Alterations in Synaptic Plasticity in a Mouse Model of Fragile X Syndrome

Fragile X Syndrome (FXS), a form of inherited intellectual disability that is caused by a mutation in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, is commonly studied using the Fmr1 knockout (KO) mouse model. Studies in Fmr1 KO mice have demonstrated altered synaptic plasticity, — dysfunctional up- and down-regulation of synaptic strength — synaptic potentiation and depression, respectively. Early interventions in FXS focussed on metabotropic glutamate receptor (mGluR) long-term depression, which is enhanced in Fmr1 KO mice. However, inhibitors of mGluRs, which normalise FXS phenotypes in pre-clinical models, were unsuccessful in clinical trials. Deficits in N-methyl-D-aspartate receptor (NMDAR) long-term potentiation (LTP) have also been identified in the Fmr1 KO mouse, however there are discrepancies in the literature when it comes to the severity of LTP phenotypes. Meanwhile, NMDAR-dependent short-term potentiation (STP) deficiencies have not been researched in the Fmr1 KO mouse. Chapter 1 describes the background of this thesis, while Chapter 2 details the methods used during the investigations in Chapters 3 – 5. Chapter 3 investigated whether the breeding strategy (termed cage effect) affects LTP, STP, contextual fear conditioning (CFC) and glutamate receptor expression in ten groups of male and female Fmr1 mice, bred and maintained in different ways. Only male non-littermate KO mice had deficits in STP, LTP and CFC. Expression of glutamate receptors was unaffected by genotype, but was strongly influenced by the cage effect in male littermate WT and KO mice. Chapter 4 demonstrated that the LTP deficiency, observed in the non-littermate KO mice, can be reversed by potentiation of NMDARs; by using a positive allosteric modulator, UBP714, or a partial NMDAR agonist, D-Cycloserine. Finally, Chapter 5 investigated the extent to which induction of STP and LTP differed between non-littermate WT and KO mice by using induction protocols of increasing strength and found that KOs have consistently smaller STP, but a higher threshold for LTP saturation than the WTs. Plasticity in KO mice showed increased sensitivity to UBP791, an NMDAR antagonist. Overall, this thesis highlights that cage effects, induction protocols and sex differences can influence phenotypes in Fmr1 colonies and may explain the phenotype discrepancies in the field.

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