Mechanisms underlying synaptic phenotypes arising from human disease mutations in NMDA receptors

Elmasri, Marwa (2020) Mechanisms underlying synaptic phenotypes arising from human disease mutations in NMDA receptors. Doctoral thesis (PhD), University of Sussex.

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The N-methyl-D-aspartate receptor (NMDAR) is a glutamate-gated ion channel that mediates the late component of excitatory neurotransmission and contributes to synaptic plasticity, processes of learning and memory and excitatory-inhibitory balance. Many diverse combinations of NMDAR subunits can assemble to form the heteromeric structure and each subunit provides unique functional characteristics, creating a heterogeneous receptor pool. Mutations in the GluN2A and GluN2B subunits, which are highly populated in the hippocampus and forebrain, have been found in various seizure and mental disorders. An increasing volume of research to uncover the mechanisms that lead from a genetic alteration to the disease phenotype has so far focused largely on the use of heterologous expression systems, from which, human disease mutants have been characterised into two sub-types: gain-of-function (GOF) and loss-of-function (LOF). GluN2A GOF and LOF mutants have been both implicated in seizure phenotypes whereas GluN2B GOF and LOF mutants have been tentatively linked to distinct phenotypes: seizure and mental disorders, respectively. Despite this, there is still a limited insight into the effects on neuronal and synaptic mechanisms. In this thesis, using the CA3-CA1 synapse in organotypic hippocampal mouse slices and dissociated neuronal cultures, it was found that GluN2A GOF and LOF mutations produced a common synaptic phenotype of prolonged NMDAR-mediated synaptic currents through either an increase in receptor functional properties (GOF) or diminished expression (LOF). GluN2B mutants also exhibited a common synaptic phenotype of rapidly decaying NMDAR-mediated synaptic currents due to a defective expression even for so-called GOF mutants. These findings caution the translation of results from non-neuronal systems into neurons and for predictions of synaptic properties that could influence the disease management in human patients. Instead of counting on the gain/loss distinction of individual subunits, the results suggest that focus should be placed more broadly on the changes in synaptic transmission that result from GluN2 subunit mutations.

Item Type: Thesis (Doctoral)
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology > QP0361 Nervous system
R Medicine > RB Pathology > RB151 Theories of disease. Etiology. Pathogenesis
R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders > RC0360 Diseases of the central nervous system
Depositing User: Library Cataloguing
Date Deposited: 03 Apr 2020 12:18
Last Modified: 03 May 2022 07:00

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