Neurotrophins in CNS regeneration: BDNF up-regulation recruits neurons and glia, and promotes recovery after spinal cord transection

• Autorzy: Skup M.
• Języki publikacji: EN

Abstrakty

EN

The neurotrophins are a family of small proteins that were first identified as survival factors for sympathetic and sensory neurons and have since been shown to control survival, development and function of neurons and myelin formation in the central and peripheral nervous systems. Prosurvival and plasticity-promoting effects of mammalian neurotrophins: NGF, BDNF, NT-3 and NT-4 are mediated through activation of the tropomyosin-related kinase family of receptor tyrosine kinases (TrkA, TrkB, TrkC). The spinal cord of the adult rat is rich in BDNF protein which exceeds brain levels and is expressed in neurons occupying all spinal laminae (Skup et al. 2002, Macias et al. 2007). Locomotor exercise of the uninjured rats, an approach used to improve motor functions after injury, increased perikaryonal levels of BDNF mRNA within the majority of cells and of BDNF protein in processes surrounding large neurons of the lumbar motor nuclei. Exercise increased also staining intensity and number of TrkB receptor immunoreactive small cells of the spinal grey matter, which were identified as oligodendrocytes. When applied to the rats with complete spinal cord transection, exercise caused BDNF up-regulation in distinct populations of neurons in motor nuclei and increased motoneuron innervation (Skup et al. 2009, 2012). Data strongly suggested that the spinal network is under BDNF control, targeting neurons but also oligodendrocytes, recruited to neurotrophin signaling by the activated network. Multifaceted functions of BDNF make this molecule a promising one in attempts to stimulate neuronal regeneration and remyelination, but until recently treatments directed to increase the BDNF supply to injury-affected spinal networks only moderately improved locomotor functions. We therefore attempted to deliver BDNF via neurons transduced with adeno-associated virus serotype 1/2 (AAV1/2) expressing BDNF under the control of the synapsin promoter in the lumbo-sacral network below the complete transection. Based on functional, histological and biochemical assessments, I shall show that BDNF secreted from BDNF-expressing neurons in lumbar segments improves locomotor functions and alters excitability of the spinal network. Searching for the mechanisms of these changes we revealed that the increased segmental BDNF concentrations led to an increase in GAP-43 expression, GAD67 mRNA and protein expression and GABA levels, reducing post-lesion GABA deficits in the thoracic/lumbar segments. BDNF did not compensate the deficit of the potassium-chloride co-transporter KCC2, responsible for GABAA receptor-mediated hyperpolarizing inhibition. We conclude that sustained delivery of BDNF to the isolated spinal cord network causes neuronal rearrangements and increases inhibitory transmission under conditions of lesion-induced altered neuronal excitability, leading to locomotor improvement in paraplegic rats. Since glia affect excitability and remyelination we study astroglial/ oligodendroglial responses to BDNF overexpression. Support: Polish-German grant S007/P-N/2007/01, EMBO ASTF211.00-2007, NCN3975/(P)1/2010/39 & 3247/2010/39.

Słowa kluczowe

EN

neurotrophin; small protein; control survival; neuron; myelin formation; central nervous system; regeneration; glial cell; spinal cord

• Wydawca: -
• Czasopismo: Acta Neurobiologiae Experimentalis
• Rocznik: 2013
• Tom: 73
• Numer: 1
• Opis fizyczny: p.163

Twórcy

autor

Skup M.

• Laboratory of Reinnervation Processes, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland