Brain-derived neurotrophic factor and its receptors in Bergmann glia cells Irais Poblete-Naredo a , Alain M. Guillem a , Claudia Juárez b , Rossana C. Zepeda b , Leticia Ramírez a , Mario Caba b , Luisa C. Hernández-Kelly a,c , José Aguilera c , Esther López-Bayghen a , Arturo Ortega a,⇑ a Departamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Apartado Postal 14-740, México D.F. 07000, Mexico b Centro de Investigaciones Biomédicas, Universidad Veracruzana, Apartado Postal 114, Xalapa, Veracruz 91000, Mexico c Institut de Neurociénces i Department de Bioquímica i Biología Molecular, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain article info Article history: Received 7 June 2011 Received in revised form 27 September 2011 Accepted 9 October 2011 Available online 14 October 2011 Keywords: BDNF Bergmann glia Transcriptional control abstract Brain-derived neurotrophic factor is an abundant and widely distributed neurotrophin expressed in the Central Nervous System. It is critically involved in neuronal differentiation and survival. The expression of brain-derived neurotrophic factor and that of its catalytic active cognate receptor (TrkB) has been exten- sively studied in neuronal cells but their expression and function in glial cells is still controversial. Despite of this fact, brain-derived neurotrophic factor is released from astrocytes upon glutamate stim- ulation. A suitable model to study glia/neuronal interactions, in the context of glutamatergic synapses, is the well-characterized culture of chick cerebellar Bergmann glia cells. Using, this system, we show here that BDNF and its functional receptor are present in Bergmann glia and that BDNF stimulation is linked to the activation of the phosphatidyl-inositol 3 kinase/protein kinase C/mitogen-activated protein kinase/ Activator Protein-1 signaling pathway. Accordingly, reverse transcription-polymerase chain reaction (RT-PCR) experiments predicted the expression of full-length and truncated TrkB isoforms. Our results suggest that Bergmann glia cells are able to express and respond to BDNF stimulation favoring the notion of their pivotal role in neuroprotection. Ó 2011 Elsevier B.V. All rights reserved. 1. Introduction Neurotrophins are low molecular weight proteins that promote survival, development and neuronal differentiation. To date, this family of factors is composed of four members identified as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin 4-5 (NT-4/5). BDNF is a small basic protein highly conserved among different species (Barde et al., 1982; Hofer et al., 1990). It is widely distributed and in fact, is the most abundant neurotrophin expressed in the Central Nervous System (CNS) (Leibrock et al., 1989; Maisonpierre et al., 1990). BDNF is critical during development and brain plastic- ity-related processes (Alonso et al., 2005; Kovalchuk et al., 2002). Even though BDNF was initially described as a factor from neu- ronal origin, it has also been identified in microglia, oligodendro- cytes, astrocytes, radial glial cells, immune cells and some peripheral tissues (Aharoni et al., 2005; Maisonpierre et al., 1990; Murer et al., 2001; Stadelmann et al., 2002). Glial BDNF synthesis has been described in cultured cells from different brain areas including cortex, cerebellum, forebrain, retina and olfactory bulb (Harada et al., 2002; Lipson et al., 2003; Miklic et al., 2004; Runyan and Phelps, 2009; Seki et al., 2005; Wu et al., 2004). BDNF levels in retinal Müller cells are higher than those of NGF and NT-3 (Taylor et al., 2003; Wu et al., 2004). Furthermore, BDNF production by astrocytes in vivo has been extensively associated with cellular stress or pathological conditions such as transient ischemia (Tokumine et al., 2003), multiple sclerosis (Stadelmann et al., 2002) or Alzheimer’s disease (Burbach et al., 2004), suggesting a glial neuroprotective role by the production and release of neuro- trophic factors. The activity of BDNF is mediated through its binding to different receptors: TrkB (p145 TrkB ) or high-affinity receptor, a member of the tropomyosin receptor kinase family; and p75 NTR or low-affinity receptor, a member of the tumor necrosis factor family of receptors (Barbacid, 1995). The binding of BDNF to TrkB triggers receptor dimerization, tyrosine trans-phosphorylation and activation of intracellular signaling cascades and effectors including the mito- gen-activated protein kinase (MAPK), phosphatidylinositol 3-ki- nase (PI3K) and phospholipase C-c1 (PLCc1) (Patapoutian and Reichardt, 2001). Moreover, TrkB is also present in a truncated iso- form called tTrkB (p95 TrkB ) that lacks the tyrosine kinase domain and is devoid of catalytic activity (Allen et al., 1994; Klein et al., 1990a,b). In a simplified scenario, neurons express the full-length form, while astrocytes only possess the truncated TrkB isoform (Rose et al., 2003). p75 NTR is involved mainly in the migrating ef- fects of pro-BDNF on cerebellar granule cells (Xu et al., 2011). 0197-0186/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.neuint.2011.10.002 ⇑ Corresponding author. Tel.: +52 5 55061 3800x5316; fax: +52 5 55061 3800x5317. E-mail address: arortega@cinvestav.mx (A. Ortega). Neurochemistry International 59 (2011) 1133–1144 Contents lists available at SciVerse ScienceDirect Neurochemistry International journal homepage: www.elsevier.com/locate/nci