Monoamine Oxidase (MAO) in Bipolar Disorder

Monoamine oxidase (MAO) is an important enzyme in the central nervous system (CNS) catalyzing the breakdown of monoamine neurotransmitters, along with other biogenic amines1. It is found in two isoenzymes in the brain, MAO-A and MAO-B, which show different anatomical distributions, substrate preferences, and inhibitor sensitivites1,2,3. Imbalances of such neurotransmitters are implicated in a number of psychiatric disorders, of which bipolar disorder will be considered here1,4. Bipolar disorder has a broad spectrum of behavioral manifestations and varying degrees of severity which makes it a complicated condition that consists of both genetic and environmental components7. Still, the MAO gene has been strongly linked to bipolar disorder and, as a result of the amine hypothesis and the traditional use of MAO-inhibitors as antidepressants, is intimately linked to the study of affective disorders1,2,5.
1.1 Amine Hypothesis
Monoamine neurotransmitters make up some of the most prominent neurotransmitters in the CNS including dopamine (DA), serotonin (5-HT), tryptamine, and 2-phenylethylamine (PEA)4. Many of these biogenic amines are known to function abnormally in individuals with affective disorders5. The amine hypothesis was proposed to explain this observation, as well as the mood enhancing effects of MAO inhibitors, which states that an excess of biogenic-amine function is associated mania, and a deficiency is associated with depression 1,4,5. MAO is an intracellular mitochondrial enzyme that functions in the breakdown of monoamine neurotransmitters and therefore MAO function is intimately associated with intracellular concentrations of these neurotransmitters in the brain1,4,5. Consequently individuals exhibiting low MAO activity levels have an increased susceptibility to develop bipolar disorder (characterized by alternating states of mania and depression) while those exhibiting above average MAO activity levels have an increased susceptibility to develop depression4,5. This is however only partly consistent with the amine hypothesis and does not explain why bipolar patients, who have below-average MAO activity levels should experience bouts of depression but this may suggest that other factors are working4.
MAO is found in all tissues in the body but there are two isoenzymes in the brain, MAO-A and MAO-B. MAO-B is also found in blood platelets and its activity has often been assumed to reflect changes in brain MAO activity since platelet MAO activity appears to correlate well with concentrations of 5-hydroxyindoleacetic acid (5-HIAA; a serotonin metabolite) in the cerebrospinal fluid (CSF)4,6. As a result, platelet MAO activity is often used in studies of individuals with affective disorders, and indeed, high platelet MAO activity has been found in cases of mania and low MAO activity in cases of unipolar depression6.
1.2 MAO Deficiency
As mentioned above, bipolar disorder is associated with an excess of certain amine neurotransmitters at important aminergic synapses within the brain and patients often exhibit below-average MAO activity1,4,5,6. Furthermore, certain polymorphisms of the MAO gene variants are associated with an increased risk of developing bipolar disorder1, 2. The genetics and enzymatic properties of the different MAO subtypes found in the brain are discussed below particularly in relation is bipolar disorder and decreased activity levels.
1.2a Genetics
Family and twin studies suggest that bipolar disorder is familial and heritable and therefore has a genetic component7. The MAO variants found in the brain (MAO-A and MAO-B) are expressed from separate genes located adjacent to each other on the short arm of the X-chromosome and show 70% sequence identity1,2. They also have identical exon-intron organization which suggests that they arose from the same ancestral gene by duplication8. The MAO-A promoter is 0.14kb long and lacks a TATA box while the MAO-B promoter is 0.15kb long and both are GC-rich9. The two genes differ in the organization of transcription factor binding sites which may contribute to their differential expression patterns9. Furthermore, the MAO-A and MAO-B genes are arranged in a tail-to-tail configuration with the 3’-coding sequences about 50kb apart1.
Several MAO-A gene variants have been studied as potential risk factors for bipolar disorder, among other psychiatric disorders such as schizophrenia, and include a dinucleotide repeat polymorphism in intron two, a 23 base pair variable number tandem repeat (VNTR) near exon one, two different restriction fragment length polymorphisms (Fnu4HI and EcoRV), and a 30 base pair VNTR located 1.2kb upstream of the transcription initiation site1. The latter 30-bp repeat is found in 2, 3, 3.5, 4, 5 or 6 copies of which the 4 copy polymorphism (4R variant) has shown a moderate overtransmission among bipolar patients (and also among patients with panic disorder)1,2. Interestingly, in luciferase reporter assays, this polymorphism (as well as that with 3.5 copies) appeared to be 2-10 times more active than the 3 copy polymorphism2. In addition to this increased transcriptional efficiency, the 4R variant has also been associated with higher enzymatic activity levels and is also prevalent in patients with major depression1,8. Furthermore, the 3R variant has been associated with an increased risk of certain behavioral traits seen in bipolar disorder such as impulsive aggressiveness1. Still other studies have found no significant difference in brain MAO-A catalytic activity between carriers of the 3R and 4R variants1. Since many environmental factors are known to affect MAO-A expression and activity, such as diet, smoking, exercise, stress, and aging, carriers of particular polymorphic variants likely only carry a predisposition for particular mood extremes1. Furthermore, a G to T substitution at position 941 of MAO-A has also been associated with increased risk of bipolar disorder2. Additionally, several other genes that are associated with schizophrenia are also associated with bipolar disorder including catechol-O-methyl transferase (COMT; which acts in concert with MAO in the breakdown of catecholamine neurotransmitters) and neurlegulin (NRG1)1,7.
The best characterized MAO-B variant is an A to G substitution in intron 131. The A allele has been associated with a lower catalytic activity in platelets and although a mild association exists with Parkinson’s disease, many studies have failed to find a connection of either polymorphism with disease1. Still several other MAO-B polymorphic variants have been linked to negative emotionality and attention-deficit hyperactivity disorder (ADHD)1.
1.2b Isoenzymes
While MAO-A gene variants have been linked to bipolar disorder (see above), MAO-B activity has also been associated with many neurological and psychiatric disorders, including bipolar disorder, and is also the isoenzymes whose activity level is often measured in blood platelets6,9. Furthermore, MAO-B may act in combination with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) to play a role in alcoholism9. The MAO-A and MAO-B variants, although they share 70% sequence identity, have different, yet overlapping substrate specificities and inhibitor sensities9. They also show differential anatomical distribution1,2,9. For instance, within the CNS, MAO-A is predominantly found in catecholaminergic neurons while MAO-B is preferentially found in serotonergic and dopaminergic neruons9. Additionally, MAO-A preferentially oxidises 5-HT, norepinephrine (NE), and epinephrine and is inhibited irreversibly by clorgyline at low doses1,9. MAO-B, on the other hand, oxidises PEA preferentially and is inhibited by low doses of deprenyl1,9. The degradation of DA and tryptamine, on the other hand, appears to be mediated by both variants1. Both variants are anchored in the mitochondrial outer membrane in dimeric form by a carboxy-terminal transmembrane helix1.
MAO-B is the variant expressed in platelets which are a readily available source of MAO for study and since it is considered a reliable measure of brain MAO activity (see The Amine Hypothesis) it is often used in both clinical and experimental settings6.
1.3 Endophenotypes
Knockout studies in mice have shown have shown that MAO-B deficiency results in reduced anxiety, increased novelty-seeking, and behavioral disinhibition1. The main substrate of MAO-B, PEA, is regarded as an endogenous amphetamine exhibiting effects which include alertness, euphoria, insomnia, and tremor1. PEA has also been associated with the pathophysiology of schizophrenia, among other psychiatric disorders1. MAO-B inhibitors (such as selegiline) exhibit mood-enhancing effects1. MAO inhibitors were used for their antidepressant properties long before it was discovered that this property is due to increases of 5-HT concentrations at serotonergic synapses (these are MAO-A inhibitors)1. MAO-A knockout mice show increased aggressiveness and enhanced exploratory activity, but they also show decreased defensive behaviours and risk-assessment postures (simultaneous decreased avoidance or fear-related behaviours and increased approach or exploratory activity)1. Additionally, they show exaggerated freezing responses to relatively minor stressors with no subsequent defensive behaviors1. MAO levels can be affected be a number of other factors including aging which tends to result in an increase of MAO activity which has been suggested to contribute to the increased frequency of depression in the elderly1.
1.4 Treatments and Future Perspectives
The most common treatment for bipolar disorder is lithium which has shown to have mood stabilizing effects1,4,10. This treatment however does not affect MAO but rather enters cells through Na+ channels and affects a wide range of second messenger systems (cAMP and phosphoinositol pathways) and neurotransmitter systems including the amine neurotransmitters implicated in bipolar disorder 5-HT and DA11. Other treatments for bipolar disorder include everything from pharmacological treatments (mood stabilizers, antidepressants, neuroleptics, carbamazepine, etc.) and electro-convulsive therapy to psychosocial interventions such as cognitive behavioral therapy, compliance therapy and mood monitoring10. Treatments which specifically target MAO, namely MAO inhibitors, are used most often for individuals with major depression (exhibiting above-average MAO activity levels) and have even been shown to enhance the onset of bipolar disorder in patients who have been previously misdiagnosed with major depression9. Specifically, MAO-A inhibitors have antidepressant effects while MAO-B inhibitors have widely been used in the treatment of Parkinson’s Disease and shows neuroprotective effects9.
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