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Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons.

ABSTRACT: Regrowth of peripheral spiral ganglion neuron (SGN) fibers is a primary objective in efforts to improve cochlear implant outcomes and to potentially reinnervate regenerated hair cells. Cyclic adenosine monophosphate (cAMP) regulates neurite growth and guidance via activation of protein kinase A (PKA) and Exchange Protein directly Activated by Cylic AMP (Epac). Here we explored the effects of cAMP signaling on SGN neurite length in vitro. We find that the cAMP analog, cpt-cAMP, exerts a biphasic effect on neurite length; increasing length at lower concentrations and reducing length at higher concentrations. This biphasic response occurs in cultures plated on laminin, fibronectin, or tenascin C suggesting that it is not substrate dependent. cpt-cAMP also reduces SGN neurite branching. The Epac-specific agonist, 8-pCPT-2'-O-Me-cAMP, does not alter SGN neurite length. Constitutively active PKA isoforms strongly inhibit SGN neurite length similar to higher levels of cAMP. Chronic membrane depolarization activates PKA in SGNs and also inhibits SGN neurite length. However, inhibition of PKA fails to rescue neurite length in depolarized cultures implying that activation of PKA is not necessary for the inhibition of SGN neurite length by chronic depolarization. Expression of constitutively active phosphatidylinositol 3-kinase, but not c-Jun N-terminal kinase, isoforms partially rescues SGN neurite length in the presence of activated PKA. Taken together, these results suggest that activation of cAMP/PKA represents a potential strategy to enhance SGN fiber elongation following deafness; however such therapies will likely require careful titration so as to promote rather than inhibit nerve fiber regeneration.

SUBMITTER: Xu N

PROVIDER: S-EPMC3277666 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons.

Xu Ningyong N Engbers Jonathan J Khaja Sobia S Xu Linjing L Clark J Jason JJ Hansen Marlan R MR

Hearing research 20111203 1-2

Regrowth of peripheral spiral ganglion neuron (SGN) fibers is a primary objective in efforts to improve cochlear implant outcomes and to potentially reinnervate regenerated hair cells. Cyclic adenosine monophosphate (cAMP) regulates neurite growth and guidance via activation of protein kinase A (PKA) and Exchange Protein directly Activated by Cylic AMP (Epac). Here we explored the effects of cAMP signaling on SGN neurite length in vitro. We find that the cAMP analog, cpt-cAMP, exerts a biphasic ...[more]

PMID: 22154930

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Project description:The Delta/Notch‑like epidermal growth factor‑related receptor (DNER) serves an important role in the developing central nervous system. However, the actions of DNER in the development of the spiral ganglion in the inner ear have yet to be elucidated. Wild‑type C57BL/6 mice were housed and time‑mated for use in the present study. Primary neuronal cultures were prepared using spiral ganglion progenitors isolated from the modiolus of postnatal day 1 (P1) mice. DNER recombinant lentiviral vectors were constructed and transfected into the cultured primary neurons. The relative proportion of differentiated neurons and the length of their neurites were evaluated using microscopy. The results of the present study demonstrated that DNER was expressed in spiral ganglion neurons (SGNs) that exhibited significant polarity in the early differentiation stages; DNER expression gradually decreased until the polarity was lost on week 35. The in vitro expression of DNER was revealed to be similar to that in vivo. When DNER expression was silenced using RNA interference, the polarity of the differentiated neurons was altered and they exhibited significantly reduced dendritic length. In addition, the proportion of bipolar neurons was decreased compared with the control group. Furthermore, the expression of α‑synuclein and the GluR2/3 subunits of the α‑amin‑o‑3‑hydroxy‑5‑methyl‑4-isoxazolepropionic acid glutamate receptor were also reduced in cultured neurons in which DNER was silenced. Notch1 was co‑expressed with DNER in SGNs isolated from P1 mice. The indirect Notch inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]‑S‑phenylglycine t‑butyl ester also affected the polarity and the formation of protrusions, and reduced the expression of DNER and glial fibrillary acidic protein in SGNs. In conclusion, the present study demonstrated that DNER was expressed in SGNs and appeared to be involved in the mechanisms underlying neuronal polarity and neuritogenesis, via a Notch‑dependent signaling pathway.

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Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons.

Publications

Influence of cAMP and protein kinase A on neurite length from spiral ganglion neurons.

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