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@ARTICLE{Falck:151528,
author = {Falck, Joanne and Bruns, Christine and Hoffmann, Sheila
Sook-Hi and Straub, Isabelle and Plautz, Erik J. and
Orlando, Marta and Munawar, Humaira and Rivalan, Marion and
Winter, York and Izsvák, Zsuzsanna and Schmitz, Dietmar and
Hamra, F. Kent and Hallermann, Stefan and Garner, Craig
Curtis and Ackermann, Frauke},
title = {{L}oss of {P}iccolo {F}unction in {R}ats {I}nduces
{C}erebellar {N}etwork {D}ysfunction and {P}ontocerebellar
{H}ypoplasia {T}ype 3-like {P}henotypes},
journal = {The journal of neuroscience},
volume = {40},
number = {14},
issn = {0270-6474},
address = {Washington, DC},
publisher = {Soc.8825},
reportid = {DZNE-2020-01112},
pages = {2943-2959},
year = {2020},
abstract = {Piccolo, a presynaptic active zone protein, is best known
for its role in the regulated assembly and function of
vertebrate synapses. Genetic studies suggest a further link
to several psychiatric disorders as well as Pontocerebellar
Hypoplasia type 3 (PCH3). We have characterized recently
generated Piccolo KO (Pclogt/gt) rats. Analysis of rats of
both sexes revealed a dramatic reduction in brain size
compared with WT (Pclowt/wt) animals, attributed to a
decrease in the size of the cerebral cortical, cerebellar,
and pontine regions. Analysis of the cerebellum and
brainstem revealed a reduced granule cell layer and a
reduction in size of pontine nuclei. Moreover, the
maturation of mossy fiber afferents from pontine neurons and
the expression of the α6 GABAA receptor subunit at the
mossy fiber-granule cell synapse are perturbed, as well as
the innervation of Purkinje cells by cerebellar climbing
fibers. Ultrastructural and functional studies revealed a
reduced size of mossy fiber boutons, with fewer synaptic
vesicles and altered synaptic transmission. These data imply
that Piccolo is required for the normal development,
maturation, and function of neuronal networks formed between
the brainstem and cerebellum. Consistently, behavioral
studies demonstrated that adult Pclogt/gt rats display
impaired motor coordination, despite adequate performance in
tasks that reflect muscle strength and locomotion. Together,
these data suggest that loss of Piccolo function in patients
with PCH3 could be involved in many of the observed
anatomical and behavioral symptoms, and that the further
analysis of these animals could provide fundamental
mechanistic insights into this devastating disorder.},
keywords = {Animals / Cerebellum: metabolism / Cerebellum: pathology /
Cerebellum: physiopathology / Cytoskeletal Proteins:
metabolism / Disease Models, Animal / Female / Gene Knockout
Techniques / Male / Neuropeptides: metabolism /
Olivopontocerebellar Atrophies / Phenotype / Rats},
cin = {AG Garner / AG Ackermann},
ddc = {610},
cid = {I:(DE-2719)1810001 / I:(DE-2719)1813004},
pnm = {341 - Molecular Signaling (POF3-341)},
pid = {G:(DE-HGF)POF3-341},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC7117892},
pubmed = {pmid:32122952},
doi = {10.1523/JNEUROSCI.2316-19.2020},
url = {https://pub.dzne.de/record/151528},
}