Bdnf mRNA splice variants differentially impact CA1 and CA3 dendrite complexity and spine morphology in the hippocampus.
Brain-derived neurotrophic factor (BDNF) is an activity-dependent neurotrophin critical for neuronal plasticity in the hippocampus. BDNF is encoded by multiple transcripts with alternative 5' untranslated regions (5'UTRS) that display activity-induced targeting to distinct subcellular compartments. While individual Bdnf 5'UTR transcripts influence dendrite morphology in cultured hippocampal neurons, it is unknown whether Bdnf splice variants impact dendrite arborization in functional classes of neurons in the intact hippocampus. Moreover, the contribution of Bdnf 5'UTR splice variants to dendritic spine density and shape has not been explored. We analyzed the structure of CA1 and CA3 dendrite arbors in transgenic mice lacking BDNF production from exon (Ex) 1, 2, 4, or 6 splice variants (Bdnf-e1, -e2, -e4, and -e6-/-mice) and found that loss of BDNF from individual Bdnf mRNA variants differentially impacts the complexity of apical and basal arbors in vivo. Consistent with the subcellular localization studies, Bdnf Ex2 and Ex6 transcripts significantly contributed to dendrite morphology in both CA1 and CA3 neurons. While Bdnf-e2-/-mice showed increased branching proximal to the soma in CA1 and CA3 apical arbors, Bdnf-e6-/-mice showed decreased apical and basal dendrite complexity. Analysis of spine morphology on Bdnf-e6-/-CA1 dendrites revealed changes in the percentage of differently sized spines on apical, but not basal, branches. These results provide further evidence that Bdnf splice variants generate a spatial code that mediates the local actions of BDNF in distinct dendritic compartments on structural and functional plasticity.
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA.
Kristen R
KR
Maynard
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA.
John W
JW
Hobbs
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA.
Mahima
M
Sukumar
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA.
Alisha S
AS
Kardian
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA.
Dennisse V
DV
Jimenez
Sheppard-Pratt Lieber Research Institute, Baltimore, MD, 21204, USA.
Robert J
RJ
Schloesser
Lieber Institute for Brain Development, Johns Hopkins Medical Campus, 855 North Wolfe Street, Suite 300, Baltimore, MD, 21205, USA. keri.martinowich@libd.org.|Departments of Psychiatry & Behavioral Sciences, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. keri.martinowich@libd.org.
Keri
http://orcid.org/0000-0003-0031-8468
K
Martinowich
D000704:Analysis of Variance; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000166:cytology*; D056654:CA3 Region, Hippocampal / Q000166:cytology*; D003712:Dendrites / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D009474:Neurons / Q000166:cytology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics*
D019208:Brain-Derived Neurotrophic Factor; D020033:Protein Isoforms; D012333:RNA, Messenger; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins
BDNF transcripts; Dendrite branching; Hippocampus; Spatial code; Spine morphology