Epilepsy: GABRB3 Gene and Medical Treatment

Zhichao Dai

1,† a

and Sicheng Pan

2,† b

Maple Leaf International School Shanghai, 201501, SH, China

The University of New Hampshire, 03824, Durham, NH, U.S.A.

†

These authors contributed equally

Keywords: Epilepsy, GABRB3 Gene.

Abstract: Epilepsy is one of the most common central nervous system disorders and chronic diseases on the existing

human. By writing this essay, we summarize and combine the genetic level with the macroscopic view of the

disease. In definition, epilepsy is described as repeating occurrences of sudden excessive or synchronous

discharge in the cerebral cortical neuron that leading to various symptoms, depending on the brain region it

affects. So, epilepsy is classified into 4 types, focal epilepsy, complex focal seizures, generalized epilepsy,

and combined generalized and focal epilepsy. It is worldwide spread, affecting 50 million people, mostly kids,

and elders, and the prevalence was slightly higher in males than females. At the genetic and molecular biology

level, a strong association of GABRB3(Gamma-aminobutyric acid receptor subunit beta-3) gene and GABAA

receptor it encodes for is shown to epilepsy because of the function of the GABAA receptor is inhibiting nerve

impulses, mutation of the GABRB3 gene would psychologically lead to anxiety and restlessness, physically

disorders like epilepsy. Based on looking and summarizing the macroscopic aspects of the disease, brain

activities, and genetic views, we suggest therapies like CRISPR on the GABRB3 gene would likely to provide

treatments for epilepsy in the future.

1 INTRODUCTION

Epilepsy is very time-honored and is with the

continuous development of human civilization and

development. The earliest descriptions were in texts

written in 2000 BC in Akkadian and used in

Mesopotamia. Descriptions related to epilepsy also

appeared in the many ancient civilizations, such as

ancient Egyptian, ancient Babylon, and ancient

Greek. In this ancient literature, epilepsy was

generally considered as evil spirits or divine

punishment. This occult interpretation continued to

influence what people thought about epilepsy until

the appearance of Hippocrates. Hippocrates raised the

first formal description of epilepsy as a kind of

disease, and in his classic treatise on the Sacred

Disease, he said that epilepsy was not more sacred

than any other disease, and it had the same properties

as other diseases and some causes of individual

diseases. Complete liberation of epilepsy from

superstition appeared in the 18th and 19th centuries,

although the description that epilepsy is a kind of

https://orcid.org/0000-0002-3338-1431

https://orcid.org/0000-0002-1645-9161

disease appeared at the Hippocrates times. And the

most important progresses that appeared in the 20th

century included the invention of

electroencephalograph (EEG), the advance in

neurosurgery, the discovery of antiepileptic drugs,

and the delineation of underlying pathophysiological

mechanisms. And because of these progresses, the

myth about epilepsy has been shattered, and social

acceptance has risen to a new level. When doing a

general survey about epilepsy’s history, epilepsy is so

important that attract scientists and doctors from

ancient times to the present constantly explore and try

the solutions of the cure of epilepsy. And even now,

epilepsy researching is continuing and becomes

deeper into the nature of epilepsy. Science seems to

be dominated by genetic research and advances in

computer and information technology in the 21st

century. The future of epilepsy research is

researching the gene that causes epilepsy, including

the Gamma-aminobutyric acid receptor subunit beta-

3 gene (GABRB3 gene). This article would introduce

760

Dai, Z. and Pan, S.

Epilepsy: GABRB3 Gene and Medical Treatment.

DOI: 10.5220/0011294600003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 760-766

ISBN: 978-989-758-595-1

epilepsy’s basic information, epilepsy-related gene

and discuss some new treatment means.

2 INTRODUCTION OF EPILPESY

Epilepsy is a central nervous system disorder that can

affect the brain and cause frequent seizures. Epilepsy

is a very common neurological and chronic disease

but compared with the other similar chronic disease,

the patients of epilepsy are more likely to have some

physical, social, and psychological problems. By

choosing one hundred patients with epilepsy from the

neurological outpatient department from two

hospitals in Baghdad/Iraq and doing the research, the

study showed that most of the patients with epilepsy

were threatened by death (88%) and felt fear from

epilepsy seizure (77%). More than the half of the

sample expressed feeling disappointment after the

attack. Moreover, the study showed that 86% of the

selected sample were severely affected by the social

stigma and 64% of the selected sample thought they

were a heavy burden for their family. This series of

evidence shows that the psychological combat from

epilepsy is very serious and can affect other aspects

of life for patients. The patients of epilepsy are

difficult to have marriage and children because they

are afraid of their children have epilepsy and studies

in many countries and cultures have shown that many

families still oppose their children marrying epilepsy

patients because they believed that the epilepsy

patients were unable to meet their social and

economic needs roles and obligations.

When a seizure happens, repeated occurrences of

sudden excessive or synchronous discharge in

cerebral cortical neurons result in a disruption of

unconsciousness, disturbance of sensation,

movement, and impairment of mental function. It is

different between epilepsy and seizures, while

epilepsy and seizure are often mixed. A seizure is a

single occurrence; however, epilepsy is a

neurological condition characterized by two or more

unprovoked seizures.

2.1 Types of Epilepsy

Epilepsy has four types: focal epilepsy, complex focal

seizures, generalized epilepsy, and combined

generalized and focal epilepsy. These four types of

epilepsy are identified by various brain positions

where sudden excessive or synchronous discharges

are repeated. Generalized epilepsy is the seizures

happening that involve all areas of the patient’s brain;

nevertheless, focal epilepsy can appear to involve just

the specific area of the brain. And the combined

generalized and focal epilepsy is like the suggestion

of the name, which is a form of epilepsy, and patients

have both generalized and focal seizures. It is very

important to identify the types of epilepsy because

one medication may treat one specific type of

epilepsy well but may worsen another type of

epilepsy simultaneously.

2.2 Prevalence of Epilepsy

The prevalence of epilepsy is the proportion of any

population affected by epilepsy at a specific time

worldwide. The estimated proportion of the general

population with active epilepsy at a given time is

between 4 and 10 per one thousand people. And

epilepsy affects around 50 million people in the

world. Moreover, an estimated five million people are

diagnosed with epilepsy each year globally. But it is

worth noticing that the reported incidence of epilepsy

(the rate of new cases in the population) is different

between high-income and low-income economies.

The incidence of epilepsy in high-income economies

is obviously lower than the incidence in low-income

economies. In fact, nearly 80% of people with

epilepsy live in low-and middle-income countries.

However, one study showed that although the

incidence of epilepsy is higher in low- and middle-

income countries, the lifetime prevalence appears to

be roughly the same worldwide. According to a data

review, lifetime epilepsy ranged from 3.2 to 30.1 per

1,000 population in high-income economies, from 4.5

to 18.6 in upper-middle-income economies, from 2.5

to 32.1 in lower-middle-income economies, and from

4.7 to 23.3 in low-income economies.

Besides regional differences in income levels,

epilepsy prevalence is different by gender, which the

prevalence of males with epilepsy is slightly higher

than females with epilepsy. The Rochester epilepsy

study found that the prevalence of epilepsy was

slightly higher in males than females, and the

proportion between males and females is about 6.5 to

6.0 per 1000 persons. The reason that causes this

condition may be the various prevalence of the most

common risk factors in gender and the concealment

of the condition in women for sociocultural reasons

in certain regions.

2.3 The Symptoms of Epilepsy

The symptoms of epilepsy have a great variety and

exist huge differences between them. Overall,

epilepsy symptoms mainly include staring at the

empty space, temporary confusion, uncontrollable

Epilepsy: GABRB3 Gene and Medical Treatment

761

jerking of limbs, losing consciousness and awareness,

and psychically fear, anxiety, or deja vu. However,

patients with different types of epilepsy may have

some of these symptoms. And even if two patients

have the same kind of epilepsy, the symptoms

between them may be totally different. For example,

generalized tonic-clonic seizures are the most well

recognized, also called ‘grand mal seizures in the

past. When these seizures happen, the first symptom

is a sudden loss of consciousness, and then the body

would become stiff, followed by jerking of the

muscles. And often, patients may turn red or blue, bite

their tongue, and lose control of the bladder, but these

symptoms vary with each individual. In addition, the

symptoms of generalized absence seizures are much

milder and briefer than generalized absence seizures,

although they belong to generalized seizures. The

symptoms of generalized absence seizures involve

staring, loss of expression, unresponsiveness, and

stopping activity. And sometimes, the patients with

generalized absence seizures just show eye blinking

or upward eye movements.

2.4 The Risk Factors of Epilepsy

Epilepsy is a complex disease with many causes, and

seizures can be led by caused by anything that

disrupts the normal electrical patterns of the brain.

Epilepsy has no identifiable cause in about half the

people with the condition. In the other half, the

condition may be traced to various factors, including

genetic influence, head trauma, brain conditions,

infectious diseases, prenatal injury, and

developmental disorders. First, epilepsy is considered

a high genetic disease, and under many conditions,

epilepsy can be heritable. For example, in idiopathic

generalized epilepsy, the first-degree relatives of

epilepsy patients have an 8-12% risk of developing

epilepsy, which is much higher than the risk in the

general genetic component. Then head trauma is

related to epilepsy, and the recurrent seizure disorder

because of injury to the brain following head trauma

is called Posttraumatic epilepsy (PTE). Studies

showed that traumatic brain injury makes up about

10-20 % of symptomatic epilepsy in the general

population and 5% of all epilepsy. Third, infectious

and infestations are one of the most common risk

causes for seizures and acquired epilepsy and maybe

the most common preventable risk factor for epilepsy

worldwide, especially in resource-poor countries.

Many types of infectious diseases can develop

seizures, ranging from toxoplasma in the newborn,

early childhood infection with human herpesvirus

(HHV)-6 to Creutzfeldt-Jakob disease (CJD) in the

elderly. And seizures maybe just one symptom in

some infectious diseases such as neurocysticercosis

(NCC). Then, prenatal injury can also result in

epilepsy, which is brain damage before babies’ birth

that could be caused by several factors, such as poor

nutrition or oxygen deficiencies. Finally, sometimes

epilepsy can have linkage with developmental

disorders, such as autism and neurofibromatosis.

2.5 The Brain Activity of Epilepsy

The brain activity of epilepsy is the key to a cure for

epilepsy. By researching the brain activity of

epilepsy, scientists can know better the mechanism of

action of epilepsy, influencing factors, and so on,

which provides some new ideas to find the cure

methods for epilepsy. Because the brain activity of

epilepsy is hard to observe and some moral and

ethical barriers and so on, the research of the brain

activity of epilepsy is not very rich and impeccable. It

is hard to observe the brain activity directly, and

scientists have to use some roundabout methods to

research the brain activity of epilepsy, for example,

using the method that compares with the healthy

control group. The main method to detect brain

activity is using a series of scientific instruments,

such as electroencephalography (EEG), magnetic

resonance imaging (MRI), High-density

electroencephalography. EEG is used to record the

brain's electrical activity, which is also the most

common and basic method of detecting epileptic

activity. But although EEG has high temporal

resolution and sensitivity, it is less spatial resolution

and is not sensitive to an activity deep in the brain.

Moreover, EEG can only detect abnormal signals

when the seizure happens, so EEG also has some

imperfections. MRI is often used cooperatively with

EEG to make the detection method more impeccable

because of its better spatial resolution. To be sum,

these are only short-term brain activities.

2.5.1 Short-term Brain Activity

The brain activity of epilepsy researching can be

divided into short-term changes and long-term

changes. The most obvious brain change for short-

term brain activity is the repeated occurrences of

sudden excessive or synchronous discharge in the

cerebral cortical neuron. These discharges can be

detected by EEG and be used to help doctors make a

diagnosis of epilepsy. The EEG of epilepsy which is

different from normal EEG, is called epileptiform

discharge, and it occurs in up to 98% of patients with

epilepsy depending on age and epileptogenicity. The

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patterns of the epileptiform discharges are considered

to have the following types: spikes, sharp waves,

benign epileptiform discharges of childhood, spike-

wave complexes, slow spike-wave complexes, 3-Hz

spike-wave complexes, polypiles, hypsarrhythmia,

seizure pattern, and status pattern. Although

epileptiform discharge has many patterns, the

epileptiform discharge has no objective definition,

and even experienced electroencephalographers

sometimes feel confused about the diagnosis of

epileptiform.

2.5.2 Long-Term Brain Activity

For long-term brain changes of epilepsy, epilepsy can

alter patients’ neuromagnetic activities and brain

network in the high-frequency ranges. These

alterations become more pathological as the duration

of epilepsy grows longer. According to new research

led by the UCL Institute of Neurology and the Keck

School of Medicine of USC, the team found reduced

grey matter thickness in parts of the brains’ outer

layer and reduced volume in subcortical brain regions

in all epilepsy groups when compared to the control

group. And from a study of children’s epilepsy,

seizures alter brain functions by over activating,

interrupting, or destroying vital networks of brain

activity. It is clear that epilepsy has profound effects

on the developing child’s brain. About half of

children with epilepsy experience learning

difficulties, especially those involving problems with

attention and memory.

3 EPILEPSY AND THE GAMMA-

AMINOBUTYRIC ACID

RECEPTOR SUBUNIT BETA-3

GENE (GABRB3 GENE)

In the molecular neurobiology domain, well-known

disorders like autism spectrum disorder (ASD),

bipolar disorder, and schizophrenia disorder are

proved to have a strong relationship with mutation of

genes of neurological structures like some

neurotransmitters and synaptic receptors that

influence not only mental aspects but also the ability

to coordinate and movements. In the case of epilepsy,

the most related gene is the Gamma-aminobutyric

acid receptor subunit beta-3 gene.

3.1 The Gamma-Aminobutyric Acid

Receptor Subunit Beta-3 Gene and

the GABAA Receptor

Research and studies have shown that the mutation of

the Gamma-aminobutyric acid receptor subunit beta-

3 gene and the protein it codes for have a significant

association with many neurodevelopmental disorders

other than Epilepsy, like Angelman syndrome and

autism. By analysing this particular gene and protein,

more treatments and therapies could be found to aim

at those common disorders that this gene involved in.

Going back to the mid-1950s, researchers and

experimenters had made dozens of efforts on gamma-

aminobutyric acid in both humans and animals’

brains, and how some available drugs like

benzodiazepines and barbiturates (function as

enhancing the currents of GABAA receptor) which

could affect GABAA receptor that it is one of the

most common prolific targets for therapeutic.

3.2 The GABRB3 Gene

The belief that the GABRB3 gene is associate with

epilepsy and childhood absence epilepsy (CAE)

originated from the team of Lydia Urak, who

analysed this gene’s single nucleotide

polymorphisms (SNPs) in particular exons. They

tested 45 patients of CAE in the Medical University

of Vienna, and the results showed that the strong

association of CAE with 13 single nucleotide

polymorphisms in the GABRB3 gene, from exon 1a

promoter to the beginning of intron 3 among 45

subjects. The GABRB3 gene is located at

chromosome 15, region q12 of the human genome. It

has 10 exons in its coding region, and since the

alternative splicing, the GABRB3 gene could code

for various other protein isoforms that are subunits of

the GABAA receptor.

GABRB3 gene is frequently expressed in the

human brain during the proliferation and

differentiation of human embryonic developments. In

contrast, it is not expressed in the adult brain

extensively except the hippocampus.

Epilepsy: GABRB3 Gene and Medical Treatment

763

Figure 1: Conserveness of GABRB3 protein across different species and the sharing similarities.

3.3 The GABRB3 Protein

Studies have shown that the GABRB3 protein is

conserved among various species. Most other

mammals and vertebrates’ gene models are similar to

humans, k, some even have identically matched over

90%, especially the Chimpanzee and Rhesus

monkeys. This illustrates the importance of this gene

that the protein it encodes is necessary for the

neuronal growth of the Craniata species and animals

in lower classes. There are over 10 types of subunits

combined to form a chloride channel (for example,

GABAA receptor), and the GABRB3 protein is one

of those, which will be discussed in detail in the next

chapter.

3.4 The GABA and the GABAA

Receptor

The Gamma (γ) -aminobutyric acid (GABA) is one of

the most important inhibitory neurotransmitters

involves in the central nervous system (CNS)

development. As its reducing function acts on the

inhibiting excitabilities of neurons, it would

hyperpolarize the neurons at the resting potential of

the action potential by binding to GABAA receptor

or GABAAR and GABAB receptor or GABABR.

The GABA controls all excitabilities areas in the

human brain with another neurotransmitter. To keep

a balance in the brain, those excitabilities are

regulated by both the GABAergic activities and

glutamatergic neurons, which produce the most

common and critical excitatory neurotransmitters —

glutamate that stimulates action potentials. In

opposite, the inhibitory neurotransmitters GABA in

GABAergic activities inhibits action potentials.

When two of these neurotransmitters could not

function properly depending on situations, symptoms

like anxiety, restlessness, insomnia, and even

disorders like schizophrenia and Parkinson's disease

would occur when reducing the GABAergic

activities. In addition, sedation, amnesia, and ataxia

will appear when the GABAergic activities outweigh

the glutamatergic activities. And the neurotransmitter

GABA is manufactured by GABAergic neurons,

which are neurons that use and produce GABA as

their neurotransmitter that is commonly distributed in

the CNS but not common outside the brain and in the

spinal cord.

The GABA receptor that is significant to epilepsy

is code by GABRB3, the GABAA receptor. It is

wildly distributed in the human brain that it could be

found in 20% to 50% of all the brain synapses. The

GABAAR and GABA are most concentrated in the

human limbic system that involves human emotions

and memories, especially when one is under a strong

feeling or challenges and traumas. And the GABAA

receptor is only one of the receptors that could be

activated by GABA, an ionotropic receptor and

ligand-gated ion channel. By allowing the permeation

of chloride ions (Cl−) in or out of the membrane, its

function is to maintain or mediate the synaptic

membrane potential and inhibit action potentials.

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764

Figure 2: Structure of GABAA receptor, within 5 subunits

composed a channel in the middle.

The structure of the GABAA receptor is quite

normal, just like most other ligand-gated receptors, it

is formed by five subunit proteins, that each of which

is about 50,000 Daltons in size, and every last one of

these amino acid strings goes into and out the cell

membrane 4 times, leaves an N-terminal at the

extracellular space, which is the end of the

polypeptide that, it would function as mediating the

channel’s interactions. And in the middle of those

amino acids, there is a large area of looping inside,

with four sites where phosphorylation occurs. Those

subunits that composed to this receptor have been

classed into α1–α6, β1–β3, γ1–γ3, δ, ε, π, θ, and ρ1–

ρ3. It seems alpha and beta are the key components of

GABAA receptors since most of them are arranged

by two alpha and beta subunits in the limited 5

maximums.

When GABA binds to the GABAA receptor, the

ion pore in the middle will open, which facilitates the

influx or efflux of chloride ions (Cl-), depending on

the concentration difference of Cl- outside and inside

the cell that regulates by the potassium chloride

(KCC2) and sodium-potassium chloride (NKCC1)

co‐transporters.

3.5 Medical Treatment of Epilepsy:

Benzodiazepines

Benzodiazepines (BZDs), as mentioned, are one of

the most significant medical agents of epilepsy since

the 1960s. They are targeted on the GABAA

receptors, that they have had a strong preference

towards status epilepticus and seizures. Besides,

BZDs have also been used in febrile or repetitive

seizures and alcohol withdrawal seizures. They

became the first choice when those symptoms came

since they have high efficacy, rapid onset, and less

toxicity on functions like sedation, anxiety-reducing,

and muscle relaxation. Each type of BZD shows

different pharmacologic effects according to

particular symptoms, and among all of these 35 kinds

of BZDs, there are some used in epilepsy. When

BZDs bind to the GABAA receptor, they are not

substituting the GABA but acting as an enhancing

agent to provide more chances of the channel opening

to allow more Cl- get in or out to increase or decrease

the current. The BZDs are sharing a structure of a

benzene ring and seven-membered diazepine ring

fusion.

Figure 3: General chemical structure of 1,4-

benzodiazepines

4 CONCLUSIONS

This dissertation resulted from an investigation into

the macroscopic level, molecular biology, and genetic

level of epilepsy. It concentrated on the symptoms

and brain activity of epilepsy, mutation of GABAA

receptor, and its gene. As an overview, the current

state of knowledge we had summarized about

epilepsy shows a strong association it has with the

GABRB3 gene. Still, since the limitation of more

recent data of how epilepsy is prevalent beyond all

ages, genders, and regions and the genetic experiment

of GABRB3 gene, further research needs to be

conducted on those aspects.

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