%0 Journal Article %J eNeuro %D 2021 %T Contribution of NMDA Receptors to Synaptic Function in Rat Hippocampal Interneurons. %A Booker, Sam A %A Sumera, Anna %A Kind, Peter C %A Wyllie, David J A %X

The ability of neurons to produce behaviorally relevant activity in the absence of pathology relies on the fine balance of synaptic inhibition to excitation. In the hippocampal CA1 microcircuit, this balance is maintained by a diverse population of inhibitory interneurons that receive largely similar glutamatergic afferents as their target pyramidal cells, with EPSCs generated by both AMPA receptors (AMPARs) and NMDA receptors (NMDARs). In this study, we take advantage of a recently generated GluN2A-null rat model to assess the contribution of GluN2A subunits to glutamatergic synaptic currents in three subclasses of interneuron found in the CA1 region of the hippocampus. For both parvalbumin-positive and somatostatin-positive interneurons, the GluN2A subunit is expressed at glutamatergic synapses and contributes to the EPSC. In contrast, in cholecystokinin (CCK)-positive interneurons, the contribution of GluN2A to the EPSC is negligible. Furthermore, synaptic potentiation at glutamatergic synapses on CCK-positive interneurons does not require the activation of GluN2A-containing NMDARs but does rely on the activation of NMDARs containing GluN2B and GluN2D subunits.

%B eNeuro %V 8 %8 2021 Jul-Aug %G eng %N 4 %R 10.1523/ENEURO.0552-20.2021 %0 Journal Article %J Cell Rep %D 2021 %T Correction of amygdalar dysfunction in a rat model of fragile X syndrome. %A Fernandes, Giselle %A Mishra, Pradeep K %A Nawaz, Mohammad Sarfaraz %A Donlin-Asp, Paul G %A Rahman, Mohammed Mostafizur %A Hazra, Anupam %A Kedia, Sonal %A Kayenaat, Aiman %A Songara, Dheeraj %A Wyllie, David J A %A Schuman, Erin M %A Kind, Peter C %A Chattarji, Sumantra %X

Fragile X syndrome (FXS), a commonly inherited form of autism and intellectual disability, is associated with emotional symptoms that implicate dysfunction of the amygdala. However, current understanding of the pathogenesis of the disease is based primarily on studies in the hippocampus and neocortex, where FXS defects have been corrected by inhibiting group I metabotropic glutamate receptors (mGluRs). Here, we observe that activation, rather than inhibition, of mGluRs in the basolateral amygdala reverses impairments in a rat model of FXS. FXS rats exhibit deficient recall of auditory conditioned fear, which is accompanied by a range of in vitro and in vivo deficits in synaptic transmission and plasticity. We find presynaptic mGluR5 in the amygdala, activation of which reverses deficient synaptic transmission and plasticity, thereby restoring normal fear learning in FXS rats. This highlights the importance of modifying the prevailing mGluR-based framework for therapeutic strategies to include circuit-specific differences in FXS pathophysiology.

%B Cell Rep %V 37 %P 109805 %8 2021 Oct 12 %G eng %N 2 %R 10.1016/j.celrep.2021.109805 %0 Journal Article %J Mol Autism %D 2020 %T Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns. %A Das Sharma, Shreya %A Pal, Rakhi %A Reddy, Bharath Kumar %A Selvaraj, Bhuvaneish T %A Raj, Nisha %A Samaga, Krishna Kumar %A Srinivasan, Durga J %A Ornelas, Loren %A Sareen, Dhruv %A Livesey, Matthew R %A Bassell, Gary J %A Svendsen, Clive N %A Kind, Peter C %A Chandran, Siddharthan %A Chattarji, Sumantra %A Wyllie, David J A %X

BACKGROUND: Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP).

METHODS: Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced.

RESULTS: Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca-activated K currents and the persistent Na current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines.

CONCLUSIONS: Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered.

%B Mol Autism %V 11 %P 52 %8 2020 Jun 19 %G eng %N 1 %R 10.1186/s13229-020-00351-4 %0 Journal Article %J Elife %D 2020 %T A sex difference in the response of the rodent postsynaptic density to synGAP haploinsufficiency. %A Mastro, Tara L %A Preza, Anthony %A Basu, Shinjini %A Chattarji, Sumantra %A Till, Sally M %A Kind, Peter C %A Kennedy, Mary B %X

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.

%B Elife %V 9 %8 2020 Jan 15 %G eng %R 10.7554/eLife.52656 %0 Journal Article %J Sci Transl Med %D 2019 %T Sustained correction of associative learning deficits after brief, early treatment in a rat model of Fragile X Syndrome. %A Asiminas, Antonis %A Jackson, Adam D %A Louros, Susana R %A Till, Sally M %A Spano, Teresa %A Dando, Owen %A Bear, Mark F %A Chattarji, Sumantra %A Hardingham, Giles E %A Osterweil, Emily K %A Wyllie, David J A %A Wood, Emma R %A Kind, Peter C %X

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'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.

%B Sci Transl Med %V 11 %8 2019 May 29 %G eng %N 494 %R 10.1126/scitranslmed.aao0498 %0 Journal Article %J Hum Mol Genet %D 2015 %T Conserved hippocampal cellular pathophysiology but distinct behavioural deficits in a new rat model of FXS. %A Till, Sally M %A Asiminas, Antonis %A Jackson, Adam D %A Katsanevaki, Danai %A Barnes, Stephanie A %A Osterweil, Emily K %A Bear, Mark F %A Chattarji, Sumantra %A Wood, Emma R %A Wyllie, David J A %A Kind, Peter C %X

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.

%B Hum Mol Genet %V 24 %P 5977-84 %8 2015 Nov 1 %G eng %N 21 %R 10.1093/hmg/ddv299