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. 2007 May;97(5):3365-75.
doi: 10.1152/jn.00686.2006. Epub 2007 Mar 21.

Metabotropic glutamate receptors in the lateral superior olive activate TRP-like channels: age- and experience-dependent regulation

F Aura Ene  1 , Abigail Kalmbach, Karl Kandler
Affiliations

Metabotropic glutamate receptors in the lateral superior olive activate TRP-like channels: age- and experience-dependent regulation

F Aura Ene et al. J Neurophysiol. 2007 May.

Abstract

The lateral superior olive (LSO) is the primary auditory nucleus for processing of interaural sound level differences, which is one of the major cues for sound localization. During development, survival and maturation of LSO neurons critically depend on synaptic activity and intracellular calcium signaling. Before hearing onset, glutamatergic synaptic inputs from the cochlear nucleus (CN) to the LSO activate group I metabotropic glutamate receptors (mGluRs), which leads to calcium release from intracellular stores and large calcium influx from the extracellular milieu. Here, we investigated the nature of the mGluR-activated membrane channel that mediates the influx of extracellular calcium. Using Fura-2 calcium imaging in brain stem slices of neonatal and juvenile mice, we found that this calcium channel is blocked by Ni(2+), La(3+), and 2-aminoethoxydiphenylborane (2-APB), known antagonists of transient receptor potential (TRP) channels. During postnatal development, the contribution of extracellular calcium influx to mGluR-mediated Ca(2+) responses gradually decreased and was almost abolished by the end of the third postnatal week. Over this period, the contribution of Ca(2+) release from internal stores remained unchanged. The developmental decrease of TRP-like channel-mediated calcium influx was significantly less in congenitally deaf waltzer mice, suggesting that early auditory experience is necessary for the normal age-dependent downregulation of functional TRP channels.

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Figures

FIG. 1
FIG. 1
Comparisons between bulk-labeling and spin-labeling. A: examples of lateral superior olive (LSO) slices labeled using bulk (left) and spin-labeling (right) at postnatal day 0 (P0: the day of birth). Images show fluorescence at 360 nm (exposure time 20 ms, ×20 objective). Dotted lines outline the boundaries of the LSO. D, dorsal; L, lateral. B: example of changes in intracellular Ca2+ elicited by bath application of (S)-3,5-dihydroxyphenylglycine (DHPG, 50 μM, 90 s) and KCl (60 mM, 30 s). LSO neurons from a P3-old mouse.
FIG. 2
FIG. 2
Developmental changes of group I metabo-tropic glutamate receptor (mGluR)–mediated Ca2+ responses in LSO neurons. A: example of DHPG-elicited (50 μM, 90 s) Ca2+ responses in 3 LSO neurons, each from a P0, P10, and P14 mouse. Responses undergo a transition from a profile characterized by peak and plateau (pp) to a profile characterized by a smaller peak and a smaller plateau (psp), and finally to a profile characterized by a peak only [peak and no plateau (pnp)]. Dotted line indicates baseline Ca2+ levels. B: group data of peak amplitudes, plateau amplitudes, area, and duration of DHPG-evoked Ca2+ responses at different ages. Number of cells in each age group: P0–P5: 222; P9–P12: 165; P13–P16: 135; P17–P19: 54 (asterisks: P < 0.05, ANOVA). C: developmental changes in the percentage of pp-type (black bars), psp-type (gray bars), and pnp-type (white bars) responses (asterisks: P < 0.05, chi-square test). Number of cells in each age group: P0–P5: pp n = 222; P9–P12: pp n = 46; psp n = 75, pnp n = 59; P13–P16: pp n = 15, psp n = 42, pnp n = 75; P17–P19: pp n = 4, psp n = 7, pnp n = 43.
FIG. 3
FIG. 3
Developmental changes in the contribution of extracellular Ca2+ to group I mGluR-mediated Ca2+ responses. A: examples of individual responses to DHPG application in 2 mM extracellular Ca2+ (left traces) and in 0 mM Ca2+ (right traces). B: peak and area of Ca2+ responses after removal of extracellular Ca2+ as a function of age and response type. n, number of cells. Asterisks: P < 0.05 (paired t-test)
FIG. 4
FIG. 4
Effect of Ni2+ on mGluR-mediated Ca2+ responses. A: examples of DHPG-elicited (20–50 μM) Ca2+ responses from individual LSO neurons. Ai: short application of Ni2+ (2 mM, 2 min) during the plateau phase reduces the response to baseline. Aii: application of Ni2+ (2 mM, 2 min) together with DHPG reduces the amplitude of the initial peak response. Example is from a P5 neuron. Aiii–Avi: DHPG-elicited (50 μM, 90 s) responses of the pp and psp type (iii and v) are reduced by Ni2+ (2 mM). Plateau phase is completely abolished and the peak phase is substantially reduced. Examples are from a P2 (pp response) and a P10 mouse (psp response). Avii–Aviii: DHPG-elicited (50 μM, 90 s) responses of the pnp type are unaffected by Ni2+ (2 mM). Example is from a P15 mouse. B: summary of the effects of Ni2+ on DHPG-elicited Ca2+ responses. Asterisks: sig-nificantly different from control (P < 0.05, paired t-test).
FIG. 5
FIG. 5
Effect of 2-aminoethoxydiphenylborane (2-APB) on group I mGluR-mediated Ca2+ responses. A: effect of increasing concentrations of 2-APB on DHPG-elicited Ca2+ responses in a P10 LSO neuron. B. summary data. C: effect of 2-APB on KCl-elicited (60 mM) Ca2+ responses. Data are from the same cells as in B.
FIG. 6
FIG. 6
Effect of La3+ on group I mGluR-mediated Ca2+ responses. A: dose-dependent effect of La3+ on peak and area of DHPG-evoked (50 μM, 90 s) responses at P0–P5. B and C: in LSO neurons from P9–P12 mice (B: psp responses; C: pnp responses), La3+ potentiated responses at 0.1 and 0.5 mM, whereas it had no effect at 1.0 mM.
FIG. 7
FIG. 7
Group I mGluR-mediated Ca2+ responses in deaf waltzer mice. A: examples of DHPG-elicited Ca2+ responses in wild-type and waltzer mice. B: cumulative distribution plots of peak (i) and duration (ii) of DHPG-elicited responses of LSO neurons from wild-type (wt, black lines, P11–P16: n = 68 cells, P17–P20: n = 72 cells) and waltzer mice (wz, gray lines, P11–P16: n = 107 cells, P17–P20: n = 58 cells). P values for Kolmogorov–Smirnov (KS) test.
FIG. 8
FIG. 8
Durations of group I mGluR-mediated Ca2+responses in waltzer, heterozygote, and wild-type mice. A: cumulative distribution of DHPG-elicited Ca2+ response durations in P11 to P16 LSO neurons from homozygote waltzer (wz, gray line, n = 107 cells), hearing heterozygote (het, dotted line, n = 44 cells), and hearing wild-type mice (wt, black line, n = 68 cells). Durations in heterozygote mice were significantly shorter compared with homozygote mice (P < 0.005) and were not different from wild-type mice (P > 0.1). B: same as A but for postnatal days 17–20. Durations in heterozygote mice were not significantly different from wild-type or homozygote mice (wz: n = 58 cells; het: n = 16 cells; wt: n = 72 cells). C: response durations in heterozygote mice with a startle response (black line; P14–P16, n = 44 cells) and mice lacking a startle response (gray line; P12–P13, n = 29 cells). Durations in mice lacking a startle response were significantly longer than in mice with a startle response (P < 0.001). D: examples of DHGP-elicited Ca2+-responses from heterozygote mice with and without startle response. Scale bars, 0.02 ΔR/R (top traces), 0.01 ΔR/R (bottom traces), 50 s. P values for KS test.
FIG. 9
FIG. 9
Developmental changes in response types in wild-type and waltzer mice. A: percentage of pp and psp responses is greater in wz than in wt mice for both age groups (P11–P16: wt = 32 cells, wz = 80 cells; Fisher’s exact test, P < 0.05; P17–P20: wt = 17 cells, wz = 21 cells; Fisher’s exact test, P > 0.05). B: percentage of pnp responses is smaller in wz than in wt mice (P11–P16: wt = 36 cells, wz = 27 cells; Fisher’s exact test, P < 0.05; P17–P20: wt = 55 cells, wz = 37 cells; Fisher’s exact test, P > 0.05)
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