TY  - JOUR
A1  - Schaefer, Natscha
A1  - Vogel, Nicolas
A1  - Villmann, Carmen
T1  - Glycine receptor mutants of the mouse: what are possible routes of inhibitory compensation?
JF  - Frontiers in Molecular Neuroscience
N2  - Defects in glycinergic inhibition result in a complex neuromotor disorder in humans known as hyperekplexia (OMIM 149400) with similar phenotypes in rodents characterized by an exaggerated startle reflex and hypertonia. Analogous to genetic defects in humans single point mutations, microdeletions, or insertions in the Glra1 gene but also in the Glrb gene underlie the pathology in mice. The mutations either localized in the  (spasmodic, oscillator, cincinnati, Nmf11) or the  (spastic) subunit of the glycine receptor (GlyR) are much less tolerated in mice than in humans, leaving the question for the existence of different regulatory elements of the pathomechanisms in humans and rodents. In addition to the spontaneous mutations, new insights into understanding of the regulatory pathways in hyperekplexia or glycine encephalopathy arose from the constantly increasing number of knock-out as well as knock-in mutants of GlyRs. Over the last five years, various efforts using in vivo whole cell recordings provided a detailed analysis of the kinetic parameters underlying glycinergic dysfunction. Presynaptic compensation as well as postsynaptic compensatory mechanisms in these mice by other GlyR subunits or GABA(A) receptors, and the role of extra-synaptic GlyRs is still a matter of debate. A recent study on the mouse mutant oscillator displayed a novel aspect for compensation of functionality by complementation of receptor domains that fold independently. This review focuses on defects in glycinergic neurotransmission in mice discussed with the background of human hyperekplexia en route to strategies of compensation.
KW  - GlyRs
KW  - rescue
KW  - hyperekplexia
KW  - knockout mice
KW  - spontaneous mouse mutants
KW  - synaptic inhibition
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-123839
VL  - 5
IS  - 98
ER  - 
TY  - JOUR
A1  - Meiser, Elisabeth
A1  - Mohammadi, Reza
A1  - Vogel, Nicolas
A1  - Holcman, David
A1  - Fenz, Susanne F.
T1  - Experiments in micro-patterned model membranes support the narrow escape theory
JF  - Communications Physics
N2  - The narrow escape theory (NET) predicts the escape time distribution of Brownian particles confined to a domain with reflecting borders except for one small window. Applications include molecular activation events in cell biology and biophysics. Specifically, the mean first passage time τ can be analytically calculated from the size of the domain, the escape window, and the diffusion coefficient of the particles. In this study, we systematically tested the NET in a disc by variation of the escape opening. Our model system consisted of micro-patterned lipid bilayers. For the measurement of τ, we imaged diffusing fluorescently-labeled lipids using single-molecule fluorescence microscopy. We overcame the lifetime limitation of fluorescent probes by re-scaling the measured time with the fraction of escaped particles. Experiments were complemented by matching stochastic numerical simulations. To conclude, we confirmed the NET prediction in vitro and in silico for the disc geometry in the limit of small escape openings, and we provide a straightforward solution to determine τ from incomplete experimental traces.
KW  - membrane biophysics
KW  - single-molecule biophysics
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-358121
VL  - 6
ER  -