Transient Receptor Potential Channels and Their Role in Modulating Radial Glial–Neuronal Interaction: A Signaling Pathway Involving mGluR5

Abstract

The guidance of developing neurons to the right position in the central nervous system is of central importance in brain development. Canonical transient receptor potential (TRPC) channels are thought to mediate turning responses of growth cones to guidance cues through fine control of calcium transients. Proliferating and 1-to 5-day-differentiated neural progenitor cells (NPCs) showed expression of Trpc1 and Trpc3 mRNA, while Trpc4-7 was not clearly detected. Time-lapse imaging showed that the motility pattern of neuronal cells was phasic with bursts of rapid movement ( > 60 mm/h), changes in direction, and intermittent slow phases or stallings ( < 40 mm/ h), which frequently occurred in close contact with radial glial processes. Genetic interference with the TRPC3 and TRPC1 channel enhanced the motility of NPCs (burst frequency/stalling frequency). TRPC3-deficient cells or cells treated with the TRPC3 blocker pyr3 infrequently changed direction and seldom contacted radial glial processes. TRPC channels are also activated by group I metabotropic glutamate receptors (mGluR1 and mGluR5). As shown here, pyr3 blocked the calcium response mediated through mGluR5 in radial glial processes. Furthermore, 2-methyl-6-(phenylethynyl)pyridine, a blocker of mGluR5, affected the motility pattern in a similar way as TRPC3/6 double knockout or pyr3. The results suggest that radial glial cells exert attractant signals to migrating neuronal cells, which alter their motility pattern. Our results suggest that mGluR5 acting through TRPC3 is of central importance in radial glial-mediated neuronal guidance.

Regulation of radial glial process growth by glutamate via mGluR5/TRPC3 and neuregulin/ErbB4

“…In Figure A, neuronal cells (denoted with “N”) move outside or in close contact with these processes (Jansson et al, ). Immunostaining of the thick glial‐like processes have previously shown positive staining for radial glial marker GLAST, brain lipid binding protein (BLBP) and Musashi as well as for mGluR5 and ionotropic glutamate receptor GluR3 while the neuronal cells show positive staining for neuronal markers MAP‐2, Tuj1 and tyrosine receptor kinase B (TrkB) as well as for ionotropic glutamate receptors GluR1 and GluR2 but hardly any detectable staining for mGluR5 (Jansson et al, ; Louhivuori et al, ). The staining of the thick radial processes with GLAST/BLBP and Musashi would suggest that these cells are analogous to radial glia.…”

“…Blocking mGluR5 and TRPC3 caused a drastic reduction in radial process growth (Jansson et al, ; Louhivuori et al, ). As shown here, NRG was able to restore the growth of radial glial processes.…”

“…The metabotropic glutamate receptor 5 (mGluR5) has emerged as being essential for normal neurogenesis (Di Giorgi Gerevini et al, ). We have recently shown that during the early in vitro differentiation process of embryonically derived cortical neural progenitor cells this receptor is predominantly located on radial glial cells and its inhibition disturbs radial process extensions (Jansson et al, ; Louhivuori et al, ). mGluR5 is coupled to activation of a nonselective cation channel, canonical transient receptor potential 3 (TRPC3) (Berg, Sen, & Bayliss, ; Kim et al, ; Louhivuori et al, ) which has previously been shown to act as a signal for chemotaxis (Amaral & Pozzo‐Miller, ; H. S. Li, Xu, & Montell, ).…”

“…mGluR5 is coupled to activation of a nonselective cation channel, canonical transient receptor potential 3 (TRPC3) (Berg, Sen, & Bayliss, ; Kim et al, ; Louhivuori et al, ) which has previously been shown to act as a signal for chemotaxis (Amaral & Pozzo‐Miller, ; H. S. Li, Xu, & Montell, ). Loss of TRPC3 or its inhibition by the selective blocker pyr3 leads to a disruption of radial processes (Louhivuori et al, ). Furthermore, disrupting mGluR5/TRPC3 signaling revealed that mGluR5 acting via TRPC3 may be of central importance in radial glial neuronal interactions (Louhivuori et al, ).…”

“…S. Li, Xu, & Montell, 1999). Loss of TRPC3 or its inhibition by the selective blocker pyr3 leads to a disruption of radial processes (Louhivuori et al, 2015). Furthermore, disrupting mGluR5/TRPC3 signaling revealed that mGluR5 acting via TRPC3 may be of central importance in radial glial neuronal interactions (Louhivuori et al, 2015).…”