RT Journal Article
SR Electronic
T1 Progranulin Deficiency Decreases Gross Neural Connectivity But Enhances Transmission at Individual Synapses
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 11126
OP 11132
DO 10.1523/JNEUROSCI.6244-10.2011
VO 31
IS 31
A1 Lucia Tapia
A1 Austen Milnerwood
A1 Aobo Guo
A1 Fergil Mills
A1 Eileen Yoshida
A1 Cristina Vasuta
A1 Ian R. Mackenzie
A1 Lynn Raymond
A1 Max Cynader
A1 William Jia
A1 Shernaz X. Bamji
YR 2011
UL http://www.jneurosci.org/content/31/31/11126.abstract
AB Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivity in vitro and that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients.