title: Infusion of BDNF into the nucleus accumbens of aged rats improves cognition and structural synaptic plasticity through PI3K-ILK-Akt signaling.
abstract: To investigate the involvement of the nucleus accumbens (NAc) in cognitive impairment and the therapeutic effects of brain-derived neurotrophic factor (BDNF) in an animal model of cognitive deficit, we infused BDNF into the NAc of cognitively impaired aged rats. Cognition was evaluated by Morris water maze test. Structural synaptic plasticity was measured by Golgi staining. Brain tissue homogenization was used to measure the changes in signal molecules. Cultured PC-12 cells expressing tyrosine kinase receptor (Trk) B/p75 neurotrophin receptor (p75(NTR)), p75(NTR) or TrkA/p75(NTR) receptors were used for BDNF stimulation assays. Significant decreases in the levels of BDNF, phosphatidylinositol-3-kinase (PI3K) and integrin-linked kinase (ILK) activity, protein kinase B (Akt) Ser⁴⁷³ phosphorylation, dendritic branching, and density of dendritic spines on medium spiny neurons were observed in the NAc. Importantly, infusion of BDNF restored cognition, synaptic plasticity, and cell signaling. In cultured PC-12 cells, BDNF activated PI3K/Akt signaling through the TrkB receptor, whereas stimulation of ILK/Akt occurred through TrkA/p75(NTR) heteroreceptor. Our study suggested that the decreased BDNF level and its downstream signaling as well as loss of synaptic plasticity in the NAc are associated with cognitive impairments in aged rats. The BDNF-activated PI3K-Akt and ILK-Akt signaling play a key role in structural synaptic plasticity. Our study also suggested that BDNF could be a mechanism-based treatment for dementia.
authors.affiliation: Department of Neurology, Xiangya Hospital, Central South University, Changsha 410078, PR China.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Fu-Rong
authors.initials: FR
authors.lastname: Dai
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Du
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: Yang
authors.forename: Xiuwu
authors.initials: X
authors.lastname: Zhang
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020917:Receptor, trkA / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020917:Receptor, trkA; D020813:Receptor, trkB; D000099200:Scaffold Protein ILK