Compromised Survival of Cerebellar Molecular Layer Interneurons Lacking GDNF Receptors GFRα1 or RET Impairs Normal Cerebellar Motor Learning

Abstract

SummaryThe role of neurotrophic factors as endogenous survival proteins for brain neurons remains contentious. In the cerebellum, the signals controlling survival of molecular layer interneurons (MLIs) are unknown, and direct evidence for the requirement of a full complement of MLIs for normal cerebellar function and motor learning has been lacking. Here, we show that Purkinje cells (PCs), the target of MLIs, express the neurotrophic factor GDNF during MLI development and survival of MLIs depends on GDNF receptors GFRα1 and RET. Conditional mutant mice lacking either receptor lose a quarter of their MLIs, resulting in compromised synaptic inhibition of PCs, increased PC firing frequency, and abnormal acquisition of eyeblink conditioning and vestibulo-ocular reflex performance, but not overall motor activity or coordination. These results identify an endogenous survival mechanism for MLIs and reveal the unexpected vulnerability and selective requirement of MLIs in the control of cerebellar-dependent motor learning.

Cell-autonomous role of GFRα1 in the development of olfactory bulb GABAergic interneurons

“…The expression of GFRα1 in migratory precursors, but not in mature OB GABAergic interneurons, indicates that this receptor is downregulated during the final maturation of these cells. Transient expression of GFRα1 by migratory precursors of GABAergic neurons seems to be a common property of this type of cell as it has also been observed in GABAergic precursors of the MGE that give rise to cortical interneurons ( Canty et al, 2009 ; Pozas and Ibáñez, 2005 ), immature molecular layer interneurons of the cerebellum ( Sergaki et al, 2017 ) and in migratory precursors of Purkinje cells ( Sergaki and Ibáñez, 2017 ). It remains unclear why or how GABAergic precursor cells downregulate expression of GFRα1 as they develop, but it may be related to their cessation of cell migration and incorporation into mature neuronal circuits.…”

HITS-CLIP in various brain areas reveals new targets and new modalities of RNA binding by fragile X mental retardation protein

“…For instance, the implication and regulation of (Estrogen Receptor) Erb2 and Erb3 by FMRP is very intriguing and, if extended to ASD, could provide a molecular clue to explain the 1 to 4 ratio between female and male ASD patients ( 57 ). In addition, for instance, one of the pathways specifically modulated by FMRP in cerebellum is the GDNF (Glial Cell Line-derived Neurotrophic Factor) that has been recently associated to normal cerebellar motor learning ( 58 ). In conclusion, all these pathways may contribute to cellular and/or behavioral phenotypes of FXS.…”

The gamma-Protocadherins regulate the survival of GABAergic interneurons during developmentally-regulated cell death

“…We focused on the PV+ cerebellar molecular layer interneurons that originate from a Ptf1a-expressing GABAergic lineage in the ventricular zone of the cerebellar primordium (Hoshino et al, 2005;Leto et al, 2006). Between P5 and P12, these interneurons normally undergo apoptosis in the cerebellar prospective white matter, where precursors proliferate and differentiate, and in the cerebellar cortex (Sergaki et al, 2017;Yamanaka et al, 2004). Apoptosis of the molecular layer interneurons is also Bax-dependent ( Collectively, our results demonstrate that the Pcdhgs promote the survival of two unrelated GABAergic interneuron populations during postnatal PCD.…”

“…Diverse cPcdhs isoforms might also signal together as Pcdh-alpha and Pcdh-beta members multimerize and functionally cooperate with the Pcdhgs to contribute to neuronal survival (Goodman et al, 2017;Goodman et al, 2016;Han et al, 2009;Hasegawa et al, 2016;Ing-Esteves et al, 2018). Also, developmental survival of cerebellar interneurons is regulated by GDNF receptors RET and GFR1a (Sergaki et al, 2017), raising the interesting possibility of co-signaling through interactions between RET and Pcdh-alpha members (Schalm et al, 2010).…”