Cellular and synaptic pathophysiology in a rat model of Fragile X syndrome
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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.