Altered cerebellar organization and function in monoamine oxidase A hypomorphic mice

Alzghoul, Loai; Bortolato, Marco; Delis, Foteini; Thanos, Panayotis K.; Darling, Ryan D.; Godar, Sean C.; Zhang, Junlin; Grant, Samuel C.; Wang, Gene‐Jack; Simpson, Kate; Chen, Kevin; Volkow, Nora D.; Lin, Rick C.S.; Shih, Jean C.

doi:10.1016/j.neuropharm.2012.08.003

Cited by 12 publications

(6 citation statements)

References 91 publications

(107 reference statements)

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“…Similar to Maoa KO mice, Maoa Neo mice display impairments in social behavior, as well as communication deficits and perseverative behaviors (Bortolato et al, 2011 and unpublished data). In addition, we found that these animals feature alterations in their cerebellar morphology (Alzghoul et al, 2012) reminiscent of abnormalities documented in autism-spectrum disorder patients. In contrast with KO mice, however, their Maoa Neo counterparts display no spontaneous aggression, affording a unique experimental platform to test the effects of early adversities on the development of this trait.…”

Section: Role Of Maoa Allelic Variants In the Ontogeny Of Aggressionmentioning

confidence: 59%

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

Godar

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McFarlin

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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Drawing upon the recent resurgence of biological criminology, several studies have highlighted a critical role for genetic factors in the ontogeny of antisocial and violent conduct. In particular, converging lines of evidence have documented that these maladaptive manifestations of aggression are influenced by monoamine oxidase A (MAOA), the enzyme that catalyzes the degradation of brain serotonin, norepinephrine and dopamine. The interest on the link between MAOA and aggression was originally sparked by Han Brunner’s discovery of a syndrome characterized by marked antisocial behaviors in male carriers of a nonsense mutation of this gene. Subsequent studies showed that MAOA allelic variants associated with low enzyme activity moderate the impact of early-life maltreatment on aggression propensity. In spite of overwhelming evidence pointing to the relationship between MAOA and aggression, the neurobiological substrates of this link remain surprisingly elusive; very little is also known about the interventions that may reduce the severity of pathological aggression in genetically predisposed subjects. Animal models offer a unique experimental tool to investigate these issues; in particular, several lines of transgenic mice harboring total or partial loss-of-function Maoa mutations have been shown to recapitulate numerous psychological and neurofunctional endophenotypes observed in humans. This review summarizes the current knowledge on the link between MAOA and aggression; in particular, we will emphasize how an integrated translational strategy coordinating clinical and preclinical research may prove critical to elucidate important aspects of the pathophysiology of aggression, and identify potential targets for its diagnosis, prevention and treatment.

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Section: Role Of Maoa Allelic Variants In the Ontogeny Of Aggressionmentioning

confidence: 59%

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

Godar

Fite

McFarlin

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…Similarly, early exposure of rats to MAO inhibitors (both MAO-A and B), throughout development has been shown to produce increase in impulsivity, stereotypic behavior and seizures (Whitaker-Azmitia et al 1994). Further, altered cerebellar organization and function has been reported in MAO A hypomorphic mice (Alzghoul et al 2012). On a similar line, rats exposed prenatally to the serotonin reuptake inhibitor cocaine show less interactions in social interaction tasks as juveniles and adults and exhibit impaired ability to sustain attention (Overstreet et al 2000; Gendle et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Lasting neurobehavioral abnormalities in rats after neonatal activation of serotonin 1A and 1B receptors: possible mechanisms for serotonin dysfunction in autistic spectrum disorders

et al. 2013

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Rationale Perinatal exposure of rats to selective serotonin reuptake inhibitors (SSRIs) produces sensory and social abnormalities paralleling those seen in Autistic Spectrum Disorders (ASD). However, the possible mechanism(s) by which this exposure produces behavioral abnormalities is unclear. Objective We hypothesized that the lasting effects of neonatal SSRI exposure are a consequence of abnormal stimulation of 5-HT1A and/or 5-HT1B receptors during brain development. We examined whether such stimulation would result in lasting sensory and social deficits in rats in a manner similar to SSRIs using both direct agonist stimulation of receptors as well as selective antagonism of these receptors during SSRI exposure. Methods Male and female rat pups were treated from postnatal day 8 to 21. In Experiment 1, pups received citalopram (20mg/kg/d), saline, 8-OH-DPAT (0.5 mg/kg/d) or CGS-12066B (10 mg/kg/d). In Experiment 2, a separate cohort of pups received an citalopram (20 mg/kg/d), or saline which was combined with either WAY-100635 (0.6 mg/kg/d) or GR-127935 (6 mg/kg/d) or vehicle. Rats were then tested in paradigms designed to assess sensory and social response behaviors at different time points during development. Results Direct and indirect neonatal stimulation of 5-HT1A or 5-HT1B receptors disrupts sensory processing, produces neophobia, increases stereotypic activity, and impairs social interactions in manner analogous to that observed in ASD. Conclusion Increased stimulation of 5-HT1A and 5-HT1B receptors plays a significant role in the production of lasting social and sensory deficits in adult animals exposed as neonates to SSRIs.

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“…Cerebellum has been implicated in catecholaminergic dysfunction. Mice generated with decreased levels of monoamine oxidase A (MAO-A), an enzyme integral to maintaining normal catecholamine levels, exhibit smaller cerebellums, decreased Purkinje cell count and dendritic density, and vermal hypoplasia (Alzghoul et al, 2012 ). MAO-A/B knockout mice also show enhanced eye-blink conditioning, which depends on cerebellar integrity, suggesting another critical cerebellar process contingent on catecholaminergic signaling (Singh et al, 2013 ).…”

Section: Discussionmentioning

confidence: 99%

The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults

Kline

Zhang

Farr

et al. 2016

Front. Hum. Neurosci.

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Background: Methylphenidate (MPH) influences catecholaminergic signaling. Extant work examined the effects of MPH on the neural circuits of attention and cognitive control, but few studies have investigated the effect of MPH on the brain's resting-state functional connectivity (rsFC).Methods: In this observational study, we compared rsFC of a group of 24 healthy adults who were administered an oral 45 mg dose of MPH with a group of 24 age and gender matched controls who did not receive MPH. We focused on three seed regions: basal nucleus of Meynert (BNM), locus coeruleus (LC), and ventral tegmental area/substantia nigra, pars compacta (VTA/SNc), each providing cholinergic, noradrenergic and dopaminergic inputs to the cerebral cortex. Images were pre-processed and analyzed as in our recent work (Li et al., 2014; Zhang et al., 2015). We used one-sample t-test to characterize group-specific rsFC of each seed region and two-sample t-test to compare rsFC between groups.Results: MPH reversed negative connectivity between BNM and precentral gyri. MPH reduced positive connectivity between LC and cerebellum, and induced positive connectivity between LC and right hippocampus. MPH decreased positive VTA/SNc connectivity to the cerebellum and putamen, and reduced negative connectivity to left middle occipital gyrus.Conclusion: MPH had distinct effects on the rsFC of BNM, LC, and VTA/SNc in healthy adults. These new findings may further our understanding of the role of catecholaminergic signaling in Attention Deficit Hyperactivity Disorder (ADHD) and Parkinson's disease and provide insights into the therapeutic mechanisms of MPH in the treatment of clinical conditions that implicate catecholaminergic dysfunction.

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Altered cerebellar organization and function in monoamine oxidase A hypomorphic mice

Cited by 12 publications

References 91 publications

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

Lasting neurobehavioral abnormalities in rats after neonatal activation of serotonin 1A and 1B receptors: possible mechanisms for serotonin dysfunction in autistic spectrum disorders

The Effects of Methylphenidate on Resting-State Functional Connectivity of the Basal Nucleus of Meynert, Locus Coeruleus, and Ventral Tegmental Area in Healthy Adults

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