Chronic minocycline treatment improves hippocampal neuronal structure, NMDA receptor function, and memory processing in Fmr1 knockout mice

Yau, Suk-Yu; Bettio, Luis E.B.; Vetrici, Mariana; Truesdell, Aaron; Chiu, Christine L; Chiu, Jason; Truesdell, E.; Christie, Brian R.

doi:10.1016/j.nbd.2018.01.014

Cited by 24 publications

(22 citation statements)

References 54 publications

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“…Since our study shows that these mice display abnormalities in visual perception, we investigated the link between visual perception and the achievement of a cognitive task commonly used in laboratories, the NOR test. However, since Fmr1 −/y mice present an impaired recognition memory, as widely described in the literature (Ventura et al, 2004; Pardo et al, 2017; Yan et al, 2018; Yau et al, 2018), the study of the involvement of vision in this type of test can only be based on the behavior of WT mice.…”

Section: Discussionmentioning

confidence: 99%

Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

Felgerolle

Hébert

Ardourel

et al. 2019

Front. Behav. Neurosci.

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Fragile X Syndrome (FXS), the most common inherited form of human intellectual disability (ID) associated with autistic-like behaviors, is characterized by dys-sensitivity to sensory stimuli, especially vision. In the absence of Fragile Mental Retardation Protein (FMRP), both retinal and cerebral structures of the visual pathway are impaired, suggesting that perception and integration of visual stimuli are altered. However, behavioral consequences of these defects remain unknown. In this study, we used male Fmr1−/y mice to further define visual disturbances from a behavioral perspective by focusing on three traits characterizing visual modality: perception of depth, contrasts and movements. We performed specific tests (Optomotor Drum, Visual Cliff) to evaluate these visual modalities, their evolution from youth to adulthood, and to assess their involvement in a cognitive task. We show that Fmr1−/y mice exhibit alteration in their visual skills, displaying impaired perspective perception, a drop in their ability to understand a moving contrasted pattern, and a defect in contrasts discrimination. Interestingly, Fmr1−/y phenotypes remain stable over time from adolescence to late adulthood. Besides, we report that color and shape are meaningful for the achievement of a cognitive test involving object recognition. Altogether, these results underline the significance of visual behavior alterations in FXS conditions and relevance of assessing visual skills in neuropsychiatric models before performing behavioral tasks, such as cognitive assessments, that involve visual discrimination.

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Section: Discussionmentioning

confidence: 99%

Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

Felgerolle

Hébert

Ardourel

et al. 2019

Front. Behav. Neurosci.

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“…As genetic deletion of MMP-9 can also reverse FXS-associated behaviors in Fmr1 KO mice ( Bilousova et al., 2009 ; Sidhu et al., 2014 ), MMP-9 is an attractive therapeutic target to reduce sensory deficits in FXS and potentially other FXS-associated behaviors. Indeed, minocycline, which beside its antibiotic effects inhibits MMP-9, has emerged as a potential treatment for FXS ( Bilousova et al., 2009 ; Paribello et al., 2010 ; Dansie et al., 2013 ; Dziembowska et al., 2013 ; Leigh et al., 2013 ; Schneider et al., 2013 ; Rotschafer & Razak, 2014 ; Yau et al., 2018 ). In humans with FXS, minocycline can reduce MMP-9 levels, reverse auditory ERP deficits, and improve FXS-associated behaviors ( Paribello et al., 2010 ; Dziembowska et al., 2013 ; Leigh et al., 2013 ; Schneider et al., 2013 ).…”

Section: Auditory Hypersensitivity and Underlying Mechanismsmentioning

confidence: 99%

Sensory Processing Phenotypes in Fragile X Syndrome

et al. 2018

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Fragile X syndrome (FXS) is a neurodevelopmental disorder that causes intellectual disability. It is a leading known genetic cause of autism. In addition to cognitive, social, and communication deficits, humans with FXS demonstrate abnormal sensory processing including sensory hypersensitivity. Sensory hypersensitivity commonly manifests as auditory, tactile, or visual defensiveness or avoidance. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity, impaired habituation to repeated sounds, and reduced auditory attention in humans with FXS. Children with FXS also exhibit significant visuospatial impairments. Studies in infants and toddlers with FXS have documented impairments in processing texture-defined motion stimuli, temporal flicker, perceiving ordinal numerical sequence, and the ability to maintain the identity of dynamic object information during occlusion. Consistent with the observations in humans with FXS, fragile X mental retardation 1 (Fmr1) gene knockout (KO) rodent models of FXS also show seizures, abnormal visual-evoked responses, auditory hypersensitivity, and abnormal processing at multiple levels of the auditory system, including altered acoustic startle responses. Among other sensory symptoms, individuals with FXS exhibit tactile defensiveness. Fmr1 KO mice also show impaired encoding of tactile stimulation frequency and larger size of receptive fields in the somatosensory cortex. Since sensory deficits are relatively more tractable from circuit mechanisms and developmental perspectives than more complex social behaviors, the focus of this review is on clinical, functional, and structural studies that outline the auditory, visual, and somatosensory processing deficits in FXS. The similarities in sensory phenotypes between humans with FXS and animal models suggest a likely conservation of basic sensory processing circuits across species and may provide a translational platform to not just develop biomarkers but also to understand underlying mechanisms. We argue that preclinical studies in animal models of FXS can facilitate the ongoing search for new therapeutic approaches in FXS by understanding mechanisms of basic sensory processing circuits and behaviors that are conserved across species.

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“…The time spent immobile during the last 4 min of the testing session was scored by an observer blind to the treatment conditions and presented as an indicator for depression-like behavior. Immobility was defined as any movement beyond what was needed to keep the head above the water (Yau et al, 2014, 2018).…”

Section: Methodsmentioning

confidence: 99%

Effects of Maternal Voluntary Wheel Running During Pregnancy on Adult Hippocampal Neurogenesis, Temporal Order Memory, and Depression-Like Behavior in Adult Female and Male Offspring

et al. 2019

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Research suggests that maternal exercise in pregnancy may have beneficial effects on the brain function of offspring. This study sought to determine if voluntary wheel running during pregnancy improves depression-like behavior, temporal order memory, and hippocampal neurogenesis in both female and male offspring mice. Pregnant mice were allowed to run voluntarily by introducing running wheels into the housing cages throughout the gestational period. Male and female mice offspring at the age of 8- to 9-week-old were then tested on the temporal order task and forced swim test, then euthanized for immunostaining for examining adult hippocampal cell proliferation and neuronal differentiation. Results showed that both male and female pups had reduced depression-like behavior, while only male offspring demonstrated improvement in temporal order memory. Immunostaining revealed that male offspring showed an increase in the number of immature neurons in the ventral hippocampus, whereas female offspring showed enhanced cell proliferation in the dorsal hippocampus. These findings indicate that maternal voluntary wheel running benefits both female and male offspring on reducing depression-like behavior, but with gender effect on promoting hippocampal cell proliferation, neuronal differentiation, and temporal order memory.

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Chronic minocycline treatment improves hippocampal neuronal structure, NMDA receptor function, and memory processing in Fmr1 knockout mice

Cited by 24 publications

References 54 publications

Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

Visual Behavior Impairments as an Aberrant Sensory Processing in the Mouse Model of Fragile X Syndrome

Sensory Processing Phenotypes in Fragile X Syndrome

Effects of Maternal Voluntary Wheel Running During Pregnancy on Adult Hippocampal Neurogenesis, Temporal Order Memory, and Depression-Like Behavior in Adult Female and Male Offspring

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