Molecular Neurobiology Of Clinical Depression & Related Mood Disorders

Depression affects a large portion of world population. It is caused by both genetic and non-genetic/environmental factors. It is of several types and accordingly symptoms like sad mood, loss of interest, insomnia, suicidal behavior, agitation or retardation, etc. are observed in patients with depression. Synaptic transmission of nerve impulse from one neuron to the next involves the role of neurotransmitters mainly norepinephrine, dopamine and serotonin. The deficiency or imbalance of these neurotransmitters is associated with the prevalence of this disease. Likewise, stress response circuits, circadian rhythms and adult brain neurogenesis also justify the causes of this illness. Based on these findings, antidepressants are developed which either have primary action on the neurotransmitters or they regulate the neurogenesis in the brain region. Various areas of brain have been the targets of these drugs and the effect of Electroconvulsive Therapy on increasing acetylated histone proteins has been understood. There is a clear interaction between the neuroendocrine and neuroimmune systems of human body that also explain the molecular basis of depression. Lithium is an important constituent of antidepressants and its role in treatment of this disease is being studied. There have been some breakthroughs with the discovery of several genes associated with the disease such as ANK3, CACNA1C, SLC6A15 and MIF. As WHO has forecast that depression will be the second most common cause of disability by 2020, development of newer and effective forms of medication have been extremely essential.

KEYWORDS: Depression,

INTRODUCTION:
Depression is a kind of mood disorder which has become a serious health issue in many countries of the world. In 2012, World Health Organization estimated that it affects 350 million people worldwide and it has forecast that unipolar depression will be the second most common cause of disability by the year 2020. 40 to 50% of the cases of depression have been attributed to multiple genetic factors. However, non-genetic factors like stress, trauma, infection by viruses and abnormalities in the development of neurons may aid in the development of this disease as well [11].

Symptoms of depression:
The clinical diagnosis of Depression is done based on these indications: sad mood for two or more weeks, loss of interest, fatigue or decreased energy, loss of confidence or self-esteem, self-reproach or guilt, recurrent thoughts of death, suicide or suicidal behavior, agitation or retardation, diminished concentration, indecisiveness, sleep disturbance/ insomnia, appetite & weight change (increase or decrease). Accordingly, patients are identified to have severe, moderate and mild depression [13]

Types of depression:
There are various forms of depression based on the duration, intensity or age at which it affects a person. Some of the well-known types are Major depressive Disorder (MDD), Dysthymia/Chronic depression, Bipolar disorder/manic depression, Unipolar depression, Seasonal depression/ seasonal affective disorder (SAD), Psychotic depression, Adjustment disorder and Post-Partum Psychosis [14].

Introduction to the chemical synapse:
Signaling between two nerve cells known as presynaptic and postsynaptic cells, takes place through a process called synaptic transmission. It is facilitated by release of chemicals called neurotransmitters. Structures called synaptic vesicles which contain such chemicals are present in the axon terminal of the presynaptic cell. A tiny gap of about 20 nm called synaptic cleft separates the two cells.
Influx of Calcium ions occurs in presynaptic cell through voltage-dependent calcium channels on the onset of an action potential. The synaptic vesicles then release their contents into the synaptic cleft. These neurotransmitters get diffused across the cleft in about 5 ??s which bind to either Ligand-gated ion channels or G-protein-coupled receptors on post-synaptic membrane. The permeability of the latter to certain ions is now altered resulting in formation of postsynaptic potentials. The consequence of this event is that the postsynaptic cell may either increase the firing of action potential in which case it is called excitatory or it may reduce the chance of initiating the action potential which gives it the name of inhibitory response. Accordingly, the neurotransmitters can also be excitatory or inhibitory based on their ability to trigger or reduce action potentials [1].


Causes of depression:
Various hypotheses have been put forward to explain the progression of clinical depression. Some of these are described below:
1) Monoamine hypothesis:
According to this hypothesis, the deficiency or imbalance in monoamine neurotransmitters like serotonin, dopamine & norepinephrine are the causative factors for depression. This finding is supported by the fact that mutant mice lacking monoamine degrading enzymes like monoamine oxidase A (MAOA) & Catechol-methyltransferase (COMT) have been shown to display depression-like behaviors [12].

2) Gene-environment interactions, Stress response circuits and Circadian rhythms(CR):

Polymorphisms in serotonin transporter 5-Hydroxyl Tryptamine Transporter (5-HTT) have been linked to depression. A study done in 847 New Zealanders indicated that short allele of 5-HTTLPR variants is connected with stressful life events such as loss of job or divorce with the spouse.
The hypothalamic pituitary-adrenal (HPA) axis is a neuroendocrine circuit that plays a significant role in stress management. Three parts of human body, the hypothalamus, pituitary gland and adrenal cortex are involved in this system.
First of all, the hypothalamus part of brain receives neurosensory signals which trigger the secretion of Corticotrophin-Releasing Factor (CRF) & arginine vasopressin. Both of these chemicals activate the HPA axis (hyperactivity of HPA-axis).
The pituitary gland and the adrenal cortex secrete Adrenocorticotrophin (ACTH) and glucocorticoid, respectively. The high level of glucocorticoids in blood increases the excitotoxicity of CA3 pyramidal neurons in hippocampus region of brain. The consequences of this are dendriritic atropy, apoptosis of neurons & inhibition of adult neurogenesis.
Inadequate length of light phase to determine Circadian Rhythm can be another cause of depression. Furthermore, the abnormal regulation of sleep/wake cycles, body temperature and blood pressure which are under the control of circadian clock are the indications of depression [11].

3) Adult brain neurogenesis :

It has been well-known that most of the neurons in the brain and spinal cord of mammals including human, are created during the pre- and perinatal periods of their development. However, according to a new theory, there are two regions in the brain in which the neurons are constantly formed throughout the lifespan of an individual. These regions are the olfactory bulb and the dentate gyrus of hippocampus. Such neurons are derived from the progenitor cells which remain in quiescent or GO stage of the cell cycle. On arrival of certain signals, the cells undergo cell cycle or mitosis thus producing the neurons. This insight has given rise to the new methodology in the development of anti-depressant class of drugs which were previously based on their action on neurotransmitters. New drugs aim in controlling the neurogenesis in brain as well as aid in the continued existence of newly formed neurons, which can have a bigger therapeutic value [3].

Targets for Anti-depressants:
Anti-depressant class of drugs aims to abate the functions of HPA axis as described above. Accordingly, the targets for them are CRF receptors in pituitary, Glucocorticoid receptors in hippocampus & other brain regions and Vasopressin receptors in amygdala & other parts of limbic system [11].
Similarly, the neurotrophic factors like Brain Derived Neurotrophic Factor (BDNF) and its receptor TrkB have known to be other potent candidates justified by the fact that the expression of BDNF is decreased due to stress for a long duration [10]. Furthermore, research has shown that the Electroconvulsive therapy (ECT) increases the level of acetylated histone H3 at the promoters 3 and 4 of the BDNF .This modification facilitates the rise in the expression of BDNF [8]. Studies also demonstrate that anti-depressants downregulate Histone Deacetylase 5 (HDAC5) in the hippocampal region.

Cytokines have also been discovered to mediate mood. A study in mice showed that small doses of LPS or IL-1 cause social withdrawal & decreased sexual behavior. This was found to be due to release of pro-inflammatory cytokines like IFN-' and TNF-' that activate HPA axis. Hence stalling the effects of these cytokines can produce anti-depressant effects [12].
Altering the actions of Glutamate, the major brain neurotransmitter has been a new area of interest in the treatment of depression [15].

Role of Lithium
An important component of anti-depressant drugs is Lithium (Li). It has no receptor to which it can bind in the brain. Its transport into the cell occurs through the sodium (Na) channel. On the depolarization of neuron, it enters the cell along with sodium through the open Na channel. Na-K-ATP pump then actively pumps out but Li remains in the intracellular compartment.
Li has significance in reorganizing ionic homeostasis in neurons either directly or by interacting with the second messenger systems. It also increases neurogenesis in the hippocampus [9].

Some recent breakthroughs
As research on molecular pathophysiology and mechanism of depression are being carried out in different parts of the world, novel discoveries have been made in terms of genes responsible for it. For instance, Single Nucleotide Polymorphism (SNP) within ANK3, the gene that codes for a protein called Ankyrin3 is associated with Bipolar Disorder. This protein aids in the propagation of action potentials by regulating the assembly of sodium gated ion channels. Likewise, variation in a Calcium channel gene CACNA1C found in the brain showed the second strongest association with bipolar disorder. The protein encoded by this gene regulates the influx and outflow of calcium [7].
Macrophage migration inhibitory factor (MIF) is also connected with neurogenesis and anxiety [16]. Recently, it was discovered that the lowered expression of another gene named SLC6A15 in the hippocampal region of mice is associated with chronic social stress which has been identified as a risk factor for depression [17].

Conclusion:
Mental health has remained as a neglected area in the field of patient care especially in the developing nations. But the alarming rate at which Depression is progressing worldwide has aroused the need for serious considerations to be made in the field of more effective therapeutics. Hence understanding the mechanisms and pathophysiology of the disease can certainly facilitate in the development of new line of anti-depressant drugs that have bigger therapeutic value than the conventional drugs.

References:
1)Alan Longstaff, Neuroscience, Third Edition.
2) Alan F. Schatzberg et. al.: Molecular and Cellular mechanisms of Depression, Neuropsychopharmacology: The Fifth Generation of Progress
3) B L Jacobs, H van Praag and F H Gage: Adult brain neurogenesis and psychiatry: a novel theory of depression, Molecular Psychiatry, 262-269 (2000)
4) Ferreira MA, O'Donovan MC, Meng YA, Jones IR, Ruderfer DM, et. al.: Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder. Nat Genet 40, 1056'1058 (2008)
5) Gregory S. Berns & Charles B. Nemeroff: The Neurobiology of Bipolar Disorder, American Journal Of Medical Genetics Part C (Semin. Med. Genet.)123C:76-84 (2003)
6) John Hopkins Medicine:Genetic Links, Fall 2009
7) Kloiber S, Czamara D, Karbalai N, M??ller-Myhsok B et. al. : ANK3 and CACNA1C - Missing genetic link for bipolar disorder and major depressive disorder in two German case-control samples, J Psychiatr Res. 46(8):973-9 (2012)
8) Nadia M. Tsankova, Arvind Kumar, and Eric J. Nestler: Histone Modifications at Gene Promoter Regions in Rat Hippocampus after Acute and Chronic Electroconvulsive Seizure, The Journal of Neuroscience,24(24):5603'5610 (2004)

9)Rodrigo Machado-Vieiraa, Husseini K Manjib, and Carlos A Zarate Jra: The role of lithium in the treatment of bipolar disorder: convergent evidence for neurotrophic effects as a unifying hypothesis, NIH Public Access (2010)

10)Ronald S. Duman and Lisa M. Monteggia, A Neurotrophic Model for Stress-Related Mood Disorders, BIOL PSYCHIATRY 59:1116'1127 (2006)

11) Saebom Lee, Jaehoon Jeong, Yongdo Kwak and Sang Ki Park: Depression research: where are we now?, Molecular Brain 3:8 doi:10.1186/1756-6606-3-8 (2010)
12) Vaishnav Krishnan & Eric J. Nestler: The Molecular Neurobiology Of Depression, Nature|Vol 455|16 (2008)
13) The ICD-10 Classification of Mental and Behavioural Disorders, World Health Organization

14) National Institute of Mental Health, Depression

15) Eva M. Tsapakis & Michael J. Travis, Glutamate and psychiatric disorders, Advances in Psychiatric Treatment (2002), vol. 8, pp. 189-197

16) Joshua Bloom and Yousef Al-Abed, MIF: Mood Improving/Inhibiting Factor?, Journal of Neuroinflammation 2014, 11:11

17) Martin A. Kohli1, Susanne Lucae1, Philipp G. Saemann et al. The neuronal transporter gene SLC6A15 confers risk to major depression; 70(2): 252'265. doi:10.1016/j.neuron.2011.04.005

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