Research in vivo quantification of metabolites in localized brain

Research Goals

            This research aims
to focus on the glutamate system and shifts the attention from the monoamine
hypothesis as the basis for mental disorders in an attempt to discover new
alternative treatments that are more effective for depression and stress
disorders. In targeting the glutamate system, we seek to answer several
questions that will help us in solidifying the glutamate hypothesis of
depression which implies that any abnormalities in the concentration of
glutamate/glutamine in different brain regions is what causes brain
pathophysiology like major depressive disorder (MDD). The ability of the
glutamate system to harmfully influence mental health have been considered and
viewed by researchers, however, there are few studies, compared to studies on the
monoamine principle, that target the glutamate system as a potential for curing
mental disorders. Here I will investigate how the glutamate/glutamine cycle and
its neurons/glial cells control the clearance of Glx in the brain, and whether
a dysfunction in the pattern of this activity have a direct impact on MDD. Also,
considerable number of neurons and synapses in limbic and cortical areas of the
brain go through morphological changes such as increasing in the remodeling of
some dendrites and reduction in synapse firing rate. These changes are quite
similar to what is observed in patients suffering from MDD; thus, examining if
enhanced release and transmission of glutamate levels is the reason behind
these changes since neurons and circuits at these areas are dominantly
controlled by glutamate the neurotransmitter. This research will also study and
analyze the level of glutamate its release and uptake in subjects diagnosed
with major depressive disorder, bipolar disorders and mood disorders. Is there
an emerging pattern or trend that specifically links mental disorder to the
glutamate system?

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Definition of Terms

1.    
Glx—Stands
for glutamate/glutamine.

2.    
NMDA—N-methyl-D-aspartate,
ionotropic glutamatergic receptor.

3.    
mGLuR—G-protein-coupled
metabotropic receptor.

4.    
MRS—Proton
magnetic resonance spectroscopy. A neuroimaging technique that allows in vivo
quantification of metabolites in localized brain regions.

5.    
ROI—region
of interest.

6.    
EAAT—
Excitatory amino acids transporters.

Literature
Review/Previous Research

            Clinical studies have found abnormal
levels of glutamate in MDD. For example, one of the earliest study done by the department
of clinical psychiatry, University of Milan in Italy found that levels of
glutamate plasma were higher in patients with mood disorders (Altamura, Moro et
al.,1993)4. Another study conducted in 2009 that looked into the relationship
between plasma Glx levels and MDD in diagnosed subjects found that glutamate
and glutamine play an influential role in depression (Saygin et al., 2009)5,19,16.

A more direct methods of evaluating glutamate dysfunction in the brain has been
done using MRS. For instance, proton MRS showed a reduction of
glutamate/glutamine levels in the hippocampus (Block, Von Widdern et al., 2009)6.

Additional MRS studies of the dorsomedial and ventromedial prefrontal cortex
determined that depressed patients had decreased Glx levels in ROIs (Hasler,
Tumonis et al., 2007)6. Moreover, postmortem studies have found
changes in the expression of NMDA receptor subunits in MDD patients. for example,
a study conducted in 2014 by the Department of Psychiatry, University of
Pittsburgh, found Abnormal glutamate receptor expression in the medial temporal
lobe in patients with MDD and mood disorders (Szebeni, Crawford et al., 2014)7,11,16.

 Recent studies focusing on the NMDA
receptor and its antagonists, ketamine, have showed a rapid antidepressant
effect. Also, low-dose I.V infusion of ketamine produces fast and sustained therapy
for MDD patients (Hao X, Zhu X et al,. 2016)8,2,13,17.

Research
Plan

            In studying the impact of Glx on
mental illness I will follow several methods based on earlier studies

                                         
I.        
Collecting data from postmortem subjects who have been
diagnosed with MDD and from healthy control. Observing the Glx levels in
different areas of the brain and comparing data. Similar to a study done in
2015 where frozen postmortem brain tissues were obtained from MDD group and a
control group of healthy subjects. The experiment included cDNA preparation,
gene expression assays and then analyzing of the gene expression (Gray, Hyde et
al,. 2015)9,14,16.

                                       
II.        
Using qPCR to compare gene expression patterns in the
prefrontal cortex of the astrocytic Glx cycle and glial glutamate transporters
in depressed patients and healthy controls.

                                     
III.        
Testing different glutamate receptor antagonists like
Ketamine and MEPE on animals such as rats and observing their
antidepressants-like behavior and how effective they are.