Achucarro Seminars

07 Apr [2017]

at 13.00 CET

Astrocytes replacement recovers global neuronal synchronizations in Atm-deficient cerebellar circuits in-vitro

Paolo Bonifazi

BioCruces HRI (Barakaldo)


Ataxia Telangiectasia (A-T) is a human genetic disease caused by mutations in the ATM gene, which encodes the ATM protein kinase. Patients with A-T suffer from progressive cerebellar degeneration that develops into severe motor dysfunction.

Previous mice studies have shown that ATM deficiency leads to pathological changes in astrocytes. To study the effect of ATM deficiency on neuronal circuits, we compare the neuronal dynamics (recorded through calcium imaging) and the astrocyte morphology in primary cerebellar cultures grown from postnatal Atm−/− and wild-type mice. Cerebellar neuronal dynamics exhibited spontaneous network events after two weeks in-vitro. Compared to WT circuits, Atm−/−  circuits displayed a lower number of global synchronizations (i.e. recruiting nearly all the imaged neurons) and a larger number of sparse synchronizations (i.e. recruiting less than ten percent of the imaged neurons). Immunochemical staining of astrocytes revealed an atrophied arborization in Atm−/− versus WT circuits. Replacement of Atm−/− astrocytic cells with WT cells in in-vitro cerebellar circuits restored physiological neuronal synchronizations. Using Synapsin immunochemistry and Western blot analysis, we observed a significative larger number of pre-synaptic sites in Atm−/−  vs. WT networks, and control WT levels were restored when replacing Atm−/− astrocytic cells with WT cells.

These results support the notion that neuronal network dysfunction failures in brain degenerative diseases are strictly correlated with structural damage of astroglial cell type. In this context, a disease could induce a multi-scale accumulation of structural-functional defects into neuronal circuits, scaling up from molecular pathways, synaptic level to cell assemblies and neuronal circuits' further reaching brain networks dynamics and functions.