ABSTRACT
Over the past two decades, increasing evidence has indicated that the pathophysiology of major depressive disorder (MDD) and the action of antidepressants both involve brain-derived neurotrophic factor (BDNF). BDNF, a major neuronal growth factor in the brain, promotes neuronal survival and maturation, as well as plasticity during development and adulthood (Barde 1990; Thoenen 1995; Figurov et al. 1996). Reductions in BDNF levels may cause atrophy and cell loss in the hippocampus (HIP) and prefrontal cortex (PFC), which are morphological changes observed in depressed subjects. On the other hand, neuroprotective actions of BDNF that repair atrophy and
19.1 Introduction .......................................................................................................................... 391 19.2 BDNF Hypothesis of Depression.......................................................................................... 392
19.2.1 History ...................................................................................................................... 392 19.2.2 Causation Studies: Does BDNF Dysfunction Lead to Depression? ......................... 392
19.2.2.1 Previous Controversial Results .................................................................. 392 19.2.2.2 Critical Components to Be Considered-Endogenous Gene
Regulation of BDNF .................................................................................. 393 19.2.2.3 Role of Activity-Dependent Promoter IV-Driven Expression of
BDNF in Depression .................................................................................. 394 19.3 BDNF Gene Structure, Expression, and Functions .............................................................. 395
19.3.1 Structure, Protein Processing, and Functions of the BDNF Gene ........................... 395 19.3.2 Differential Expression of BDNF Exons at Baseline Conditions ............................. 397
19.4 Gene Regulation of BDNF.................................................................................................... 399 19.4.1 BDNF Gene Upregulation by Neuronal Activity ..................................................... 399 19.4.2 BDNF Gene Upregulation by Antidepressant Treatments ....................................... 399 19.4.3 Signaling Pathways Involved in an Induction of BDNF Transcription ....................400 19.4.4 Promoter-Speci˜c Gene Regulation by Neuronal Activity and Antidepressants ..... 401 19.4.5 Promoter-Speci˜c Downregulation of BDNF Expression ........................................402 19.4.6 Effects of Early-Life Stress on BDNF Expression ...................................................404
19.5 BDNF and Depression in Human Studies ............................................................................404 19.5.1 Studies with Postmortem Human Brain Samples .....................................................404 19.5.2 Serum BDNF Levels in Living Patients with Depression ........................................405 19.5.3 Genetic Research of BDNF in Depression ...............................................................405
