BDNF/Brain-Derived Neurotrophic Factor: From Neuroplasticity Regulation to Core Target for Neuropsychiatric Disease Therapy

1. Biological Characteristics and Signaling Pathways of BDNF

1.1 BDNF Gene Structure and Protein Processing

The BDNF gene has a complex transcriptional regulatory structure, containing multiple promoters and exons. Transcription driven by different promoters produces multiple mRNA isoforms, which are basically identical in the coding region but differ in the 5' untranslated region, thus conferring different expression regulatory characteristics ^[1]. Neuronal activity regulates BDNF expression through Ca²⁺ signaling and transcription factors such as cAMP response element-binding protein (CREB), but this regulation differs significantly between brain regions ^[2].

In addition to neuronal activity regulation, various hormones and transcription factors are also involved in BDNF expression regulation. For example, estradiol, glucocorticoids, and myocyte enhancer factor-2 (MEF2) can all affect BDNF transcription levels by acting on the BDNF promoter region ^[3]. Furthermore, epigenetic mechanisms such as DNA methylation and microRNAs have also been shown to regulate BDNF expression ^[4,5].

At the protein level, BDNF is first synthesized as a precursor form pro-BDNF, which is then processed by proteases to generate mature BDNF. The two have distinct functional differences: pro-BDNF usually mediates synaptic weakening or apoptosis through the p75NTR receptor, while mature BDNF promotes neuronal survival and synaptic enhancement through the TrkB receptor ^[7]. Therefore, the dynamic balance between pro-BDNF and mature BDNF is considered a key mechanism regulating neuroplasticity.

In addition, the BDNF gene Val66Met (rs6265) polymorphism affects the intracellular transport and secretion efficiency of BDNF and is associated with the risk of various neurological diseases ^[6]. Structural biology studies further indicate that mutations in key residues of the BDNF protein may alter its conformational stability and receptor binding ability, thereby affecting signal transduction efficiency ^[8].

1.2 BDNF-TrkB Signaling Pathway

The main biological functions of BDNF are mediated by the high-affinity receptor TrkB (tropomyosin receptor kinase B). Binding of BDNF to TrkB induces receptor dimerization and autophosphorylation of tyrosine residues, thereby activating multiple downstream signaling pathways including PI3K/Akt, MAPK/ERK, and PLC-γ pathways ^[9,10]. These signaling networks collectively regulate neuronal survival, axon growth, and synaptic plasticity.

1.2.1 MAPK/ERK Pathway

The MAPK/ERK pathway is one of the most classical downstream pathways of BDNF-TrkB signaling. After phosphorylation, the TrkB receptor activates the Ras-Raf-MEK-ERK cascade through adaptor proteins such as Shc and Grb2. Activated ERK enters the nucleus and phosphorylates various transcription factors, such as CREB, thereby regulating neuronal differentiation and synapse-related gene expression. This pathway plays important roles in dendrite growth, synapse formation, and long-term memory formation, and is the key molecular basis for BDNF regulation of learning and memory.

1.2.2 PI3K-Akt Pathway

The PI3K-Akt signaling pathway is mainly involved in cell survival and anti-apoptotic regulation. TrkB activation recruits PI3K and promotes Akt phosphorylation. Akt further phosphorylates proteins such as Bad and GSK-3β, thereby inhibiting apoptosis and enhancing neuronal survival ^[10].

In various neurodegenerative disease models, activation of the PI3K-Akt pathway is usually associated with neuroprotective effects, and is therefore considered one of the important mechanisms of BDNF-mediated neuroprotection.

1.2.3 PLC-γ Pathway

The PLC-γ pathway is mainly involved in intracellular calcium signal regulation. TrkB activation phosphorylates PLC-γ, which catalyzes the hydrolysis of PIP2 to produce IP3 and DAG. IP3 promotes Ca²⁺ release from the endoplasmic reticulum, while DAG activates protein kinase C (PKC). These signals collectively regulate neurotransmitter release and synaptic plasticity. PLC-γ signaling plays an important role in synaptic plasticity processes such as long-term potentiation (LTP).

1.2.4 p75NTR Signaling Pathway

In addition to TrkB, the BDNF precursor pro-BDNF also functions through the low-affinity receptor p75NTR. p75NTR is usually associated with neuronal apoptosis, axon pruning, and synaptic weakening. This receptor regulates cell fate through signaling pathways such as JNK and NF-κB.

Therefore, the balance between the pro-BDNF/p75NTR and mBDNF/TrkB signaling axes is considered a key factor determining neuronal survival and synaptic plasticity.

2. BDNF-Related Diseases

2.1 Neurodegenerative Diseases

In neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease, BDNF expression is generally decreased, which is closely related to neuronal loss and synaptic dysfunction. Reduced BDNF weakens the TrkB signaling pathway, thereby reducing neuronal survival signals and accelerating the neurodegenerative process.

In Alzheimer's disease models, decreased BDNF expression is closely associated with impaired hippocampal synaptic plasticity and cognitive decline. Restoring BDNF signaling can improve synaptic function and reduce cognitive impairment to a certain extent.

2.2 Psychiatric Disorders

BDNF also plays an important role in psychiatric disorders such as depression, anxiety, and schizophrenia. Studies have shown that serum BDNF levels are usually decreased in patients with depression, and antidepressant treatment can partially restore its expression.

BDNF participates in mood regulation by modulating hippocampal neurogenesis and synaptic plasticity, so abnormal expression may lead to dysfunction of mood regulation.

2.3 Nerve Injury

In conditions such as stroke, spinal cord injury, and traumatic brain injury, BDNF expression changes dynamically. BDNF participates in neurological function recovery by promoting axon regeneration, synapse reconstruction, and neural network remodeling.

Experimental studies have shown that increasing BDNF levels can promote nerve regeneration and improve neurological function recovery.

2.4 Pain and Drug Dependence

BDNF plays an important role in chronic pain and the formation of opioid tolerance. At the spinal cord level, BDNF enhances synaptic transmission and regulates pain signal transduction.

In morphine tolerance models, spinal BDNF expression is significantly increased, and intervention in BDNF signaling can partially alleviate the tolerance phenomenon ^[1]. These studies suggest that BDNF may be an important molecular target for pain regulation and drug dependence research.

2.5 Neurodevelopmental Disorders

BDNF participates in neuronal migration, axon guidance, and synapse formation during neurodevelopment. Therefore, abnormal expression may affect neural network formation and lead to neurodevelopmental disorders.

Recent studies have found that BDNF is associated with autism spectrum disorders and attention deficit hyperactivity disorder, particularly abnormal conversion of pro-BDNF to mature BDNF may affect synaptic plasticity and participate in developmental abnormalities ^[7].