@article {2077, title = {A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency.}, journal = {Elife}, volume = {9}, year = {2020}, month = {2020 Jan 15}, abstract = {

SynGAP is a postsynaptic density (PSD) protein that binds to PDZ domains of the scaffold protein PSD-95. We previously reported that heterozygous deletion of in mice is correlated with increased steady-state levels of other key PSD proteins that bind PSD-95, although the level of PSD-95 remains constant (Walkup et al., 2016). For example, the ratio to PSD-95 of Transmembrane AMPA-Receptor-associated Proteins (TARPs), which mediate binding of AMPA-type glutamate receptors to PSD-95, was increased in young mice. Here we show that only females and not males show a highly significant correlation between an increase in TARP and a decrease in synGAP in the PSDs of rodents. The data reveal a sex difference in the adaptation of the PSD scaffold to synGAP haploinsufficiency.

}, issn = {2050-084X}, doi = {10.7554/eLife.52656}, author = {Mastro, Tara L and Preza, Anthony and Basu, Shinjini and Chattarji, Sumantra and Till, Sally M and Kind, Peter C and Kennedy, Mary B} } @article {1738, title = {Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome.}, journal = {Sci Transl Med}, volume = {11}, year = {2019}, month = {2019 May 29}, abstract = {

Fragile X Syndrome (FXS) is one of the most common monogenic forms of autism and intellectual disability. Preclinical studies in animal models have highlighted the potential of pharmaceutical intervention strategies for alleviating the symptoms of FXS. However, whether treatment strategies can be tailored to developmental time windows that define the emergence of particular phenotypes is unknown. Similarly, whether a brief, early intervention can have long-lasting beneficial effects, even after treatment cessation, is also unknown. To address these questions, we first examined the developmental profile for the acquisition of associative learning in a rat model of FXS. Associative memory was tested using a range of behavioral paradigms that rely on an animal{\textquoteright}s innate tendency to explore novelty. knockout (KO) rats showed a developmental delay in their acquisition of object-place recognition and did not demonstrate object-place-context recognition paradigm at any age tested (up to 23 weeks of age). Treatment of KO rats with lovastatin between 5 and 9 weeks of age, during the normal developmental period that this associative memory capability is established, prevents the emergence of deficits but has no effect in wild-type animals. Moreover, we observe no regression of cognitive performance in the FXS rats over several months after treatment. This restoration of the normal developmental trajectory of cognitive function is associated with the sustained rescue of both synaptic plasticity and altered protein synthesis. The findings provide proof of concept that the impaired emergence of the cognitive repertoire in neurodevelopmental disorders may be prevented by brief, early pharmacological intervention.

}, issn = {1946-6242}, doi = {10.1126/scitranslmed.aao0498}, author = {Asiminas, Antonis and Jackson, Adam D and Louros, Susana R and Till, Sally M and Spano, Teresa and Dando, Owen and Bear, Mark F and Chattarji, Sumantra and Hardingham, Giles E and Osterweil, Emily K and Wyllie, David J A and Wood, Emma R and Kind, Peter C} } @article {398, title = {Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS.}, journal = {Hum Mol Genet}, volume = {24}, year = {2015}, month = {2015 Nov 1}, pages = {5977-84}, abstract = {

Recent advances in techniques for manipulating genomes have allowed the generation of transgenic animals other than mice. These new models enable cross-mammalian comparison of neurological disease from core cellular pathophysiology to circuit and behavioural endophenotypes. Moreover they will enable us to directly test whether common cellular dysfunction or behavioural outcomes of a genetic mutation are more conserved across species. Using a new rat model of Fragile X Syndrome, we report that Fmr1 knockout (KO) rats exhibit elevated basal protein synthesis and an increase in mGluR-dependent long-term depression in CA1 of the hippocampus that is independent of new protein synthesis. These defects in plasticity are accompanied by an increase in dendritic spine density selectively in apical dendrites and subtle changes in dendritic spine morphology of CA1 pyramidal neurons. Behaviourally, Fmr1 KO rats show deficits in hippocampal-dependent, but not hippocampal-independent, forms of associative recognition memory indicating that the loss of fragile X mental retardation protein (FMRP) causes defects in episodic-like memory. In contrast to previous reports from mice, Fmr1 KO rats show no deficits in spatial reference memory reversal learning. One-trial spatial learning in a delayed matching to place water maze task was also not affected by the loss of FMRP in rats. This is the first evidence for conservation across mammalian species of cellular and physiological hippocampal phenotypes associated with the loss of FMRP. Furthermore, while key cellular phenotypes are conserved they manifest in distinct behavioural dysfunction. Finally, our data reveal novel information about the selective role of FMRP in hippocampus-dependent associative memory.

}, issn = {1460-2083}, doi = {10.1093/hmg/ddv299}, author = {Till, Sally M and Asiminas, Antonis and Jackson, Adam D and Katsanevaki, Danai and Barnes, Stephanie A and Osterweil, Emily K and Bear, Mark F and Chattarji, Sumantra and Wood, Emma R and Wyllie, David J A and Kind, Peter C} }