The Role of BDNF in Age-Dependent Changes of Excitatory and Inhibitory Synaptic Markers in the Human Prefrontal Cortex

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 41; no. 13; pp. 3080 - 3091
• Main Authors: Oh, Hyunjung, Lewis, David A, Sibille, Etienne
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.12.2016
• Subjects: Adolescent; Adult; Age; Aged; Aged, 80 and over; Aging; Animals; Atrophy; Brain research; Brain-derived neurotrophic factor; Brain-Derived Neurotrophic Factor - metabolism; Female; gamma-Aminobutyric Acid - metabolism; Gene Expression Profiling; Gene Expression Regulation - genetics; Humans; Kinases; Male; Medical research; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mental depression; Mental disorders; Mental health; Mice; Mice, Transgenic; Middle Aged; Neuronal Plasticity - genetics; Oligonucleotide Array Sequence Analysis; Original; Prefrontal Cortex - physiology; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Receptor, trkB; RNA, Messenger - metabolism; Signal Transduction - physiology; Synapses - genetics; Young Adult; Toronto Ontario Canada; Canada
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/npp.2016.126

Reduced brain-derived neurotrophic factor (BDNF) may underlie age-related synaptic loss, in turn contributing to cerebral atrophy, cognitive decline, and increased risk for psychiatric disorders. However, the specific contribution of BDNF to the age-related expression changes in synaptic markers and their temporal trajectories remain uncharacterized. Using microarray data from orbitofrontal cortex of control subjects (n=209; 16-96 years), we identified genes whose expression positively correlates with BDNF (r>0.575; n=200 genes) and analyzed them for enriched biological pathways. qPCR was performed to measure the expression level of transcript variants of BDNF, NTRK2, and selected BDNF-coexpressed genes in younger and older subjects. We confirmed age-related downregulation of BDNF and show 78 of the top 200 BDNF-coexpressed genes are associated with synaptic function. Both excitatory and inhibitory synaptic genes show decreased expression with age and are positively correlated with BDNF and NTRK2 expression and negatively correlated with dominant-negative truncated NTRK2 level. Results were validated at the RNA level in an independent cohort and at the protein level for selected findings. We next tested the causal link between the correlative human findings using mice with conditional blockade of BDNF/NTRK2 signaling. Blockade of NTRK2 activity in adult mice recapitulate the age-like pattern in the expression of markers for inhibitory presynaptic but notably not for excitatory synaptic genes. Together, these findings suggest that age-dependent decrease in BDNF signaling may cause synaptic alterations through an initial and preferential effect on GABA presynaptic genes. These results have implications for neuropsychiatric disorders characterized by accelerated aging molecular profiles, such as major depression.