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Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities

Michelle Stewart, Petrina YP Lau, Gareth Banks, Rasneer Sonia Bains, Enrico Castroflorio, Peter L Oliver, Christine L Dixon, Michael C Kruer, Dimitri M Kullmann, Abraham Acevedo-Arozena, Sara E Wells, View ORCID ProfileSilvia Corrochano, View ORCID ProfilePatrick Nolan
doi: https://doi.org/10.1101/388561
Michelle Stewart
MRC Harwell Institute;
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Petrina YP Lau
MRC Harwell Institute;
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Gareth Banks
MRC Harwell Institute;
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Rasneer Sonia Bains
MRC Harwell Institute;
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Enrico Castroflorio
MRC Harwell Institute;
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Peter L Oliver
MRC Harwell Institute;
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Christine L Dixon
University College London;
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Michael C Kruer
Phoenix Childrens Hospital;
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Dimitri M Kullmann
University College London;
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Abraham Acevedo-Arozena
Unidad de Investigacion Hospital Universitario de Canarias;
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Sara E Wells
MRC Harwell Institute;
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Silvia Corrochano
MRC Harwell
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  • For correspondence: s.corrochano@har.mrc.ac.uk
Patrick Nolan
MRC Harwell Institute;
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Abstract

Loss of function mutations in the human AMPA receptor-associated protein, ferric chelate reductase 1-like (FRRS1L), are associated with a devastating neurological condition incorporating choreoathetosis, cognitive deficits and epileptic encephalopathies. Furthermore, evidence from overexpression and ex vivo studies have implicated FRRS1L in AMPA receptor biogenesis and assembly, suggesting that changes in glutamatergic signalling might underlie the disorder. Here, we investigated the neurological and neurobehavioural correlates of the disorder using a mouse Frrs1l null mutant. The study revealed several neurological defects that mirrored those seen in human patients. We established that mice lacking Frrs1l suffered from a broad spectrum of early-onset motor deficits with no progressive, age-related deterioration. Moreover, Frrs1l-/- mice were hyperactive irrespective of test environment, exhibited working memory deficits and displayed significant sleep fragmentation. Longitudinal electroencephalographic recordings also revealed abnormal EEG in Frrs1l-/- mice. Parallel investigations into disease aetiology identified a specific deficiency in AMPA receptor levels in the brain of Frrs1l-/- mice, while the general levels of several other synaptic components remained unchanged with no obvious alterations in the number of synapses. Furthermore, we established that Frrsl1 deletion results in glycosylation deficits in GLUA2 and GLUA4 AMPA receptor proteins, leading to cytoplasmic retention and a reduction of those specific AMPA receptor levels in the postsynaptic membrane. Overall, this study determines, for the first time in vivo, how loss of FRRS1L function can affect glutamatergic signalling and provides mechanistic insight into the development and progression of a human hyperkinetic disorder.

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Posted August 10, 2018.
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Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities
Michelle Stewart, Petrina YP Lau, Gareth Banks, Rasneer Sonia Bains, Enrico Castroflorio, Peter L Oliver, Christine L Dixon, Michael C Kruer, Dimitri M Kullmann, Abraham Acevedo-Arozena, Sara E Wells, Silvia Corrochano, Patrick Nolan
bioRxiv 388561; doi: https://doi.org/10.1101/388561
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Loss of Frrs1l disrupts synaptic AMPA receptor function, and results in neurodevelopmental, motor, cognitive and electrographical abnormalities
Michelle Stewart, Petrina YP Lau, Gareth Banks, Rasneer Sonia Bains, Enrico Castroflorio, Peter L Oliver, Christine L Dixon, Michael C Kruer, Dimitri M Kullmann, Abraham Acevedo-Arozena, Sara E Wells, Silvia Corrochano, Patrick Nolan
bioRxiv 388561; doi: https://doi.org/10.1101/388561

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