Differential Effects of Neurotrophins and Schwann Cell-Derived Signals on Neuronal Survival/Growth and Synaptogenesis

Abstract

Recent studies have shown that the survival of mammalian motoneurons in vitro is promoted by neurotrophins (NTs) and cAMP. There is also evidence that neurotrophins enhance transmitter release. We thus investigated whether these agents also promote synaptogenesis. Cultured Xenopus spinal cord neurons were treated with a mixture of BDNF, glia-derived neurotrophic factor, NT-3, and NT-4, in addition to forskolin and IBMX or the cell-permeant form of cAMP, to elevate the cAMP level. The outgrowth and survival of neurons were dramatically increased by this trophic stimulation. However, when these neurons were cocultured with muscle cells, the trophic agents resulted in a failure of synaptogenesis. Specifically, the induction of ACh receptor (AChR) clustering in cultured muscle cells was inhibited at nerve-muscle contacts, in sharp contrast to control, untreated cocultures. Because AChR clustering induced by agrin or growth factor-coated beads in muscle cells was unaffected by trophic stimulation, its effect on synaptogenesis is presynaptic in origin. In the control, agrin was deposited along the neurite and at nerve-muscle contacts. This was significantly downregulated in cultures treated with trophic stimuli. Reverse transcriptase-PCR analyses showed that this decrease in agrin deposition was caused by an inhibition of agrin synthesis by trophic stimuli. Both agrin synthesis and induction of AChR clustering were restored under trophic stimulation when Schwann cell-conditioned medium was introduced. These results suggest that trophic stimulation maintains spinal neurons in the growth state, and Schwann cell-derived factors allow them to switch to the synaptogenic state.

Mechanisms and Roles of Axon-Schwann Cell Interactions

“…In cultures con- taining embryonic Xenopus spinal neurons and muscle, neurotrophic factors and elevated cAMP induce a dramatic increase in neuron survival and neurite outgrowth (Peng et al, 2003). However, the number of nerve-muscle contacts that showed AChR clusters was greatly inhibited.…”

“…However, the number of nerve-muscle contacts that showed AChR clusters was greatly inhibited. Interestingly, addition of medium conditioned by SCs or TGF-␤1 increased AChR clusters at neuron-muscle contacts (Peng et al, 2003;Feng and Ko, 2004). These findings suggested that Schwann cell-derived factors allow neurons to switch from a "growth phase" to a "synaptogenic phase."…”

New roles for astrocytes: Regulation of CNS synaptogenesis

“…Notably, an interesting study showed recently that neurotrophins support survival and growth of cultured frog spinal cord neurons, but inhibit agrin synthesis and thus NMJ formation. However, soluble, as-yet unidentified Schwann-cell-derived factors override this inhibition and switch motoneurons to a synaptogenic state [16]. It will be interesting to see whether such a binary regulation of NMJ formation is implemented in vivo and whether a similar principle applies to synaptogenesis in the CNS.…”

“…Owing to space limitations, the article focuses mainly on connections in the CNS. However, it should be noted that glial cells also appear to influence synaptogenesis in the peripheral nervous system (PNS) [14][15][16][17][18][19]). …”

Schwann Cell-Derived Factors Modulate Synaptic Activities at Developing Neuromuscular Synapses

“…To investigate how Schwann cells promote synaptogenesis, we have shown previously that Schwann cell-conditioned medium (SC-CM) can increase the number of nerve-muscle contacts in Xenopus tissue culture (Peng et al, 2003). However, it has been unclear whether Schwann cells promote synaptic function at developing NMJs.…”