TY  - JOUR
A1  - Dombert, Benjamin
A1  - Balk, Stefanie
A1  - Lüningschrör, Patrick
A1  - Moradi, Mehri
A1  - Sivadasan, Rajeeve
A1  - Saal-Bauernschubert, Lena
A1  - Jablonka, Sibylle
T1  - BDNF/trkB induction of calcium transients through Ca\(_{v}\)2.2 calcium channels in motoneurons corresponds to F-actin assembly and growth cone formation on β2-chain laminin (221)
JF  - Frontiers in Molecular Neuroscience
N2  - Spontaneous Ca\(^{2+}\) transients and actin dynamics in primary motoneurons correspond to cellular differentiation such as axon elongation and growth cone formation. Brain-derived neurotrophic factor (BDNF) and its receptor trkB support both motoneuron survival and synaptic differentiation. However, in motoneurons effects of BDNF/trkB signaling on spontaneous Ca\(^{2+}\) influx and actin dynamics at axonal growth cones are not fully unraveled. In our study we addressed the question how neurotrophic factor signaling corresponds to cell autonomous excitability and growth cone formation. Primary motoneurons from mouse embryos were cultured on the synapse specific, β2-chain containing laminin isoform (221) regulating axon elongation through spontaneous Ca\(^{2+}\) transients that are in turn induced by enhanced clustering of N-type specific voltage-gated Ca\(^{2+}\) channels (Ca\(_{v}\)2.2) in axonal growth cones. TrkB-deficient (trkBTK\(^{-/-}\)) mouse motoneurons which express no full-length trkB receptor and wildtype motoneurons cultured without BDNF exhibited reduced spontaneous Ca\(^{2+}\) transients that corresponded to altered axon elongation and defects in growth cone morphology which was accompanied by changes in the local actin cytoskeleton. Vice versa, the acute application of BDNF resulted in the induction of spontaneous Ca\(^{2+}\) transients and Ca\(_{v}\)2.2 clustering in motor growth cones, as well as the activation of trkB downstream signaling cascades which promoted the stabilization of β-actin via the LIM kinase pathway and phosphorylation of profilin at Tyr129. Finally, we identified a mutual regulation of neuronal excitability and actin dynamics in axonal growth cones of embryonic motoneurons cultured on laminin-221/211. Impaired excitability resulted in dysregulated axon extension and local actin cytoskeleton, whereas upon β-actin knockdown Ca\(_{v}\)2.2 clustering was affected. We conclude from our data that in embryonic motoneurons BDNF/trkB signaling contributes to axon elongation and growth cone formation through changes in the local actin cytoskeleton accompanied by increased Ca\(_{v}\)2.2 clustering and local calcium transients. These findings may help to explore cellular mechanisms which might be dysregulated during maturation of embryonic motoneurons leading to motoneuron disease.
KW  - growth cone
KW  - BDNF
KW  - trkB
KW  - Ca\(_{v}\)2.2
KW  - F-actin
KW  - motor axon
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159094
VL  - 10
IS  - 346
ER  - 
TY  - JOUR
A1  - Tejero, Rocio
A1  - Alsakkal, Mohammad
A1  - Hennlein, Luisa
A1  - Lopez-Cabello, Ana M.
A1  - Jablonka, Sibylle
A1  - Tabares, Lucia
T1  - Nifedipine ameliorates cellular differentiation defects of Smn-deficient motor neurons and enhances neuromuscular transmission in SMA mice
JF  - International Journal of Molecular Sciences
N2  - In spinal muscular atrophy (SMA), mutations in or loss of the Survival Motor Neuron 1 (SMN1) gene reduce full-length SMN protein levels, which leads to the degeneration of a percentage of motor neurons. In mouse models of SMA, the development and maintenance of spinal motor neurons and the neuromuscular junction (NMJ) function are altered. Since nifedipine is known to be neuroprotective and increases neurotransmission in nerve terminals, we investigated its effects on cultured spinal cord motor neurons and motor nerve terminals of control and SMA mice. We found that application of nifedipine increased the frequency of spontaneous Ca\(^{2+}\) transients, growth cone size, cluster-like formations of Cav2.2 channels, and it normalized axon extension in SMA neurons in culture. At the NMJ, nifedipine significantly increased evoked and spontaneous release at low-frequency stimulation in both genotypes. High-strength stimulation revealed that nifedipine increased the size of the readily releasable pool (RRP) of vesicles in control but not SMA mice. These findings provide experimental evidence about the ability of nifedipine to prevent the appearance of developmental defects in SMA embryonic motor neurons in culture and reveal to which extent nifedipine could still increase neurotransmission at the NMJ in SMA mice under different functional demands.
KW  - spinal muscular atrophy
KW  - motor neurons
KW  - synaptic transmission
KW  - neuromuscular junction
KW  - calcium channels
KW  - nifedipine
KW  - growth cone
KW  - axons
KW  - synaptic vesicles
KW  - postsynaptic potentials
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313636
SN  - 1422-0067
VL  - 24
IS  - 8
ER  -