PDGF‐BB Exerts Trophic Activity on Cultured GABA Interneurons from the Newborn Rat Cerebellum

Abstract

Platelet-derived growth factor (PDGF) is a well known mitogen for mesenchyme-derived cells and glial cells. Its presence in neuronal cells of the central nervous system has only recently been described. We have shown earlier that neurons of newborn rat brains in culture express PDGF beta-receptors and that PDGF-BB, a homodimer of PDGF B-chain, increases survival and promotes neurite outgrowth of newborn cerebellar cells (Smits et al., Proc. Natl Acad. Sci. USA, 88, 8159-8163, 1991). In this study, the effects of PDGF on early postnatal rat cerebellar cells were further explored. By using chemically defined serum-free medium, we have established primary cell cultures of rat cerebella (postnatal day 4-5) containing 70-80% neuronal cells. During the first 10 days in vitro, no difference in total cell number was found between PDGF-BB-treated and untreated cultures. After this time period, however, increased survival of the PDGF-BB-treated cells was found. Within the first 10 days in vitro, the addition of PDGF-BB to the cultures resulted in a relative increase in survival of interneurons expressing glutamic acid decarboxylase (GAD), the GABA biosynthetic enzyme. Moreover, addition of PDGF-BB in the untreated cell culture resulted in a rapid increase of GAD mRNA. These results show that PDGF-BB acts as a trophic factor on GABAergic interneurons of the cerebellum by up-regulating GAD synthesis and prolonging the survival of these cells. Furthermore, in situ hybridization revealed that there are scattered cells present in the early postnatal cerebellum that express PDGF beta-receptor mRNA.(ABSTRACT TRUNCATED AT 250 WORDS)

Normal developing rat brain expresses a platelet-derived growth factor B chain (c-sis) mRNA truncated at the 5′ end

“…In the CA1 and CA3 areas of the rodent hippocampus, the relative postnatal growth of the comissural/associational terminal ®elds, and the elaboration of stratum radiatum pyramidal dendrites, are most rapid in the second postnatal week (Loy, 1980;Pokorny and Yamamoto, 1981). PDGF-B/c-SIS has been shown to exhibit various properties, including enhancement of neurite extension, induction of c-fos (Smits et al, 1993), stimulation of tyrosine phosphorylation (Cooper et al, 1982), inhibition of gapjunctional communication (Maldonado et al, 1988), and inhibition of NMDA receptor function (Valenzuela et al, 1996), all of which are consistent with the possible involvement of PDGF-B/c-SIS in synaptic transmission. Considering the abundant receptor (PDGFR-b) expression in neonatal neurons (Smits et al, 1991), the expression of PDGF-B/c-SIS in the hippocampus during the second postnatal week may be related to the maturation of neurons, including as neurite extension and elaboration of synaptic network.…”

Analysis of Mutant Platelet-Derived Growth Factor Receptors Expressed in PC12 Cells Identifies Signals Governing Sodium Channel Induction during Neuronal Differentiation

“…Here, we have analyzed the actions of a series of PDGF receptors in these cells in an effort to identify signals important for Na ϩ channel expression, a crucial aspect of neuronal differentiation. While PDGF receptors are expressed in many populations of neurons (14,55,64,68,69), they are not normally expressed in wildtype PC12 cells. Therefore, in this study, we took advantage of previously generated PC12 sublines that stably express PDGF receptors (79).…”

“…Therefore, in this study, we took advantage of previously generated PC12 sublines that stably express PDGF receptors (79). Although there are no published estimates of the number of PDGF receptors in primary neurons for comparison, the levels of PDGF receptors in these PC12 sublines are such that PDGF elicits in them many of the same responses that it does in primary neurons, including increases in survival, c-fos induction, neurite outgrowth, and the induction of enzymes involved in neurotransmitter synthesis (55,68,69). Furthermore, in these sublines, PDGF mimics the actions of NGF in all responses examined so far, including the induction of Na ϩ channel expression and the activation of signaling molecules such as Ras, B-Raf, Raf-1, and MAPK to levels comparable to those observed in response to NGF (18,79).…”

Platelet-derived Growth Factor Induces a Long-term Inhibition of -Methyl-D-aspartate Receptor Function

“…PDGF, like the neurothrophins, is 1) produced locally and is important for the development, differentiation, proliferation, and survival of neuronal and glial cells (7,10,11,17); 2) coupled to tyrosine kinase receptors that activate complex intracellular signaling pathways (2); and 3) released as part of the compensatory response to central nervous system injury or disease (13,15,16). We now report that PDGF exerts another function that is characteristic of the neurotrophic factors, which is the modulation of neurotransmitter receptors in the central nervous system (29).…”

“…It is likely that this elevation in PDGF levels is involved not only in the pathogenesis of these conditions but also in the tissue repair processes associated with these diseases. In this regard, it has been shown that PDGF exerts neurotrophic effects on GABAergic and dopaminergic neurons (17,18) and that it protects hip-pocampal neurons against energy deprivation and oxidative injury in vitro (19).…”