Modelling the functional roles of synaptic and extra-synaptic γ-aminobutyric acid receptor dynamics in circadian timekeeping.
J R Soc Interface
; 18(182): 20210454, 2021 09.
Article
em En
| MEDLINE
| ID: mdl-34520693
ABSTRACT
In the suprachiasmatic nucleus (SCN), γ-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABAA receptor subunits, often referred to as synaptic GABAA (gamma subunit) and extra-synaptic GABAA (delta subunit). To test the functional roles of these distinct GABAA in regulating circadian rhythms, we developed a multicellular SCN model where we could separately compare the effects of manipulating GABA neurotransmitter or receptor dynamics. Our model predicted that blocking GABA signalling modestly increased synchrony among circadian cells, consistent with published SCN pharmacology. Conversely, the model predicted that lowering GABAA receptor density reduced firing rate, circadian cell fraction, amplitude and synchrony among individual neurons. When we tested these predictions, we found that the knockdown of delta GABAA reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABAA densities could enhance synchrony, as opposed to increasing delta GABAA densities. Overall, our model reveals how blocking GABAA receptors can modestly increase synchrony, while increasing the relative density of gamma over delta subunits can dramatically increase synchrony. We hypothesize that increased gamma GABAA density in the winter could underlie the tighter phase relationships among SCN cells.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Núcleo Supraquiasmático
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Ácido gama-Aminobutírico
Tipo de estudo:
Prognostic_studies
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article