TY  - JOUR
AU  - Falck, Joanne
AU  - Bruns, Christine
AU  - Hoffmann, Sheila Sook-Hi
AU  - Straub, Isabelle
AU  - Plautz, Erik J.
AU  - Orlando, Marta
AU  - Munawar, Humaira
AU  - Rivalan, Marion
AU  - Winter, York
AU  - Izsvák, Zsuzsanna
AU  - Schmitz, Dietmar
AU  - Hamra, F. Kent
AU  - Hallermann, Stefan
AU  - Garner, Craig Curtis
AU  - Ackermann, Frauke
TI  - Loss of Piccolo Function in Rats Induces Cerebellar Network Dysfunction and Pontocerebellar Hypoplasia Type 3-like Phenotypes
JO  - The journal of neuroscience
VL  - 40
IS  - 14
SN  - 0270-6474
CY  - Washington, DC
PB  - Soc.8825
M1  - DZNE-2020-01112
SP  - 2943-2959
PY  - 2020
AB  - 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.
KW  - Animals
KW  - Cerebellum: metabolism
KW  - Cerebellum: pathology
KW  - Cerebellum: physiopathology
KW  - Cytoskeletal Proteins: metabolism
KW  - Disease Models, Animal
KW  - Female
KW  - Gene Knockout Techniques
KW  - Male
KW  - Neuropeptides: metabolism
KW  - Olivopontocerebellar Atrophies
KW  - Phenotype
KW  - Rats
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC7117892
C6  - pmid:32122952
DO  - DOI:10.1523/JNEUROSCI.2316-19.2020
UR  - https://pub.dzne.de/record/151528
ER  -