BDNF Therapeutic Mechanisms in Neuropsychiatric Disorders

Abstract

Brain-derived neurotrophic factor (BDNF) is the most abundant neurotrophin in the adult brain and functions as both a primary neurotrophic signal and a neuromodulator. It serves essential roles in neuronal development, maintenance, transmission, and plasticity, thereby influencing aging, cognition, and behavior. Accumulating evidence associates reduced central and peripheral BDNF levels with various neuropsychiatric disorders, supporting its potential utilization as a biomarker of central pathologies. Subsequently, extensive research has been conducted to evaluate restoring, or otherwise augmenting, BDNF transmission as a potential therapeutic approach. Promising results were indeed observed for genetic BDNF upregulation or exogenous administration using a multitude of murine models of neurological and psychiatric diseases. However, varying mechanisms have been proposed to underlie the observed therapeutic effects, and many findings indicate the engagement of disease-specific and other non-specific mechanisms. This is because BDNF essentially affects all aspects of neuronal cellular function through tropomyosin receptor kinase B (TrkB) receptor signaling, the disruptions of which vary between brain regions across different pathologies leading to diversified consequences on cognition and behavior. Herein, we review the neurophysiology of BDNF transmission and signaling and classify the converging and diverging molecular mechanisms underlying its therapeutic potentials in neuropsychiatric disorders. These include neuroprotection, synaptic maintenance, immunomodulation, plasticity facilitation, secondary neuromodulation, and preservation of neurovascular unit integrity and cellular viability. Lastly, we discuss several findings suggesting BDNF as a common mediator of the therapeutic actions of centrally acting pharmacological agents used in the treatment of neurological and psychiatric illness.

Keywords: TrkB signaling; brain-derived neurotrophic factor; neurodegeneration; neuroinflammation; neuromodulation; neuroprotection; oxidative stress; synaptic plasticity.

Figure 1

BDNF synthesis and release.

Figure 2

BDNF receptor signaling pathways. (*) different signaling pathways and cellular functions are triggered with heterodimer forms.

Figure 3

Summary of neuropsychiatric pathological alterations targeted by BDNF.