title: Despite GABAergic neurotransmission, GABAergic innervation does not compensate for the defect in glycine receptor postsynaptic aggregation in spastic mice.
abstract: In the hypoglossal nucleus of wild-type mice, early mixed glycinergic-GABAergic inhibitory transmission becomes mainly glycinergic during postnatal maturation. In spastic mice (SPA), a model of human hyperekplexic syndrome, an insertion into the gene of the glycine receptor (GlyR) beta subunit results in a decreased accumulation of GlyRs at postsynaptic sites and an impaired glycinergic neurotransmission. In SPA mice displaying a mild phenotype (B6C3Fe strain), a compensatory process involving an increased aggregation of GABA(A) receptors (GABA(A)Rs) at postsynaptic sites was proposed to explain survival of mutant animals until adulthood. However, C57BL/6J strain SPA mice which express a lower amount of GlyR beta subunit die 2-3 weeks after birth, suggesting that GABAergic compensation does not necessarily take place. We performed a morphofunctional study of inhibitory synapses in the developing hypoglossal nucleus of C57BL/6J SPA mice. In this mutant, the inhibitory synaptic activity was mainly GABAergic. Accordingly, we observed a developmental loss of glycinergic presynaptic terminals and an increase in the density of GABAergic presynaptic terminals during the first two postnatal weeks. In addition, while C57BL/6J SPA mice displayed a strong impairment in GlyR aggregation at postsynaptic loci, the proportion of inhibitory presynaptic terminals facing diffuse GABA(A)Rs significantly increased during development. Our results suggest crosstalk between postsynaptic and presynaptic elements, leading to the developmental regulation of the presynaptic terminal neurotransmitter content according to the level of postsynaptic GlyR aggregation. They also indicate that GABAergic neurotransmission does not compensate for defects in GlyR postsynaptic aggregation leading to spastic syndrome in C57BL/6J SPA mice.
authors.affiliation: UMR 7102 - Neurobiologie des Processus Adaptatifs, Université Pierre et Marie Curie, Bat. B, Case 1, 9 Quai Saint Bernard, 75252 Paris CEDEX 05, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Muller
authors.forename: Hervé
authors.initials: H
authors.lastname: Le Corronc
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Scain
authors.forename: Antoine
authors.initials: A
authors.lastname: Triller
authors.forename: Pascal
authors.initials: P
authors.lastname: Legendre
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D007002:Hypoglossal Nerve / Q000166:cytology / Q000254:growth & development / Q000378:metabolism*; D008526:Medulla Oblongata / Q000166:cytology / Q000254:growth & development / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism*; D009128:Muscle Spasticity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D011940:Receptor Aggregation / Q000187:drug effects / Q000235:genetics; D020239:Receptor Cross-Talk / Q000502:physiology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D018009:Receptors, Glycine / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D005680:gamma-Aminobutyric Acid