Muellerleile, Julia
[VerfasserIn]
;
Kössl, Manfred
[Sonstige Person, Familie und Körperschaft];
Jedlička, Peter
[Sonstige Person, Familie und Körperschaft]
Roles of the autism candidate genes neuroligin-3, neuroligin-4, and neurobeachin in synaptic plasticity and excitation-inhibition balance in the dentate gyrus
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Medientyp:
E-Book;
Hochschulschrift
Titel:
Roles of the autism candidate genes neuroligin-3, neuroligin-4, and neurobeachin in synaptic plasticity and excitation-inhibition balance in the dentate gyrus
Hochschulschrift:
Dissertation, Frankfurt am Main, Johann Wolfgang Goethe-Universität, 2022
Anmerkungen:
Beschreibung:
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with a multifarious clinical presentation. Even though many genetic risk factors have been identified and studied in mouse models, the neurophysiological mechanisms underlying the autistic phenotype are still unclear. Based on the high rates of comorbidity with epilepsy, it was hypothesized that the balance between excitation and inhibition in neural circuits may be disrupted in autistic individuals. In this dissertation, synaptic and network activity was measured in three different genetically modified mouse models that exhibit the characteristic behavioral abnormalities of the disorder: the Neurobeachin (Nbea) haploinsufficient mouse, the Neuroligin-3 (Nlgn3) knockout (KO) mouse, and the Neuroligin-4 (Nlgn4) KO mouse. Each of the affected proteins is involved in the formation and/or function of synapses in the central nervous system. Therefore, it was posited that the reduction or deletion of these proteins might alter the balance of excitatory to inhibitory synaptic transmission in individual neurons and in neural circuits. Extracellular recordings in the hippocampal dentate gyrus of anesthetized mice revealed that the excitation-inhibition (E-I) balance was reduced in Nbea haploinsufficient and Nlgn4 KO mice, but unchanged in Nlgn3 KO mice despite a reduction in excitatory synaptic transmission to dentate granule cells. Unexpectedly, the intrinsic excitability of dentate granule cells was altered in all three mouse models. These results imply that a homeostatic increase in the intrinsic excitability is able to compensate for the decreased excitatory transmission in Nlgn3 KO mice, whereas the decreased intrinsic excitability in the Nbea haploinsufficient and Nlgn4 KO mice leads to a reduction in the E-I balance. Taken together, these findings suggest that the influence of genetic factors on the E-I balance might be a potential common mechanism underlying the development of ASD. ; Autismus-Spektrum-Störung (ASS) ist eine häufig vorkommende ...