-1 and slit-3 but not of slit-2 after cerebellar and spinal cord lesions.

To determine whether members of the Netrin-1 and Slit families and their receptors are expressed after central nervous system (CNS) injury, we performed in situ hybridization for netrin-1, slit-1, 2 and 3, and their receptors (dcc, unc5h-1, 2 and 3, robo-1, 2 and 3) 8 days, 2-3 months and 12-18 months after traumatic lesions of rat cerebellum. The expression pattern of these molecules was unchanged in axotomized Purkinje cells, whereas unc5h3 expression was upregulated in deafferented granule cells. Cells expressing slit-2 or dcc were never detected at the lesion site.

Heterogeneity of NG2-expressing cells in the newborn mouse cerebellum.

The function and origin of NG2+ cells in the adult brain are still controversial. A large amount of data is available which strongly indicates that adult NG2-expressing cells form a heterogeneous population, constituted by oligodendrocyte precursor cells (OPCs) and a fourth novel type of glial cells named the synantocytes. Whether these two populations derive from the progressive maturation of perinatal NG2+ OPCs or are generated as separate populations is not known.

Quantitative effects produced by modifications of neuronal activity on the size of GABAA receptor clusters in hippocampal slice cultures.

The number and strength of GABAergic synapses needs to be precisely adjusted for adequate control of excitatory activity. We investigated to what extent the size of GABA(A) receptor clusters at inhibitory synapses is under the regulation of neuronal activity. Slices from P7 rat hippocampus were cultured for 13 days in the presence of bicuculline or 4-aminopyridine (4-AP) to increase neuronal activity, or DNQX to decrease activity.

The developmental loss of the ability of Purkinje cells to regenerate their axons occurs in the absence of myelin: an in vitro model to prevent myelination.

Axonal regeneration in the mammalian CNS is a property of immature neurons that is lost during development. Using organotypic culture of cerebellum, we have shown that in vitro Purkinje cells lose their regenerative capacity in parallel with the process of myelination. We have investigated whether myelination is involved in the age-dependent loss of regeneration of these neurons.

Inhibition of protein kinase C prevents Purkinje cell death but does not affect axonal regeneration.

In organotypic cultures, mouse Purkinje cells regenerate their axons from embryonic day 18 (E18) to postnatal day 0 (P0), die of apoptosis between P1 and P7, and survive but do not regenerate at P10. This particular behavior of Purkinje cells did not allow us to find out when the developmental switch between regeneration and lack of regeneration occurs. This work was undertaken to suppress Purkinje cell apoptosis and to investigate whether the same molecules that prevent apoptosis could also influence axonal growth, regeneration, or both.

Postnatal maturation of Na+, K+, 2Cl- cotransporter expression and inhibitory synaptogenesis in the rat hippocampus: an immunocytochemical analysis.

GABA, a major inhibitory neurotransmitter, depolarizes hippocampal pyramidal neurons during the first postnatal week. These depolarizations result from an efflux of Cl- through GABAA-gated anion channels. The outward Cl- gradient that provides the driving force for Cl- efflux might be generated and maintained by the Na+, K+, 2Cl- cotransporter (NKCC) that keeps intracellular Cl- concentration above electrochemical equilibrium.