1. MAO is an enzyme that catalyzes the oxidative deamination of biogenic amines in the brain and peripheral tissues. There are two subtypes, MAO-A and MAO-B, which have different substrate preferences and tissue localizations. 2. Studies have shown associations between MAO-A and behaviors like aggression, as well as neurological conditions like Parkinson's disease. The gut microbiota may also impact brain health and behaviors through several mechanisms. 3. There are indications that MAO and the gut microbiota could be interconnected based on their relationships to stress, behaviors, and certain disorders. MAO-A may interact with tryptophan derivatives produced by gut bacteria, suggesting a direct brain

1. MAO
Mono Amine Oxidase
Aindrila Saha

2. Background Study 1
What is MAO? Localization of MAO in different
species and parts of the body, Substrates, Role of
MAO

3. What is MAO?
-Flavin containing mono-amine oxidases. First identified in
-Two subtypes- MAO-A and MAO-B.
-Catalyzes oxidative deamination of number of biogenic amines in the brain and
peripheral tissue by production of hydrogen peroxide.
-Localization and Distribution: Shows species variation, variable distribution in
tissue specific manner as well. It is primarily expressed on the surface of the
mitochondrial membrane.
-MAO genes: MAO-A and MAO-B genes located at adjacent sites to Xp11.23
chromosome. (Norrie disease)

4. Distribution:
-Localizations have been studied by immunohistochemistry, enzyme
autoradiography, in situ hybridisation.
- MAO-A : Catecholergic Neurons
-MAO-B : Serotonergic+Histaminergic neurons and glial cells
-In brain, highest MAO-A concentration is at locus coerulus. Highest MAO-B
concentration is at Raphe Nucleus.
-MAO-A is found in some tissues like human platelets and bovine liver and kidney.
-MAO-B is found in some tissue like human placenta and bovine thyroid.

5. Source: MONOAMINE OXIDASE: From Genes to Behavior, J. C. Shih, K. Chen, and M. J. Ridd

6. Substrates:
1. MAO-A: Serotonin (5-HT), Melatonin, Epinephrin and Nor-epinephrine.
2. MAO-B: Phenylethylamine(PEA) and Benzylamine.
3. Both show equal affinity towards Dopamine, Tyramine, Tryptamine.

7. Melatonin synthesis, breakdown and effects

9. MAO-A and aggressive behavior:
1. McDermott, R., Tingley, D., Cowden, J., Frazzetto, G., and Johnson, D.D.P. (2009). Monoamine
oxidase A gene (MAOA) predicts behavioral aggression following provocation. PNAS 106,
2118–2123. (!!!!!!)
2. Cases, O., Seif, I., Grimsby, J., Gaspar, P., Chen, K., Pournin, S., Müller, U., Aguet, M., Babinet, C.,
Shih, J.C., et al. (1995). Aggressive Behavior and Altered Amounts of Brain Serotonin and
Norepinephrine in Mice Lacking MAOA. Science 268, 1763–1766.
3. Cases, O., Vitalis, T., Seif, I., De Maeyer, E., Sotelo, C., and Gaspar, P. (1996). Lack of barrels in
the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during
the critical period. Neuron 16, 297–307.
4. Holschneider, D.P., Chen, K., Seif, I., and Shih, J.C. (2001). Biochemical, behavioral, physiologic,
and neurodevelopmental changes in mice deficient in monoamine oxidase A or B. Brain Res Bull
56, 453–462.
5. Shih, J.C., Chen, K., and Ridd, M.J. (1999). Monoamine oxidase: from genes to behavior. Annu.
Rev. Neurosci. 22, 197–217.

10. Parkinson’s disease and association with MAO-B

11. Role in Stress related disorders:
-MAO-A inhibitors are used as
common anti-depressants and also
helps patients with panic attacks.
-MAO-A and MAO-B KO mice
showed increased stress in
Forced Swim test.

12. MAO in cigarette smokers and alcohol addicts
-Reduced MAO-A activity in cigarette smokers.
-Nicotine increases MAO-B activity. (Possible
trigger for Parkinsons or Alzheimers?)
-Reduced MAO-B activity in alcoholics.

13. Changes of MAO A KO Mice Compared To Wild-type Mice
Biochemical
No enzymatic MAO A activity, protein or MAO A mRNA in brain and peripheral tissues
Normal levels of MAO B in brain and peripheral tissues
Increased levels of 5-HT, NE in whole brain, hippocampus, frontal cortex, and cerebellum
Decreased tissue levels of the 5-HT metabolite 5-HIAA
Downregulation of brain postsynaptic 5-HT1A
, 5-HT2A
, 5-HT2C
receptors and the vesicular monoamine
transporter (VMAT2)
Neurodevelopmental
Abnormal development of somatosensory thalamocortical afferent fibers
Abnormal segregation of retinal afferents to the dorsal lateral geniculate nucleus, as well as to the
superior colliculus
Atypical locations of 5-HT during embryonic and postnatal development
Abnormal activity and morphology of phrenic motoneurons in neonates
Transient delay of locomotor network maturation

14. Changes of MAO A KO Mice Compared To Wild-type Mice
Behavioral: Neonatal
Prolonged righting, trembling upon locomotion, and hunched posture, Frantic running and falling over, jumping, or prompt digging to
hide under woodshavings in response to moderate sound and movement, Prolonged and stronger reactions to pinching, Propensity
to bite the experimenter, Sleep accompanied by violent shaking and jumps
Adult
Normal nesting, nursing, and pup-retrieval behavior in females
Increased territorial aggression in the resident-intruder paradigm, increased bite wounds in male, group-housed mice
Decreased social investigative behavior in males in the resident-intruder paradigm with static, hunched, fluffed-fur posture after
first olfactory stimulus.
Increased sensitivity to developing the serotonin syndrome with fenfluramine challenge
Behavioral syndrome characterized by restlessness, attentional deficits, disrupted social interaction, feeding and self-grooming
after administration of the MAO B inhibitors L-deprenyl or lazabemide
Enhancement of classical fear conditioning and step-down inhibitory avoidance learning (emotional memory) but not of eyeblink
conditioning (motor learning)
Increased mobility in the Porsolt Forced Swim Test
Increased time spent in the center in the Open Field test with much hesitation as to which direction to take
Abnormal walking on a balance-beam with adults grasping the lateral aspects of the beam with hindlimbs during movement
Altered courtship with increased grasping events in males and concurrent increased frequency and intensity of vocalization in
females.

15. Changes of MAO B KO Mice Compared To Wild-type Mice
Biochemical
No enzymatic MAO B activity, protein or MAO B mRNA in brain and peripheral tissues
Normal levels of MAO A in brain and peripheral tissues
Increased levels of PEA in whole brain
Increased urinary excretion of PEA
Normal levels of 5-HT, NE, DA, 5-HIAA, DOPAC, HVA in cortex, hippocampus, raphe nucleus, substantia nigra, thalamus
Normal levels of extracellular DA, DOPAC, 3-MT, HVA in striatum, but elevated DA levels after administration of high dose L-DOPA
Functional supersensitivity of D1
-like dopamine receptors in the nucleus accumbens
Normal density of D1
-like receptors and normal tyrosine hydroxylase immunoreactivity in striatum, nucleus accumbens, and olfactory
tubercle
Up-regulation of the D2
-like dopamine receptors in the striatum and nucleus accumbers shell, but not in substantia nigra, and ventral
tegmental area
Behavioral: Adult
No increase in aggressive behavior
Normal visual-spatial learning in adult and in aged animals in the Morris Water Maze
Intact working memory as tested in a Y-maze
Increased mobility in the Porsolt Forced Swim Test
Normal response in the Elevated Plus-Maze
Normal exploratory activity in the Open Field

16. Background Study 2
Gut microbiota - Gut brain axis?

17. Effect of Gut Microbiota on Brain Health:
1. LPS provide low grade innate immune response -CNS inflammation.
2. Bacterial proteins + Human antigens → Adaptive immune response
3. Neurotoxicity due to some harmful bacterial metabolites.
4. Synthesis of Hormones and NTs
5. Direct relation between ANS and the Vagus nerve
6. Effect on circadian rhythm.
7. Effect on stress response of HPA axis.
8. Effect on memory, mood, cognition disorders.

18. Behavior pattern and stress: Gutmicrobiota?
1. More vigilant activity in GF mice: More stress? Similar results in mice treated
with non absorbed antibiotics for 7 days. Correlation between stress levels
and the gut microbiota.
2. Specific behavior induced by specific microbiota.
Balbe/C is more susceptible to stressors and CRH than NIH swiss mice.
GF NIH Swiss mice + Balbe/C microbiome → Balbe/C like responses to stressors.
GF Balbe/C mice + NIH Swiss mice microbiome → NIH Swiss Responses to
stressors.

19. Gut Microbiota eating Brain Chemicals?
KLE1738 , a gut bacteria grows on GABA. → Low levels of GABA → depression
and mood disorder.
Gut microbiota affecting brain?
Can it suggest the reverse?
Can this mechanism be used to treat depression and mood disorders?
What are the other bacteria that depends on neurosecretory materials for their
survival?
Altering brain metabolites/ neurosecretory materials can alter the gut microbiota?

20. Finally, connecting the dots!
MAO and Gut Microbiota

21. MAO and Gut Microbiota
1. MAO-A and B are closely associated with stress, behavioral disorders,
neuropathies, immunological disorders, neurodegenerative disorders
(Parkinson’s , Alzheimer’s). These disorders are also shown to have some
form of correlation between the species and population of bacteria residing in
the gut. Can this suggest that the two are inter-linked and are somehow
regulating major physiological functions?
2. Can MAO-A be acting on any of the Tryptophan derivatives produced as
metabolites by some of the Gut Microbiota? Can this interaction essentially
confirm a direct connection between the brain and the gut?

22. Plausible Approaches
What I want to do and how?

23. Timeline of work
Coming soon!