2.2. 2023, Buněčná neurofyziologie

Laboratory name: Cellular Neurophysiology

Laboratory website

PhD project:  Functional characterization of disease-associated NMDA receptor mutations

N-methyl-D-aspartate receptors (NMDARs) are ionotropic receptors for the excitatory neurotransmitter glutamate, specialized to detect glutamate in the context of ongoing network activity.  NMDAR function is therefore critical for the development of neural circuits and for their ability to process information and learn throughout lifetime.  In recent years, changes in GRIN genes encoding NMDAR subunits have been identified in a number of human patients with neuropsychiatric and neurodevelopmental disorders, including schizophrenia, major depressive disorder,  intellectual disability, epilepsy, and autism spectrum disorder.  While over 700 patient-derived GRIN variants have been identified, some functional information is available for less than half of these, and only a handful of the known human disease-associated GRIN mutations have been studied in neuronal preparations or animal models. 

The selected PhD candidate/s will use patch-clamp electrophysiology and live-cell Ca2+ imaging to study NMDAR function, synaptic transmission and plasticity, and network activity in neuronal cultures expressing disease-associated GRIN mutations.  In parallel, the effects of GRIN mutations on NMDAR assembly, cellular localization, and regulation of glutamatergic synapses will be investigated using a variety of biochemical methods in combination with high-resolution microscopy. The observed functional changes associated with pathogenic GRIN variants will then be targeted with appropriate positive or negative pharmacological modulation, to test the feasibility of precision therapy for patients with GRIN disorders.

References:

Kysilov, Hrčka Krausová et al. (2022) Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations. British Journal of Pharmacology 179(15); 3970-3990. IF = 9.473
Smejkalová et al. (2021) Endogenous neurosteroids pregnanolone and pregnanolone sulfate potentiate presynaptic glutamate release through distinct mechanisms. British Journal of Pharmacology 178(19); 3888-3904. IF = 9.473
Hubálková et al. (2021) Palmitoylation controls NMDA receptor function and steroid sensitivity. Journal of Neuroscience 41(10); 2119-2134. IF = 6.709
Hirschfeldova  et al. (2021)  Evidence for the Association between the Intronic Haplotypes of Ionotropic Glutamate Receptors and First-Episode Schizophrenia. Journal of Personalized Medicine. 11(12):1250. IF 3.508
Hrčka Krausová, Kysilov et al. (2020) Site of action of brain neurosteroid pregnenolone sulfate at the N-methyl-D-aspartate receptor. Journal of Neuroscience. 2020; 40(31); 5922-5936. IF = 6.167

Supervisor(s):  Tereza Smejkalova, PhD (tereza.smejkalova@fgu.cas.cz), Aleš Balik, PhD (ales.balik@fgu.cas.cz)        

Candidate’s profile (requirements):

We are seeking motivated candidate/s with a master's degree or equivalent in genetics, molecular biology, biochemistry, physiology, medicine or related fields, or a student expecting to obtain their degree this year. Experience with molecular biology techniques, cell culture, animal models, and/or microscopy is an advantage.