Monoamine oxidase: from genes to behavior

Abstract

Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders.

Figure 1

Partial structural map of the monoamine oxidase (MAO) A and B genes showing the location of exons. (Filled bars) Coding regions; (unfilled bars) untranslated regions of the exons. Exon numbers are below the bars. (horizontal arrows) The regions sequenced; (vertical arrows) equivocal assignment of an exon to either restriction fragment. The prefix “λ,” λ bacteriophage clones; the prefix “p,” pUC19 subclones of λ phage DNA; E, EcoRI restriction site; H, HindIII restriction site;//, intron gap. (From Grimsby et al 1991.)

Figure 2

Clorgyline and deprenyl inhibition of (A) trout monoamine oxidase (T-MAO) (open triangles, open squares) and human (H) MAO (closed triangles, closed squares) activity expressed in COS cells using serotonin (5-HT) (100 mM) as the substrate, and of (B) T-MAO (open triangles, open squares) and H-MAO (closed triangles, closed squares) activity expressed in COS cells using phenylethylamine (PEA) (10 mM) as the substrate. (Triangles) Clorgyline; (squares) deprenyl. (From Chen et al 1994.)

Figure 3

Concentration of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) in whole brains from wild-type and monoamine oxidase (MAO) A–deficient mice. Concentrations are in picomoles per milligram (wet weight) of brain and represent the mean plus or minus the standard error of the mean. For 5-HT, n = 4 in wild-type and n = 5 in MAO A knock-out (KO) mice; NE, n = 2 in wild-type and n = 2 in MAO A KO mice; DA, n = 4 in wild-type and MAO A KO mice. (From Cases et al 1995.)

Figure 4

Histogram showing the level of dopamine (DA) in the striatum of wild-type and monoamine oxidase (MAO) B knock-out (KO) pups after subcutaneous administration of 60 mg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) per kg. Values shown are the mean plus or minus the standard deviation. Saline-treated mice, n = 10; MPTP-treated mice, n = 4. P < 0.01 level (t-test). (From Grimsby et al 1997.)