Dr Andrew Penn
Glutamate receptors and excitatory synaptic transmission in health and disease
The theme of our research is understanding the role of glutamate receptor ion channels and excitatory synaptic transmission in health and disease. Below is an example PhD research project, which could be adapted to suit individual background and preferences of the student.
- Developmental changes and mechanisms of aberrant neuronal signalling resulting from disease variants of NMDA receptor subunits. The ability of our brains to interpret sensory input, coordinate behaviour and perform cognitive tasks depends fundamentally on communication between neurons at connections called synapses. Neuronal signalling across excitatory synapses relies principally on two types of glutamate receptors: AMPA-type and NMDA-type glutamate receptors. This project will investigate dysfunctional signalling at synapses relating to disorders arising from genetic variants of the NMDA receptor. Genetic variants of NMDA subunits are responsible for rare single-gene disorders in which patients have an array of debilitating symptoms that can include epilepsy, intellectual disability, language disorders, developmental delay and Autism Spectrum Disorder (Hansen et al., 2021, Pharmacol Rev). In our recent work, we discovered that diverse GluN2 subunit variants gave rise to synaptic NMDA receptors with similar defects (Elmasri et al., 2022, Commun Biol; Elmasri et al., 2022, Brain Sci). Interestingly, the effect of the variants on synaptic transmission depended critically on the native expression of other GluN2 subunits. Since NMDA receptor subunit expression changes during development, this project will explore the impact of GluN2 variants at different stages of neuron development. The project will use cultured brain slices and neurons (either from rodents or human induced pluripotent stem cells (iPSCs)), and students will acquire valuable training in a molecular biology and a range of Neuroscience techniques, including whole-cell patch clamp electrophysiology and fluorescence imaging.
- We also have a collaborative SN PhD project available between the labs of Dr Andy Penn and Dr James Stone (Brighton and Sussex Medical School). The project will investigate whether properties of NMDA receptors and synaptic transmission in patient iPSC-derived neurons are associated with response to ketamine for treatment-resistant depression. Laboratory techniques could include cell culture, electrophysiology, pharmacology and brain imaging.
Key references
- Elmasri M, Hunter DW, Winchester G, Bates EE, Aziz W, Van Der Does DM, Karachaliou E, Sakimura K, Penn AC. (2022) Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A. Commun Biol. 5(1):174. doi: https://doi.org/10.1038/s42003-022-03115-3
- Elmasri M, Lotti JS, Aziz W, Steele OG, Karachaliou E, Sakimura K, Hansen KB, Penn AC. (2022) Synaptic Dysfunction by Mutations in GRIN2B: Influence of Triheteromeric NMDA Receptors on Gain-of-Function and Loss-of-Function Mutant Classification. Brain Sci. 12(6):789. doi: https://doi.org/10.3390/brainsci12060789
Visit the Penn Lab pages for more details and a full list of publications.