RT Journal Article
SR Electronic
T1 Brunner Syndrome associated MAOA dysfunction in human induced dopaminergic neurons results in dysregulated NMDAR expression and increased network activity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 741108
DO 10.1101/741108
A1 Y. Shi
A1 J.R. van Rhijn
A1 M. Bormann
A1 B. Mossink
A1 M. Frega
A1 M. Hakobjan
A1 S. Kittel-Schneider
A1 D. Schubert
A1 H. Brunner
A1 B. Franke
A1 N. Nadif Kasri
YR 2019
UL http://biorxiv.org/content/early/2019/08/21/741108.abstract
AB Monoamine oxidase A (MAOA) is an enzyme that catalyzes the degradation of dopamine, noradrenaline, and serotonin. Regulation of monoamine neurotransmitter abundance through MAOA activity strongly affects motor control, emotion, and cognitive function. Mutations in MAOA cause Brunner Syndrome, which is characterized by impulsive aggressive behavior and mild intellectual disability (ID). The impaired MAOA activity in Brunner Syndrome patients results in bioamine aberration, but it is currently unknown how this affects neuronal function. MAOA is highly expressed in serotonergic and dopaminergic neurons, and dysfunction of both neurotransmission systems is associated with aggressive behavior in mice and humans. Research has so far mainly focused on the serotonergic system. Here, we generated human induced pluripotent stem cell-derived induced dopaminergic neurons (iDANs) from individuals with known MAOA mutations, to investigate MAOA-dependent effects on dopamine neuronal function in the context of Brunner Syndrome. We assessed iDAN lines from three patients and combined data from morphological analysis, gene expression, single-cell electrophysiology, and network analysis using micro-electrode arrays (MEAs). We observed mutation-dependent functional effects as well as overlapping changes in iDAN morphology. The most striking effect was a clear increase in N-methyl-D-aspartate (NMDA) receptor mRNA expression in all patient lines. A marked increase was also seen in coordinated network activity (network bursts) on the MEA in all patient lines, while single-cell intrinsic properties and spontaneous excitatory postsynaptic currents activity appeared normal. Together, our data indicate that dysfunction of MAOA leads to increased coordinated network activity in iDANs, possibly caused by increased synaptic NMDA receptor expression.