Acute injury to central nervous system (CNS) triggers neurodegenerative processes that can result in serious damage or complete loss of function. After injury, production of transforming growth factor β1 (TGFβ1) increases and initiates creation of a fibrotic scar that prevents normal growth, plasticity, and recovery of damaged neurons [1]. Administration of TGFβ1 antagonists can prevent its pathological effects [2]. To define consequences of increased TGFβ1 release on calcium signaling, neuronal plasticity, excitability, and mitochondrial dynamics in CNS neurons we directly exposed a rat primary culture of cerebellar granule neurons to TGFβ1. We focused on changes in expression of intracellular calcium transporters, especially inositol-1,4,5-trisphosphate receptor (IP3R) type 1, mitochondrial dynamics, and membrane excitability. TGFβ1 significantly decreased the gene and protein expression of IP3R1 and the gene expression of additional intracellular calcium transporters such as IP3R2, ryanodine receptor type 1 (RyR1), RyR2, and SERCA2. Altered calcium signaling suppressed neurite outgrowth and significantly decreased the length of the mitochondria and the frequency of mitochondrial fusion. The resting membrane potential of cerebellar granule neurons was hyperpolarized and slow after depolarization of single action potential was suppressed. LY364947, a blocker of TGFβ1 receptor I [2], prevented these effects, and IP3 receptor blocker 2-aminoethoxydiphenyl borate (2APB) mimicked them. After CNS injury TGFβ1 downregulates intracellular calcium levels and alters calcium signaling within injured neurons. We suggest that in our model TGFβ1 may trigger both neurodegenerative and neuroprotective events through IP3-induced calcium signaling.
This work was supported by grant VEGA 2/0097/11 and by the Slovak Research and Development Agency under contract No. APVV-0212-10.
[1] Mctigue D., Experimental Neurology. 2009, 163, 220–230.
[2] Kimura-Kuroda J., Teng X., et al. Mol Cell Neurosci. 2010, 43, 177-187.
Re: otazka
Dobrý deň
Ďakujem pekne za otázku. Po poranení CNS ako napr. traumatické poškodenie mozgu alebo meningitída, dochádza ku infiltrovaní meningeálnych fibroblastov, ktoré po spojení s kortikálnymi astrocytmi vytvárajú tzv fibrotickú jazvu. Okrem hlavného už spomínaného faktora TGFbeta1 astrocyty a fibroblasty exprimujú spektrum iných axón inhibičných molekúl, akými sú Neurocan, Phosphacan, Tenascine C, Semaphorin 3A a NG2 proteoglykány. Všetky látky negatívne vplývajú na rast neuritu a týmto zmeneným prostredím zabraňujú akejkoľvek regenerácii poškodených axónov. Veľmi dôležitým faktorom s podobnými vlastnosťami ako TGFbeta1 je Kolagén IV, ktorého expresia je po poškodení CNS taktiež zvýšená. Bolo dokázané, že inhibíciou Kolagénu sa aj tvorba fibrotickej jazvy a ostatných faktorov znižuje. Takže podobných faktorom ako je TGFbeta1 je Kolagén IV.