Abstract. As depression rates increase among Americans, neuroscientists seek more efficient targets for treating major depressive disorder (MDD). Brain-derived neurotrophic factor (BDNF), a neurotrophic protein, has been shown to be associated with the development of neuropsychological disorders such as MDD. Targeting BDNF mechanisms through antidepressants, physical exercise, and gene therapy therefore represents a promising direction in the search for effective treatments for depression.
Why Target BDNF?
Major depressive disorder (MDD) affects more than 300 million people worldwide, with increasing numbers over the past decade. MDD encompasses a variety of adverse effects, including feelings of hopelessness, changes in appetite, and, in severe cases, intense thoughts of suicide. Despite these debilitating consequences, only about half of people in the United States suffering from MDD receive effective treatment [1]. In fact, government health budgets allocate a mere 3% to mental health resources. Although the Diagnostic and Statistical Manual of Mental Disorders outlines the various requirements for an MDD diagnosis, the process of diagnosis relies heavily on patient self-report and subjective clinical evaluations.
Since the external, symptomatic diagnosis of depression is largely generalized, patients often have difficulty receiving the specific treatment necessary to alleviate their symptoms. To combat this, researchers focus on internal, pathophysiological approaches to improve the subclassification of MDD among patients through the use of biomarkers [2]. Biomarkers are biological molecules that serve as indicators of functional or dysfunctional biological processes [3]. Among these are neurotrophins, proteins that play a vital role in the development, plasticity, and survival of neurons. More specifically, brain-derived neurotrophic factor (BDNF) is a neurotrophin that has been shown to significantly contribute to the pathophysiology of MDD [4]. This review evaluates the process by which BDNF abnormalities affect MDD and analyzes the various methods of BDNF-targeted treatment for MDD: antidepressant medication, physical exercise, and, more recently, gene therapy.
BDNF Correlates with Neurogenesis and Reduced Depressive-Like Symptoms
The functionality of neurogenesis mechanisms in the brain is an important concept in understanding the etiology of depression. In general, high rates of neurogenesis are associated with reduced symptoms of depression, and, conversely, low rates of neurogenesis are associated with increased symptoms. In a 2013 study by Mateus-Pinheiro et al., rats treated with methylazoxymethanol (MAM), a neurotoxin that inhibits neurogenesis, displayed significantly higher levels of depressive-like behaviors — such as anhedonia (lack of pleasure), higher latency in feeding and escaping, and reduced time in open arms — compared to rats without the neurotoxin. This demonstrates that lack of neurogenesis is a key factor in depression.
BDNF and TrkB Interactions Strengthen Neurons
The binding of BDNF ligand to its receptor, tropomyosin receptor kinase B (TrkB), is greatly involved in regulating neuronal activity [6]. BDNF first binds to its high-affinity receptor TrkB on the postsynaptic dendrite and cell body. BDNF–TrkB interactions have been found to be important for neuron survival, differentiation, dendritic spine complexity, long-term potentiation, and synaptic plasticity [7]. Immunohistochemistry (IHC) is a biomarker technique used in research to visualize the expression of genes such as TrkB and Parvalbumin, an inhibitory-neuron marker.
Val66Met Polymorphism Causes Harmful Effects on BDNF Function
Of the hundreds of known polymorphisms of the BDNF gene, the two most common are the Val and Met variants [8]. The Val polymorphism is the wild type, where the amino acid valine is found at codon 66 of the BDNF gene. In the mutant Val66Met polymorphism, which affects approximately 30 percent of the population [9], a methionine amino acid is found at codon 66 instead [10].
The Val66Met polymorphism introduces several interferences in the processing of BDNF compared to the Val polymorphism. Like most gene expression processes, the precursor protein proBDNF is first synthesized in the endoplasmic reticulum. It then passes through the Golgi apparatus, where it is cleaved to form mature BDNF (mBDNF), which then leaves the cell body through secretory vesicles [11]. In the Val66Met polymorphism, however, the proBDNF protein is less likely to pass through the Golgi apparatus, and therefore less likely to reach secretory vesicles and be secreted from the neuron body. As a result, less BDNF is expressed as ligand, resulting in fewer interactions between BDNF and TrkB, and further resulting in decreased synaptic activity and neuroplasticity [12]. In addition to reduced BDNF expression, the Val66Met polymorphism also prevents the maturation of BDNF.
ProBDNF Leads to Opposite Effects of Mature BDNF
BDNF is initially synthesized as a precursor protein (proBDNF), which is cleaved by the enzyme furin to produce mature BDNF. ProBDNF ligand binds with the p75 neurotrophin receptor, while mBDNF preferentially binds with the receptor TrkB [13]. ProBDNF–p75NTR binding has been shown to negatively modulate dendritic complexity and spine density in mice. Mice whose p75 neurotrophin receptor genes have been knocked out display a greater number of spines, more instances of co-localization, and overall greater complexity than wild-type mice [14]. This indicates that interactions between the p75 neurotrophin receptor and its ligand, proBDNF, are responsible for reducing cell survival and synaptic plasticity, which in turn increases long-term depression. This view is also supported by Teng et al., who concluded that proBDNF acts as a pro-apoptotic ligand — meaning that it correlates with increased neuronal cell death. The decrease in neuronal plasticity, coupled with these apoptotic effects, indicates that the proBDNF mechanism plays a role in inducing harmful symptoms of depression. The Val66Met polymorphism has been shown to hinder the ability of proBDNF to mature into mBDNF, prolonging such deleterious effects of proBDNF–p75NTR interactions [16].
Antidepressants as a BDNF-Targeted Treatment for MDD
Amongst the 17.5 million Americans diagnosed with depression from 2005 to 2016, around 10 million were prescribed some form of antidepressant medication, making antidepressant medication one of the most common treatments for depression [17]. Specifically, selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are used to prolong the presence of the neurotransmitter serotonin within the synaptic cleft. Aside from its impact on serotonergic pathways in the brain, fluoxetine has been shown to increase BDNF levels and, consequently, the rate of neurogenesis, especially in the dentate gyrus — a key region of the brain where adult neurogenesis occurs [3].
In many preclinical trials, fluoxetine contributes to increased BDNF–TrkB activity and reduced fear [7]. For instance, fluoxetine is known to increase synaptic plasticity in the adult hippocampus, cortex, and amygdala [18], and it reverts the neuroplastic connections responsible for remembering fear-inducing stimuli. As a result, fluoxetine-induced plasticity contributes to fear erasure, a process that is mediated by BDNF [19]. These preclinical trials provide a glimpse into the use of fluoxetine in mitigating symptoms of depression, such as fear and anxiety, through BDNF systems.
Physical Activity as an Inducer of BDNF
According to the CDC, exercise can improve cognitive health by helping people think, learn, problem-solve, and maintain emotional balance. One of the mechanisms by which physical activity improves mental health is by increasing BDNF levels. Aerobic exercise generally upregulates BDNF gene expression in the hippocampus [20]. Sleiman et al.'s study showed that BDNF gene expression and protein availability in the hippocampus correlate with an increase in exercise. In another study, as the distance run by rats increased, so did the level of BDNF mRNA in the brain [22]. Both studies implicate exercise in increasing BDNF levels.
How can researchers be sure that it is through BDNF mechanisms that physical exercise increases synaptic plasticity in the brain, as opposed to other mechanisms? Vaynman et al. investigated the effects of physical activity on synaptic plasticity in the absence of BDNF by blocking BDNF ligands on TrkB receptors. The results revealed that without BDNF–TrkB pathways, physical activity had minimal effect on synaptic plasticity compared to functioning BDNF–TrkB pathways — suggesting that physical activity alleviates symptoms of MDD only by increasing BDNF levels.
Fluoxetine and physical activity have very similar effects on BDNF regulation and synaptic plasticity. Running and fluoxetine both stimulate plasticity of new neurons by increasing neuron spine density and dendritic complexity, and by increasing short-term synaptic plasticity. When it comes to neurogenesis, fluoxetine has been shown to accelerate the S-phase of the cell cycle in dentate gyrus progenitor cells, whereas physical activity reduces the cell cycle length in each phase — meaning that cell division itself is catalyzed by exercise, while only the interphase period between divisions is accelerated by fluoxetine. Regardless, the overall process of cell division is enhanced by both antidepressants and exercise [24].
Gene Therapy: A Promising Look into the Future
An ongoing clinical trial beginning October 2022 focuses on delivering BDNF genes to specific regions of the brain in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI). Mark Tuszynski of UC San Diego, the principal investigator, seeks to deliver BDNF genes through a vector known as adeno-associated virus (AAV2). The trial will measure the cognitive effects of induced BDNF levels on symptoms of AD and MCI. The implications are twofold: to improve AD and MCI symptoms, and to increase neurogenesis and synaptic plasticity in ways that could potentially counter symptoms of depression. As the first trial of AAV2-BDNF in humans, Tuszynski's study is poised to pioneer a new and effective approach to treating depressive disorders from a genetic standpoint.