The Function of BDNF and Treatment in Neurological Disorder

Yue Dong

, Kunjie Liu

2,*

and Yushi Wu

3,*

Victoria College, University of Toronto, ON M5S 1K7, Toronto, Canada

B.S. in Biology, College of Saint Mount Vincent, 10471, New York, U.S.A.

Diablo Valley College, Pleasant Hill, CA 94523, U.S.A.

†

These authors contributed equally

Keywords: BDNF, Neurological Disorder, Nervous System Diseases.

Abstract: Brain-derived neurotrophic factor (BDNF) is one of the most well-researched factors that thas been shown to

regulate mood and stress-coping. There is growing evidence suggesting the dysfunction of the BDNF pathway

is likely to cause several types of mental disorders such as Major Depressive Disorders, Stroke, and

Parkinson's Disease. This review article provides a detailed examination of the function of BDNF and how it

relates to neurological diseases, particularly depression, as well as different studies and theories explaining

the mechanism behind how dysfunction of the BDNF relates to depression. The article also discussed different

types of treatments, including drug treatment and CRISPR, that target these neurological disorders caused by

BDNF dysfunction. Despite the uncertainty in this field, there is still enough evidence suggesting that

dysregulation of BDNF can be a risk factor for many neurological disorders. Studies on this topic will likely

evoke new perspectives on modern treatments.

1 INTRODUCTION

Neurological disorders range from Major Depressive

Disorder (MDD) to stroke, from stroke to Parkinson's

Disease (PD), millions of people worldwide are

currently estimated to suffer from neurological

disorders. This number will be expected to increase

significantly in the following years. The only stroke

kills more than 6 million people each year, accounting

for nearly 11 percent of deaths worldwide. More than

47.5 million people worldwide suffer from dementia,

of which AD is the most common cause, while more

than 50 million people suffer from epilepsy (WHO

2016). Neuroprotective strategies have been

developed to ameliorate brain injury by preserving or

restoring neurological function. Brain-derived

neurotrophic factor (BDNF) is a widely studied

treatment strategy for several neurological diseases.

This growth factor plays a significant role in the

differentiation, maturation, and survival of neurons.

Despite relative success in the laboratory,

administering neurotrophic factors has not produced

the desired results in clinical trials. Therefore, the

neuroscience field will recognize BDNF levels in

patients with major depressive disorder (MDD) as a

potential threat. The pathway by which low levels of

BDNF directly lead to MDD is not clear right now,

but using the hippocampus as a carrier for the

relationship between the low level of BDNF and

MDD may explain the direct cause-effect

relationship. Otherwise, there have been significant

advances in SSRIs, MAOIs, and CRISPR

technologies to overcome these technical limitations

in clinical trials. However, most neurological diseases

show not only disorders of BDNF but also damage to

its downstream effects-and. Its relevance as a

pathological mechanism needs to be emphasized.

This review paper attempts to consider and

understand the direct and indirect role of BDNF in

neurological diseases, the potential pathways

between BDNF signaling and depression, as well as

the techniques available for clinical trials and the

advantages and disadvantages of treatment options.

This knowledge provides opportunities and new ideas

to guide the design of feasible and effective tools and

approaches for treating brain diseases.

2 NEUROLOGICAL DISORDERS

The most significant clinical feature of the decline in

BDNF signaling is the occurrence of

254

Dong, Y., Liu, K. and Wu, Y.

The Function of BDNF and Treatment in Neurological Disorder.

DOI: 10.5220/0011269100003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 254-263

ISBN: 978-989-758-596-8

neurodegenerative motor disorders. Otherwise,

ranging from Major Depressive Disorder (MDD) to

Stroke, from Stroke to Parkinson Disease (PD), one

of the symptoms of these neurological diseases is the

occurrence of neurodegenerative motor disorders to

varying degrees. At the same time, BDNF, as an

important transmission and balance medium in the

brain, has great research value in many clinical and

neuroscientific experiments.

2.1 Depression

BDNF has some effects on the development of

depression in some ways. Much research has shown

that BDNF is closely related to depression, and the

presence of BDNF mediates the occurrence of

neuronal and synaptic plasticity. In the biological

model of stress, BDNF levels were reduced in both

the cortex and the hippocampus. In other words, after

death, BDNF levels in the brain tissue were

significantly lower in those who took antidepressants.

In contrast, BDNF expression in the hippocampus

was higher in those who did not take antidepressants.

Further research suggests that antidepressant-

dependent BDNF levels may prevent or reduce

hippocampal changes in human samples (Chen 2001).

More recently, Cattaneo et al. (2013) demonstrated

separation between predictors and targets of

antidepressant response. The antidepressant response

was associated with changes in the gene BDNF, but

the gene did not predict specific changes in

physiological indicators of antidepressant and

physiological response. As a result, each biomarker

needs further study to elucidate its role in predicting

antidepressant response. Among the genetic markers,

the brain-derived neurotrophic factor (BDNF) gene

plays a key role in neurodevelopment and therapeutic

response to antidepressants (Ibarguen-Vargas 2009),

so antidepressants are associated with increased

expression of BDNF in animals brains and human

serum (Warner-Schmidt 2006). After the disease

becomes chronic, the level of BDNF in the brain is

upregulated (Nibuya 1995). Antidepressant therapy

results in G-protein-mediated intracellular factor

phosphorylation and stimulates BDNF release

(Watanabe 2010). Therefore, BDNF secretion and

intercellular transport are associated with single

nucleotide polymorphisms (SNPS) in the BDNF

gene, which leads to valine-to-methionine

replacement (Val66Met) (Egan 2003). BDNF

expressed as a precursor proBDNF consists of the n-

terminal and c-terminal precursors of mature BDNF.

The substitution of Val66Met in the anterior domain

induces the transfer of secondary structures to replace

the surrounding region (Anastasia 2013). Neurons

secrete both the mature BDNF protein and the

premitotic domain. Interestingly, compared with the

inactive Val66 predomain, secreted predomain

containing Met replacement promoted the growth

cone retraction of cultured hippocampal neurons

(Anastasia 2013). Meanwhile, two recent meta-

analyses have shown that Met alleles respond better

to antidepressants (Kato 2010). Considering that

BDNF mediates the response to antidepressants

(D’Sa 2002), polymorphisms modifying BDNF gene

expression or different intracellular signaling

pathways may play an important role in the treatment

and pharmacological response to antidepressants.

Therefore, the imbalance BDNF decreasing in the

brain may help clarify the relationship between

neuroplasticity and the pathophysiology of

depression.

2.2 Stroke

Many studies have found that the level of BDNF will

decrease with the deterioration of stroke. Otherwise,

cerebral dysfunction is common in stroke patients,

and BDNF is important for post-stroke recovery.

Stroke is the fifth leading cause of death in the United

States. Stroke patients often show a decline in

neurological function of the brain, accompanied by

certain symptoms of movement disorders. A previous

study has shown that several therapeutic interventions

can enhance functional recovery after stroke, such as

exercise and rehabilitation. These treatments lead to

beneficial effects of BDNF and brain plasticity, such

as improved learning, memory, and motor function

and increased expression of related proteins to a

certain extent (Ploughman 2005). To date, a clinical

study has shown an increase in the number of Treg

cells that produce BDNF after stroke, suggesting that

Treg cells may be able to deliver BDNF to the site of

injury to provide neuroprotection after stroke (Chan

2015). Similarly, strategies to increase BDNF have

been widely used in rats with middle cerebral artery

occlusion (MCAO).

During stroke rehabilitation, BDNF levels in the

nervous system have enhanced the neuroplasticity

processes involved in motor relearning. The reduction

of BDNF levels in the brain completely negates the

recovery of skilled movement

(Ploughman 2009).

Therefore, the beneficial effects of brain-derived

neurotrophic factors in the central nervous system

may contribute to post-stroke recovery.

While rapid up-regulation of neurotrophic factor

expression in the penumbra has been observed for

several days (Madinier 2013), permanent reduction of

The Function of BDNF and Treatment in Neurological Disorder

255

BDNF has been observed in animal models of

ischemic stroke (Ferrer 2001). However, BDNF has

never been measured in the postmortem brain of a

stroke patient, although the slight increase in

circulating neuronutrient levels observed that stroke

might reflect intracerebral levels (Chan 2015). The

enhancement of BDNF levels after stroke is mainly

associated with peripheral neurons and microglia,

which has been considered a brain compensatory

mechanism to prevent excessive neuronal death

(Bejot 2011, Kokaia 1995). Several studies have

concluded that BDNF is not involved in functional

recovery after stroke (Zhou 2000). The most likely

explanation for this result is that BDNF fails to trigger

appropriate neurotrophic signals after stroke due to a

pathological imbalance of the TrkB receptor subtype.

In fact, TrkB-FL levels declined sharply in the infarct

core and penumbra, whereas TRKB-T1 levels were

upregulated in human ischemic stroke and ischemic

animal models (Hirata 2011). These changes are the

result of three separate mechanisms induced by

excitotoxicity (Vidaurre 2012).

2.3 PD (Parkinson Disorder)

At the same time, there is increasingly much evidence

that the loss of the BDNF signaling pathway or the

reduction of BDNF contributes to the pathogenesis of

some major diseases and disorders, such as AD and

PD (Li 2020). PD is a neurodegenerative disease that

can be associated with non-motor symptoms, such as

cognitive deficits and changes in BDNF levels. Lack

of BDNF signaling is the most common

neurodegenerative motor disorder. PD is

characterized by progressive loss of dopaminergic

neurons in the substantia nigra pars densa (SNpc),

coupled with accumulation defects in intracellular α

synuclein inclusions (known as Lewy bodies and

Lewy neurites). Postmortem studies of PD patients

showed that BDNF mRNA and protein were

decreased in the susceptible region SNpc and in the

striatum receiving neurotrophic support from SN

(Parain 1999, Altar 1998). However, the loss of the

BDNF survival signal increases the susceptibility of

SN dopaminergic neurons to cytotoxic damage and

may contribute to the development of PD (Ding 2011,

Hung 1996). In fact, inhibition of BDNF expression

leads to selective loss of SNpc dopaminergic neurons

in older animals and exacerbates motor dysfunction

(Boger 2011). In Parkinson's disease, the expression

level of BDNF was so low in the neurons that may be

facing the biggest risk of injury. It may even trigger

an ontology degradation, diseases associated with the

intensity and duration, and the severity of the

symptoms of Parkinson's disease (Costa 2015). A

study shows even neurodegenerative diseases, if, at a

more advanced stage, neurons with low BDNF

expression caused irreversible damage (Gyárfás

2010). In recent years, clinical studies have suggested

that treatment with anti-Parkinson's drugs may

increase BDNF levels (Scalzo 2010). At the same

time, exercise therapy can trigger a few plasticity-

related events in the brain of PD patients, including

cortical motor excitation and changes in BDNF levels

(Hirsch 2016). In general, BDNF may be a potential

biomarker for assessing cognitive changes in

Parkinson's disease and other neurologic syndromes

associated with cognitive decline (Costa 2015).

3 MECHANISM BEHIND BDNF

PATHWAY

The functional pathway of the BDNF gene is the key

to understanding how it relates to numerous different

neurological diseases. The BDNF gene is first

translated into a precursor proBDNF which is about

32kDa. ProBDNF can undergo an intracellular

cleavage by a furin-like convertase to produce mature

BDNF (~13kDa) and a BDNF pro-peptide (~17kDa)

(Yang 2017). Both proBDNF and mature BDNF

(mBDNF) act on hippocampal neuroplasticity by

binding to different receptors. While proBDNF

preferentially binds to a low-affinity neurotrophin

receptor (p75NTR), mBDNF has a higher affinity to

a tropomyosin-related kinase B (TrkB) receptor

(Castrén 2017). Interestingly, the two receptors show

different effects on neural development. The

activation of p75NTR by proBDNF promotes

apoptosis or neurons, synaptic pruning, as well as

NMDAR-dependent long-term depression (LPD) (Lu

2005). However, the binding of TrkB receptors can

promote neural survival, synaptogenesis, and

neuroplasticity. Many lines of evidence suggest that

mBDNF, together with protease plasmin, are highly

involved in the late-phase long-term potentiation (L-

LTP) in the hippocampus (Lu 2005). Considering its

properties and function in neural signalling and

development, BDNF has been shown to be related to

the pathology of depression and many neurological

disorders.

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3.1 BDNF and Depression

In 1995, researchers conducted the very first study on

the relationship between stress level and BDNF on an

animal model, which found that constant stress could

significantly reduce the BDNF mRNA level in the

hippocampus (Smith 1995). This finding was later

tested on depression patients as well. In a study done

by Karege and his colleagues, they measured the level

of BDNF and neurotrophin-3 in both suicide and non-

suicide victims. The result showed that the level of

BDNF was significantly low in both hippocampus

and ventral prefrontal cortex of suicide victims

compared to non-suicide victims (Karege 2004).

These studies all suggested that low levels of BDNF

could be a potential risk factor for developing

depression. Both studies found that the hippocampus

was affected also suggested that the hippocampus

might be the key link between BDNF and depression.

The pathway of how the low level of BDNF leads

to depression is still unclear. However, some theories

may be able to explain the mechanism behind it. As

mentioned before, mBDNF is crucial to the

generation of new synapses and neural development,

especially in the hippocampus. A decrease in the

mBDNF level can induce less neurogenesis in the

hippocampus. This will lead to decreased

hippocampal volume and cognitive ability since the

hippocampus controls emotions and memory. The

study also supported the study, which found patients

with depression generally have 4-5% smaller

hippocampus than the control group (Yu 2010).

Evidence has also shown that the hippocampus plays

an important role in regulating the stress-coping

mechanism hypothalamic-pituitary-adrenal (HPA)

axis and amygdala. Thus, the dysfunction in the

hippocampus can lead to difficulties in the stress

response (Yu 2010). This could lead to an increase in

the risk of major depressive disorder in patients.

Despite the direct interaction with the

neuroplasticity, dysfunction in the secretion of

mBDNF can also have a deterioration influence on

the serotonin pathway in the hippocampus. In the

study of Ren-Patterson et al., they conducted an

experiment on mice models with double mutant

SERT -/- and BDNF +/- genes. The result suggested

that the double mutant significantly reduces serotonin

in the hippocampus of 37% and hypothalamus of 43%

even compared to the single SERT -/- mutant mice.

There was also evidence indicating that BDNF plays

a crucial role in the differentiation of serotonergic

neurons. This all suggests that a low level of BDNF

can have deleterious effects on the serotonin pathway.

Depression was long known can be improved by

alleviating the level of serotonin in the synapses. This

relationship between BDNF and the serotonin

pathway also helps to explain how the deficiency in

BDNF can be related to depression.

3.2 Polymorphism of Bdnf Gene

Several single-point mutations have been found to be

associated with the low level of mBDNF in the brains

in the past few years. For instance, plenty of research

has been done on a valine to methionine substitution

mutation at codon 66, which is likely to cause

decreased secretion of mBDNF (Anastasia 2013).

According to the study by Anastasia et al. in 2013,

BDNF proteins with this mutation have less stable

secondary and tertiary structures of the prodomain,

which mediate the intracellular trafficking and active

secretion of mBDNF. This Val66Met variant

decreases the binding efficiency and therefore lowers

the amount of mBDNF available in the hippocampus

(Anastasia 2013). This theory was also supported by

some other studies, which found that patients with the

Met66 allele showed abnormal activation in the

bilateral hippocampus (Egan 2003). Mice models

with this mutation showed similar anxiety behaviors

as humans (Bath 2012). Although the mutation was

thought to be associated with many mental illnesses

such as schizophrenia and bipolar disorder, the

strength of this association is still debatable according

to current studies (Castrén 2017).

3.3 BDNF and Antidepressants

Right now, multiple different classes of

antidepressants have proven to upregulate the release

of BDNF. In a study by Nibuya et al. (1995), they

found the administration of tranylcypromine

increased the level of BDNF mRNA to about 100%

in the hippocampus (Nibuya 1995). In fact, many

types of serotonin reuptake inhibitors (SSRIs),

monoamine oxidase inhibitors (MAOIs), and even

some atypical antidepressants have been shown to

alleviate the level of BDNF in brains (Duman 2006).

Moreover, chronic treatment of antidepressants can

also block the downregulation of BDNF caused by

stress (Nibuya 1995). However, not all types of

antidepressants have similar effects. For example,

there is still some debate over if fluoxetine can alter

the expression of BDNF in any part of the brain

(Duman 2006). While one search argued that it could

increase the level of BDNF in the hippocampus

(Dwivedi 2009). Dias et al. suggested that there is no

significant difference made by fluoxetine (Duman

2006).

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Furthermore, BDNF itself can also have an

antidepressant effect on depression patients. In the

study done by Shirayama et al., they performed a

direct infusion of BDNF in the hippocampus of rat

brains and observed a decrease in depressive

symptoms. The effect could last as long as 10 days. It

is also claimed that such effect was also observed in

the treatment with other antidepressants like tricyclic

antidepressants (TCA) or SSRIs (Dias 2003).

However, this effect has only been tested on rats

using different types of behavioral tests such as

forced swim test and learned passive avoidance test

(Dias 2003). There is no evidence that BDNF will

have a similar antidepressant effect on humans, but it

suggested a potential path of a new treatment for

depression using the BDNF pathway.

4 CURRENT TREATMENT

The current treatment of depression is mainly

psychological and pharmacological. Antidepressants

can have various physiological effects on neuronal,

glial, and astrocyte functions and their interactions,

which in turn lead to alterations in signaling between

neuronal networks, ultimately regulating mood,

thinking, and stress response. Currently, there are

three main types of pharmacological treatments:

SSRIs, MAOIs, and TCAs. In recent years, with the

development of CRISPR technology, the groundwork

has also been laid for new strategies to treat

depression.

4.1 Pharmacology of Antidepressants

4.1.1 SSRIs

Selective serotonin reuptake inhibitors (SSRIs) are

usually the drug of choice for depression because they

are relatively safe and have fewer side effects than

most other types of antidepressants (Shirayama

2002). According to Olfson and Marcus in 2009

(Santarsieri 2015), nearly 67% of people taking

antidepressants in the United States were treated with

SSRIs. SSRIs work by increasing serotonin levels in

the brain. Serotonin is a messenger chemical that

transmits signals between nerve cells in the brain and

has a beneficial effect on mood, emotion, and sleep.

Serotonin is present in the form of vesicles and is

transmitted from the presynaptic neuron to the

receptor of the postsynaptic neuron via the 5-HT

transporter. After transmitting the information,

serotonin can be reabsorbed by nerve cells, called

"reuptake". Inhibitors of serotonin reuptake trigger

the reactivation of adolescent-like neuroplasticity. By

acting on the 5-HT transporter, the SSRI can increase

the concentration of 5-hydroxytryptamine in the

synaptic gap by inhibiting the reuptake of the

neurotransmitter 5-hydroxytryptamine by the

synaptic reuptake pump, leaving more serotonin

available to transmit further information between

nearby nerve cells (Olfson 2009). A 2012 Cambridge

University investigation of Short-term SSRI

treatment that normalises amygdala hyperactivity in

depressed patients also showed that short-term SSRI

treatment in depressed patients could remedy

amygdala overreaction to negative emotional stimuli

prior to clinical improvement in the depressed mood

(Cottone 2020). The amygdala is a key center for the

fear formation and expression and a key structure for

the automatic processing of negative facial

expressions. In patients with depression, the

organization and function of the amygdala are altered.

There is enhanced amygdala activation in processing

negative emotional faces in depressed patients, both

in conscious and unconscious conditions. The

regulation of emotions can be influenced clinically by

modulating the function of the amygdala to guide the

treatment of related disorders (Godlewska 2012).

Indeed, in a behavioral study by Harmer et al. (Zhong

2012), we recently found that a single dose of

reboxetine in depressed patients reversed negative

emotion bias in facial expression recognition and

emotional memory in the absence of any change in

subjective mood.

* Values represent mean eye blinks (z transformed) during

the presentation of positive, negative, and neutral pictures.

There was a significant interaction between group and

stimulus type (F=2.7, df=3, 60, p=0.04).

Figure 1. Emotion-Potentiated Eye-Blink Startle Response

in 33 Healthy Volunteers After 1 Week of Randomly

Assigned Double-Blind Intervention with Citalopram,

Reboxetine, or Placeboa (Zhong 2012)

4.1.2 MAOIs

MAOIs are one of the most effective antidepressants

and have long been used as antidepressants. Although

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MAOIs are particularly effective for atypical

depression and treatment-resistant depression,

MAOIs are not supported as first-line treatments due

to safety and tolerability concerns and the need for

dietary restrictions (Harmer 2004). By inhibiting

monoamine oxidase, MAOIs allow more of these

neurotransmitters to be retained in the brain, thereby

enhancing mood by improving communication

between brain cells. MAOIs are divided into two

main categories, non-selective and selective. Non-

selective MAOIs inhibit monoamine oxidase A and

monoamine oxidase B. As a result, serotonin,

norepinephrine, and dopamine levels are increased.

They are also known as irreversible MAOIs because

they bind irreversibly to the enzymes, permanently

blocking their function. Once these enzymes are

inhibited, the monoamine neurotransmitters are

loaded into preexisting vesicles. This way, when the

next action potential reaches the presynaptic

membrane, more neurotransmitters are released into

the synaptic cleft, thus relieving the symptoms of

depression (Tang 2014). In contrast, selective MAO-

B inhibitors have a high affinity for DA,

phenethylamine, benzylamine and selegiline,

pargyline (Thase 2012). Their inhibitory effects are

mainly found in the brain's glial cells and can lead to

an increase in dopamine (DA) levels in patients.

4.2 CRISPR Technology

4.2.1 The Concept of CRISPR

CRISPR technology is a simple yet powerful

genome-editing tool that allows researchers to easily

alter DNA sequences and modify gene function, an

adaptive immune system used by microorganisms to

defend against invading viruses by recording and

targeting their DNA sequences. It can be reused in

living cells to edit the genomes of mammals and other

organisms (Xiao). CRISPR technology was adapted

from the natural defense mechanisms of bacteria and

archaea (Lander 2016). These organisms use

CRISPR-derived RNA and Cas proteins to cut off and

destroy the DNA of foreign invaders to thwart attacks

by viruses and other foreign agents. CRISPR-Cas9

stands for clusters of regularly spaced short

palindromic repeats and CRISPR-associated protein

9. CRISPR is a specialized DNA fragment, and the

protein Cas9 is an enzyme that acts like "molecular

scissors" that cut two DNA strands at specific

locations in the genome and then add or remove DNA

fragments. A piece of RNA called guide RNA

(gRNA) consists of a small piece of pre-designed

RNA sequence (approximately 20 bases long) located

within a longer RNA scaffold (Aparna 2018),

designed to find and bind to a specific sequence in

DNA. The scaffold partially binds to the DNA, and

the RNA bases of the guide RNA are complementary

to the bases of the target DNA sequence in the

genome to ensure that the Cas9 enzyme cleaves at the

correct position in the genome (Aparna 2018). Cas9

follows the guide RNA to the same position in the

DNA sequence and cleaves on both DNA strands. In

this way, the DNA repair mechanism can be used to

alter one or more genes in the genome of the cell of

interest, acting more directly on the gene to alleviate

depression at a faster rate.

4.2.2 Applications of CRISPR

Although antidepressants are frequently used to treat

depression, at least 50% of patients respond that

antidepressants do not actually work. Moreover, the

clinical response occurs only after weeks to months

of treatment and is only effective with long-term

adherence to antidepressant therapy (Sander 2014). In

recent years, researchers are trying a new approach

based on CRISPR technology to alleviate depression

in addition to medication. Before the depression,

CRISPR technology has been widely used in other

fields. For example, in bladder cancer gene therapy,

treatment strategies have been ineffective because

certain genes, while actively expressed in tumor cells

in one organ, may also be expressed at relatively

active levels in normal cells in other different tissues.

Nowadays, researchers have cleverly used CRISPR

gene-editing technology and the principles of logical

pathways to solve these problems, providing new

ideas for studying tumor gene therapy. Researchers

established an editing system for targeted editing of

E6 and E7 genes based on CRISPR technology and

transfected the system into cervical cancer cell lines

infected with HPV-16 positive virus, and experiments

with SiHa cells also provide new ideas in the

treatment of cervical cancer and other HPV-related

cancers as a new therapeutic strategy (Masi 2011).

4.3 New Possible for CRISPR

A study at Pennsylvania State University indicated

that enhancing the activity of a subclass of neuronal

cells that produce the neurotransmitter gamma-

aminobutyric acid (GABA) and elevating GABA

neurotransmitter levels had antidepressant effects in

mice modeled with depression (Liu 2015). GABA is

part of the pathogenesis of anxiety and depression and

is responsible for many of the symptoms of these

disorders. GABA dysfunction is a major culprit of

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depression, and depressed patients often have reduced

GABA concentrations in the brain (State 2016).

Researchers at Pennsylvania State University

increased GABA signaling by disabling GABA

receptors in a specific group of neurons suspected of

being involved in major depression (Liu 2015). Under

normal conditions, this group of neurons, called

SST+ interneurons (growth inhibitor positive -

GABAergic interneurons), produce GABA, which

reduces the activity of other surrounding neurons. In

contrast, most peripheral neurons release the

neurotransmitter glutamate. When researchers

selectively disabled GABA receptors in SST+

interneurons, these cells could no longer receive

deceleration signals, so they over-released GABA,

which further slowed the glutamate-producing

neurons' activity (Liu 2015). As a result, rats

receiving this treatment behaved as if they were

taking antidepressants in a series of behavioral tests.

However, a study by Hyunjung Oh et al. in 2019

showed that GABA was the main determinant, as

manipulation of BDNF signaling resulted in an initial

deficit in GABA, not glutamate (Oh 2019). The basic

anxiolytic-antidepressant representing a GABA-A

positive modulator is very promising (Kalueff 2007).

The GABA-A type receptor is involved in cell

signaling through direct interaction with GABA.

There are also two subtypes of GABA-A receptors:

one containing the δ subunit δ and the other

containing the γ2 subunit.

4.3.1 Functional Abnormalities Associated

with Mutations

Dr. Steven Mennerick, Professor of Psychiatry at

Washington School of Medicine, induced point

mutations in the gene encoding the GABA-A δ

subunit in the mouse hippocampus using CRISPR-

Cas9 technology, making the GABA A δ subunit

resistant to picrotoxin resistant, thereby blocking the

chloride channel to inhibit receptor activity of the

chemical. Mice were then bred with these bitter toxin-

resistant GABA-A δ receptors. After dissecting and

sectioning the hippocampus of developing mice, they

stimulated neuronal cells in the presence of bitter

toxins to observe specific responses of δ subunits (Oh

2019). These experiments revealed the contribution

of the GABA-A δ subunit to short-term phase

synaptic responses after electrical stimulation.

Meanwhile, ASDS resulted in a range of emotional

and cognitive changes in adult animals, including

reduced social interest, increased anxiety-like

behavior, and impaired cognitive switch function,

accompanied by attenuated mPFC GABAergic

inhibitory synaptic transmission and a significant

reduction in the average frequency, but not amplitude,

of spontaneous inhibitory postsynaptic current

(sIPSC) delivery (CAS 2020). Further testing of

GABAergic signaling molecules by the Chinese

Academy of Sciences last year revealed that the

mRNA expression level of the mPFC GABA

synthase GAD65 was also significantly reduced.

These suggest that adolescent stress leads to sustained

suppression of GABAergic function in this brain

region. The decrease in BDNF due to ASDS is mainly

associated with reduced levels of BDNF IV promoter

transcripts. The results also suggest that mPFC

GABAergic synaptic transmission may be a

downstream mediating pathway for the depression-

like behavioral comorbid cognitive impairment and

BDNF signaling impairment caused by ASS. These

results suggest that GABAergic synaptic

transmission downstream of mPFC BDNF signaling

is primarily involved in the onset of depressive

comorbid cognitive impairment due to social stress in

adolescence, rather than depressive co-morbid

anxiety-like behaviors (CAS 2020). This study

provides a potential target for future rapid treatment

of cognitive dysfunction in depressed patients.

Given that the findings they generated have only

been relevant to mice, we must be cautious about

interpreting these results. That said, this study will

hopefully lay the groundwork for future studies on the

role of different cell types and mechanisms,

diversifying our approach to the study of depression

(Gardner 2018).

5 CONCLUSIONS

BDNF is essential for synaptogenesis, nerve growth,

and LTP in the hippocampus and many other parts of

the brain. More and more evidence suggest that low

levels of BDNF can be a risk factor for neurological

diseases like depression, stroke, and Parkinson's

disease. In the case of depression, the mutation of

Met66Val in the bdnf gene can decrease the secretion

of mBDNF, which has two possible pathways to alter

the function of the brain. Dysfunction of BDNF can

cause a decrease in the hippocampal volume and the

dysregulation in the serotonin pathway, while both

can increase the chance of major depressive disorder

in patients. In addition, it was also found that the

upregulation of BDNF has an antidepressant effect in

depression patients, which leads to new ways to treat

this disease. Currently, SSRIs and MAOIs are two of

the most common antidepressants available in the

markets. Both have shown to be effective in

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increasing the level of neurotransmitters such as

serotonin and epinephrine, which significantly

improve the symptoms of depression but with minor

side effects. CRISPR is one of the modern

technologies that can potentially treat depression by

editing genes such as the bdnf gene. There has been

an example of researchers introducing a point

mutation for the gene of GABA-A δ subunit. With

research like this, hopefully, we will be able to treat

more neurological diseases using CRISPR in the

future.

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