eprintid: 30808
rev_number: 14
eprint_status: archive
userid: 6328
dir: disk0/00/03/08/08
datestamp: 2021-12-02 13:50:17
lastmod: 2021-12-15 14:58:49
status_changed: 2021-12-02 13:50:17
type: doctoralThesis
metadata_visibility: show
creators_name: Bauersachs, Hanke Gwendolyn
title: Excitotoxicity and NMDA receptor-mediated
acquired neuroprotection in human iPSC-derived
brain organoids
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
cterms_swd: Neurobiologie
abstract: Excitotoxic cell death, resulting from excess brain glutamate and mediated predominantly
through NMDA receptors (NMDARs), is implicated in various acute and chronic pathological
conditions of the human brain, such as stroke, traumatic brain injury and neurodegenerative
diseases. In contrast, physiological NMDAR activation renders rodent neurons more resistant
to potentially toxic stressors - a mechanism referred to as acquired neuroprotection. It is,
however, not known whether such a dual action of NMDAR-signalling also exists human
neurons.
This study employed human induced pluripotent stem cell-derived forebrain organoids to
investigate NMDAR-mediated pro-death and pro-survival signalling in human neurons.
Exposure of forebrain organoids to high concentrations of NMDA caused an excitotoxic
cascade involving loss of plasma membrane potential, cessation of synaptic activity, shut-off
of the transcription factor CREB, induction of death-promoting P53 expression, structural
disintegration and ultimately cell death. In contrast, treatment of brain organoids with low
doses of NMDA triggered enhanced synaptic activity and survival-promoting signalling
including the CREB phosphorylation and the expression of neuroprotective genes. This
condition, if applied as a pre-treatment, protected organoids against excitotoxic insults within
a defined time window. Surprisingly, the protective mechanism relied solely on the activation
of NMDARs per se and occurred independently of the concomitant synaptic activation.
Moreover, application of established as well as newly developed drugs to combat excitotoxicity
protected human forebrain organoids against NMDA-induced cell death.
The findings presented here show that many aspects of the dual action of NMDAR-signalling,
including NMDAR-mediated acquired neuroprotection, are preserved in human neurons. The
forebrain organoid methodology established here may serve as a platform for the development
and testing of drugs counteracting excitotoxic cell death arising, for example, from acute
cerebrovascular ischaemia and neurodegenerative diseases in humans.
date: 2021
id_scheme: DOI
id_number: 10.11588/heidok.00030808
ppn_swb: 1782279504
own_urn: urn:nbn:de:bsz:16-heidok-308086
date_accepted: 2021-11-16
advisor: HASH(0x55a9a6357368)
language: eng
bibsort: BAUERSACHSEXCITOTOXI2021
full_text_status: public
place_of_pub: Heidelberg
citation:   Bauersachs, Hanke Gwendolyn  (2021) Excitotoxicity and NMDA receptor-mediated acquired neuroprotection in human iPSC-derived brain organoids.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/30808/1/Dissertation_Bauersachs.pdf