Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice

Abstract

The monoamine oxidase isoenzymes (MAOs) A and B play important roles in the homeostasis of monoaminergic neurotransmitters. The combined deficiency of MAO A and B results in significantly elevated levels of serotonin (5-hydroxytryptamine), norepinephrine, dopamine, and β-phenylethylamine; in humans and mice, these neurochemical changes are accompanied by neurodevelopmental perturbations as well as autistic-like responses. Ample evidence indicates that normal levels of monoamines in the hippocampus, amygdala, frontal cortex, and cerebellum are required for the integrity of learning and memory. Thus, in the present study, the cognitive status of MAO A/B knockout (KO) mice was examined with a wide array of behavioral tests. In comparison with male wild-type littermates, MAO A/B KO mice exhibited abnormally high and overgeneralized fear conditioning and enhanced eye-blink conditioning. These alterations were accompanied by significant increases in hippocampal long-term potentiation and alterations in the relative expression of NMDA glutamate receptor subunits. Our data suggest that chronic elevations of monoamines, because of the absence of MAO A and MAO B, cause functional alterations that are accompanied with changes in the cellular mechanisms underlying learning and memory. The characteristics exhibited by MAO A/B KO mice highlight the potential of these animals as a useful tool to provide further insight into the molecular bases of disorders associated with abnormal monoaminergic profiles.adult neurogenesis | autism-spectrum disorder | cognition M onoaminergic neurotransmitters, such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA), are known to play a critical role in the modulation of mood and emotion, as well as the control of motor, perceptual, and other cognitive functions (1). Abnormal levels of these monoamines have been associated with several neuropsychiatric disorders (2-5). The enzymatic metabolism of these neurotransmitters is mainly catalyzed by monoamine oxidase (MAO), a mitochondrial-bound flavoprotein (6). The two MAO isoenzymes, A and B, are encoded by different genes next to each other on the X chromosome (7), with 70% amino acid identity (8) and identical intron-exon organization (9). MAO A has a higher affinity for 5-HT, NE, and DA (6, 10). In contrast, MAO B prefers phenylethylamine (PEA) as substrate (11), although it can degrade 5-HT, NE, and DA in the absence of MAO A (12). As a consequence, the lack of both isoenzymes in mice results in significantly higher monoamine levels than those observed in single knockout (KO) counterparts (12). The deficiency of both MAO isoenzymes in humans has been found to be associated with severe intellectual and developmental disabilities, hypotonia, failure to thrive, and autisticlike symptoms (including sociocommunicative deficits and perseverative manifestations) (13-15). Although similar alterations were also featured by MAO A KO mice, the severity of the changes was typically more pervasive in MAO A/B KO mice, supporting the idea that the se...

Association study of MiRSNPs with schizophrenia, tardive dyskinesia and cognition

“…Knock down of this gene in basal forebrain region in rats induces cognitive impairments without seizure (Bender et al, 2013). As for MAOB , an important gene from the dopaminergic pathway, animal studies have reported its role in various cognitive functions (Singh et al, 2013). SYN2 codes for neuronal phosphoproteins associated with the cytoplasmic surface of synaptic vesicles, and are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases (Lee et al, 2005).…”

Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau45-230 transgenic mice

“…However, it is possible that the up-regulation of NMDA receptors could mediate such effects. This seems the case in monoamine oxidase A and B knockout mice which present similar NMDA receptor content and behavioral changes as the mutant mice expressing tau 45-230 (Singh et al, 2013). Regardless of the mechanisms, these results suggest that tau 45-230 could induce at least some of the behavioral disturbances observed in AD and related disorders.…”

Emergence in extinction of enhanced and persistent responding to ambiguous aversive cues is associated with high MAOA activity in the prelimbic cortex

“…Previous studies with MAOA/B knockout mice using perfect predictors found heightened fear conditioning (Kim et al., 1997, Singh et al., 2013). In parallel, previous fear cue ambiguity research considering extinction of recent conditioning has shown that serotonin transporter (5HTT)-overexpressing mice presented less freezing to uncertain outcome (20% cue contingency, McHugh et al., 2015) and conversely Htr1a knockout mice exhibited selectively more freezing to ambiguous cues (Klemenhagen et al., 2006), and like here to partially contingent cues, but no difference to perfectly contingent fear cue conditioning (Tsetsenis et al., 2007).…”

“…Mice selectively bred for high fear conditioning were shown to display abnormal developmental expression of mitochondrial genes, including MAO, in the prefrontal cortex (Choi et al., 2012). Conversely, genetic deletion studies revealed that MAO-A or -A/B deficient mice present amplified and less specific fear acquisition, while displaying normal spatial memory and motor abilities (Kim et al., 1997, Singh et al., 2013). In humans, studies of genetic variability of MAOA has revealed association with personality patterns (Shiraishi et al., 2006, Tsuchimine et al., 2008).…”