PhD Project - Hippocampal function in a new rat GRIN2B haploinsufficiency model of Autism Spectrum Disorder and Intellectual Disability

Vacancy Reference Number

2022-SIDB-WOOD

Closing Date

16 Jan 2022

Address

University of Edinburgh

Background:

Heterozygous loss of function mutations in GRIN2B, which codes for the GluN2B subunit of the NMDA receptor, are associated with neurodevelopmental disorders including Autism Spectrum Disorder (ASD) Intellectual Disability (ID) and epilepsy. The GluN2B subunit is known to play key roles both in neuronal development and circuit formation, and in learning, memory and synaptic plasticity. However, the effects of heterozygous loss of function of GRIN2B are not well understood. A key unanswered question is the extent to which GRIN2B haploinsufficiency affects neuronal and circuit function, plasticity and memory.

Rationale & hypothesis:

The GluN2B subunit of the NMDA receptor is highly expressed and is the predominant GluN2 subunit in the CNS of WT rats prenatally and during early postnatal development. Mice with homozygous deletion of Grin2b in mice fail to thrive, emphasising its importance in development. Later in development and in adults GluN2B is a key mediator of NMDA receptor signalling along with the GluN2A subunit. For example, adult rodents lacking GluN2B in hippocampal CA1 pyramidal cells show impaired hippocampal plasticity and impairments in a range of hippocampus-dependent memory tasks. However, the effects of heterozygous loss of function of Grin2B, which is more relevant to understanding the cognitive and circuit deficits associated with human neurodevelopmental disorders, have been little studied. Our preliminary observations in a new Grin2b+/- rat model indicate that they have impairments in hippocampus-dependent spatial learning and memory tasks. Building on these data, the PhD project will test the prediction that reduced expression of GluN2B disrupts hippocampal synaptic function, synaptic plasticity, hippocampal circuit activity, and hippocampus-dependent learning and memory.

Aims:

The aim of this PhD project is to assess how reduced of expression of GluN2B affects hippocampal function in a new Grin2b+/- rat model, including its impact on spatial learning and memory, in vivo neuronal and circuit activity, and synaptic and cellular activity.

Training outcomes:

This PhD project will take a multidisciplinary approach to the study of hippocampal pathophysiology in the Grin2b+/- rat model.  Depending on an individual’s specific interests, the student will be trained on ex vivo electrophysiological analysis using both patch-clamp and extracellular recording to study synaptic function and plasticity, in vivo electrophysiology using tetrodes or silicon probes to study spatial and temporal firing properties of neurons in freely moving animals, and behavioural approaches to investigate hippocampus-dependent learning and memory. All methodologies and approaches are routinely used in our labs and expert training in these will be provided.