Differential expression of GABAA and glycine receptors in ALS-resistant vs. ALS-vulnerable motoneurons: possible implications for selective vulnerability of motoneurons.
Summary Amyotrophic lateral sclerosis (ALS) is a devastating motoneuronal degenerative disease, which is inevitably fatal in adults. ALS is characterized by an extensive loss of motoneurons in the cerebrospinal axis, except for those motoneurons that control eye movements and bladder contraction. The reason for this selectivity is not known. Systematic differences have been found in the organization of excitatory synaptic transmission in ALS-resistant vs. ALS-susceptible motor nuclei. However, although motoneurons express high levels of glycine receptors (GlyR) and GABA(A) receptors (GABA(A)R), no such studies have been carried out yet for inhibitory synaptic transmission. In this study, we compared the subunit composition, patterns of expression, density and synaptic localization of inhibitory synaptic receptors in ALS-resistant (oculomotor, trochlear and abducens) and ALS-vulnerable motoneurons (trigeminal, facial and hypoglossi). Triple immunofluorescent stainings of the major GABA(A)R subunits (alpha1, alpha2, alpha3, and alpha5), the GlyR alpha1 subunit and gephyrin, were visualized by confocal microscopy and analysed quantitatively. A strong correlation was observed between the vulnerability of motoneurons and the subunit composition of GABA(A)R, the GlyR/GABA(A)R density ratios and the incidence of synaptic vs. extrasynaptic GABA(A)R. These differences contrast strikingly with the uniform gephyrin cluster density and synaptic GlyR levels recorded in all motor nuclei examined. These results suggest that the specific patterns of inhibitory receptor organization observed might reflect functional differences that are relevant to the physiopathology of ALS.
Lorenzo
Louis-Etienne
LE
Groupe d'Etude des Réseaux Moteurs, CNRS FRE 2722, 13009 Marseille, France.
Barbe
Annick
A
Portalier
Paule
P
Fritschy
Jean-Marc
JM
Bras
Hélène
H
D000328:Adult; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D003391:Cranial Nerves / Q000166:cytology; D004198:Disease Susceptibility; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000166:cytology / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism*; D018009:Receptors, Glycine / Q000378:metabolism*
D002352:Carrier Proteins; D008565:Membrane Proteins; D021122:Protein Subunits; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; C073441:gephyrin