Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability as well as a leading genetic cause of autism spectrum disorder. It is typically the result of a trinucleotide repeat expansion in the Fmr1 gene which leads to loss of the encoded protein, fragile X mental retardation protein (FMRP). Animal model studies over the past twenty years, mainly focusing on the Fmr1 knockout (KO) mouse, have uncovered several cellular and behavioural phenotypes associated with the loss of FMRP. Seminal work using the Fmr1 KO mouse found that metabotropic glutamate receptor mediated long-term depression (mGluR-LTD) in the hippocampus is both exaggerated (Huber et al., 2002) and independent of new protein synthesis (Nosyreva & Huber, 2006). These findings, together with studies focusing on other brain regions including the prefrontal cortex (Zhao et al., 2005) and amygdala (Suvrathan et al., 2010), have contributed to the ‘mGluR theory of FXS’ (Bear et al., 2004) which suggests that group 1 metabotropic receptor function is exaggerated in FXS. The development of genetically modified rats allows the modelling of FXS in an animal model with more complex cognitive and social behaviours than has been previously available. It also provides an opportunity for comparison of phenotypes across mammalian species that result from FMRP deletion. While the study of Fmr1 rats can significantly contribute to our understanding of FXS, we must first confirm the assumption that cellular phenotypes are conserved across mouse and rat models. In this thesis, we first aimed to test if the key cellular and synaptic phenotypes that contribute to the ‘mGluR theory of FXS’ are conserved in both the hippocampus and amygdala of Fmr1 KO rats. In agreement with mouse studies, we found mGluR-LTD was both enhanced and independent of new protein synthesis in Fmr1 KO rats. Similarly, group 1 mGluR long-term potentiation (LTP) was significantly decreased at both cortical and thalamic inputs to the lateral amygdala. Secondly, we investigated mPFC intrinsic excitability and synaptic plasticity in Fmr1 KO rats. The mPFC plays a key role in several of the cognitive functions that are affected in fragile X patients including attention, cognitive flexibility and anxiety (Goto et al., 2010). The regulation of mPFC plasticity and intrinsic excitability has also been associated with mGluR signalling. Here we found that intralaminar LTP in the mPFC showed an age-dependent deficit in Fmr1 KO rats. The mPFC also provides top down control of several cortical and subcortical regions through long-range connectivity. One pathway of interest in the study of FXS is mPFC-amygdala connectivity which is associated with fear learning and anxiety behaviours (Burgos- Robles et al., 2009). Using retrograde tracing, we showed layer 5 pyramidal neurons that provide long-range connections to the basal amygdala were intrinsically hypoexcitable in Fmr1 KO rats. This phenotype could possibly be explained through homeostatic changes in the axon initial segment which regulates neuronal excitability. This work provides the first evidence for conservation of cellular phenotypes associated with the loss of FMRP in mice and rats which will be key in the interpretation of future studies using Fmr1 KO rats. We also provide evidence of deficits in mPFC long-range connectivity to the basal amygdala, a pathway that is associated with FXS relevant behaviours. Together this highlights how study of the rat model of FXS can complement existing studies of Fmr1 KO mice as well as provide new insights into the pathophysiology resulting from the loss of FMRP. Some of this work was published in Till et al., 2015.

No description available.

Thesis (Ph.D.)--Brown University, 2008. / Advisor : Mark F. Bear. Includes bibliographical references.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication as well as ritualistic repetitive behaviors. Epidemiological studies suggest that maternal immune activation (MIA) during pregnancy may be a risk factor for ASD. To study MIA in a laboratory setting, we injected mouse dams (C57BL/6) with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly IC) during mid-gestation to mimic a bacterial or viral infection, respectively. We also performed the same Poly IC treatment on a mouse model of Fragile X syndrome (i.e. Fmr1 knockout), a genetic disease with high incidences of ASD. We found modest female-specific impairments in social interaction and striking male-specific increases in repetitive behavior in adult MIA offspring. Moreover, prenatal Poly IC treatment caused genotype-specific deficits in sociability in addition to reduced body weight and rearing in Fmr1 knockout mice only. Therefore, ASD-related behaviors caused by MIA may be sex, treatment, and/or genotype-dependent.

In the present study, performance on a range of mathematical reasoning and number processing tasks was assessed across two syndrome groups for which numerical ability is under-researched: Fragile X syndrome and Down syndrome. Given the paucity of current research, it was unknown whether all aspects of arithmetic and number processing would be globally affected across groups or whether there would be syndrome specific proficiencies and deficiencies. Statistical analysis revealed that males with fragile X syndrome performed significantly worse on all tasks even when performance was compared to typically developing children of a similar developmental level. However, when performance was compared to children with Down syndrome differing profiles emerged, with greater weaknesses by the fragile X syndrome males on specific tasks requiring mental arithmetic and basic numeracy skills. The importance of using syndrome specific information in the assessment of math disabilities and the design of early educational interventions are discussed.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social interaction and communication as well as ritualistic repetitive behaviors. Epidemiological studies suggest that maternal immune activation (MIA) during pregnancy may be a risk factor for ASD. To study MIA in a laboratory setting, we injected mouse dams (C57BL/6) with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (Poly IC) during mid-gestation to mimic a bacterial or viral infection, respectively. We also performed the same Poly IC treatment on a mouse model of Fragile X syndrome (i.e. Fmr1 knockout), a genetic disease with high incidences of ASD. We found modest female-specific impairments in social interaction and striking male-specific increases in repetitive behavior in adult MIA offspring. Moreover, prenatal Poly IC treatment caused genotype-specific deficits in sociability in addition to reduced body weight and rearing in Fmr1 knockout mice only. Therefore, ASD-related behaviors caused by MIA may be sex, treatment, and/or genotype-dependent.

Thesis (M.S.)--University of Wisconsin--Madison, 1984. / Typescript. Title from title screen (viewed July 8, 2008). Includes bibliographical references (p. 70-75). Online version of the print original.

Thesis (M.S.)--University of Wisconsin--Madison, 1984. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 70-75).

archives@tulane.edu / Autism spectrum disorders (ASD) are commonly characterized by abnormal social behaviors. Fragile X syndrome (FXS) is the most common inherited intellectual disability in humans and the most common single-gene cause of ASD symptoms. FXS is caused by the loss or malfunction of the fragile X mental retardation protein (FMRP), an mRNA-binding protein that regulates numerous synaptic proteins, both translationally and through direct protein-protein interactions. One direct-binding target is the large-conductance potassium (BK) channel. BK channels have been shown to be hypoactive in FXS, and represent possible targets for treatment in both general ASD and in FXS specifically. Also, two members of the KCNQ class of voltage-activated potassium channels, KV7.2 and KV7.3, have been identified as FMRP translation targets. Finally, a commonly observed abnormality in the ASD brain is an imbalance in the ratio of excitatory to inhibitory signaling (E/I balance) causing general hyperexcitability in numerous brain areas. One area in which altered E/I balance is often observed is the medial prefrontal cortex (mPFC), which is involved with the processing of social information. Therefore, the goal of this dissertation was to determine if stimulating potassium channel function in the mPFC of Fmr1 KO mice would correct abnormal social behavior. In addition, the possible mechanistic determinants and effects on E/I balance were investigated in WT and Fmr1 KO mice. Infusion of the potassium channel activator, BMS-204352, into the mPFC of KO mice had no effect on social approach behavior, but corrected social novelty impairments as measured by a 3-Chamber Test. Whole-cell patch clamp recordings of pyramidal neurons in layer V of the mPFC revealed no differences in mEPSCs between KO and WT mice, but did reveal higher frequency of mIPSCs in KO mice. Treatment with BMS-204352 resulted in a decrease in mEPSC amplitude in both genotypes, which was blocked by the BK channel antagonist, paxilline. Effects of BMS-204352 treatment on mIPSCs revealed two possible populations of cell types. One population of exhibited a decrease in frequency of mIPSCs, an effect seen in both genotypes. The other population exhibited a slight increase in frequency of mIPSCs, but this was seen only in KO cells. Treatment with paxilline caused a decrease in mIPSC frequency in both genotypes, which was not altered with subsequent BMS-204352 treatment. Pretreatment with the KV7 channel antagonist XE 991 prevented BMS-204352-induced cross-genotype decrease in mIPSC frequency, but did not prevent BMS-204352-induced frequency increase in KO cells. Western blot analyses revealed no changes between genotypes in BK channel expression, but a trend to increased KV7.3 expression in the PFC of KOs compared to WTs. With these data, it was concluded that aberrant activity of potassium channels in the mPFC of KOs mediates some of the social abnormalities observed in the phenotype, that KOs may exhibit increased KV7.3 expression as a potential compensatory mechanism for BK channel dysfunction, and that potassium channels are a promising potential target for future treatment of ASD symptoms / 1 / Ted Sawyer

A research report submitted to the Faculty of Medicine, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the Degree of Master of Science in Medicine. Johannesburg October, 1997 / Fragile X syndrome is, second to Down syndrome, the commonest form of genetic mental retardation. The aim of this research project was to investigate the impact of having a child with this syndrome on the family relationships. The subjects were 21 mothers and 9 fathers of affected children. The data were collected by means of specially constructed questionnaires in interviews with 19 mothers and 8 fathers and completed by post in three cases. A control group of parents with a normal child, matched for sex and age of the affected child, family size and ethnic groups, was interviewed. The data were computerised and analyzed. The results showed that more experimental parents than controls enjoyed their child’s nature, but disliked the behavioural problems. About half of the experimental parents tended not to reward good behaviour physically. However, although most of the affected children were accepted by their siblings, they had fewer friends and more problems with their peers. Some parents thought that their relationship with their spouse had improved and others thought that it had deteriorated after the affected child’s birth. Most parents in both study groups would request prenatal diagnosis in subsequent pregnancies and significantly more experimental parents than controls would request a termination of pregnancy for an affected fetus. Most parents were satisfied with the health service they received. These results show that family dynamics are disturbed by the presence of a child with FMR. Counsellors and therapists working with these families should be aware of the effects of the syndrome on the family / IT2017