. Progranulin deficiency decreases gross neural connectivity but enhances transmission at individual synapses. J Neurosci. 2011 Aug 3;31(31):11126-32. PubMed.

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  1. In this interesting paper, Tapia et al. describe how knockdown of progranulin in cultured hippocampal neurons gave rise to an impoverished dendritic arborization and spine density, which could be rescued by substituting progranulin. Likewise, the density of synapses was reduced, but the size of the pre-synaptic compartments was enlarged, containing a higher number of synaptic vesicles. This did not result in altered size or kinetics of mEPSCs, but a higher frequency of spontaneous mEPSCs was observed, suggesting that the increased synaptic transmission is attributable to increased probability of pre-synaptic release. Knockdown of progranulin did not cause enhanced neuronal death/apoptosis in this study. In brains of FTLD patients with progranulin mutations, a similar enhanced number of synaptic vesicles in the hippocampus was noted.

    Synaptic malfunctioning, loss of synapses, and decreased neuronal connectivity are thought to be important early events in neurodegeneration, and can explain neurological deficits before the loss of neuron cell bodies. This study nicely tallies with this concept and further underscores the importance of progranulin for normal neuronal functioning. The enhanced pre-synaptic terminal size, with increased number of vesicles resulting in higher rates of mEPSCs, could be an attempt by the cell to correct for the reduced number of synapses. However, it may be damaging at the same time, for example, by overloading post-synaptic neurons with glutamatergic stress. Further studies are needed to clarify how progranulin impacts synaptic integrity and transmission.

    In contrast to other studies, no reduced survival was observed in progranulin-low conditions. This may be due to the fact that no serum-free/B27 supplement-free media were used. Abundant trophic support resulting in good neuronal survival in culture will mask potential survival-enhancing effects of growth factors. On the other hand, the normal survival of neurons strengthens the paper, because it allowed the investigators to dissect the dendritic and synaptic effects of reduced progranulin levels from secondary effects in dying cells.