Synapse formation and clustering of neuroligin-2 in the absence of GABAA receptors.
GABAergic synapses are crucial for brain function, but the mechanisms underlying inhibitory synaptogenesis are unclear. Here, we show that postnatal Purkinje cells (PCs) of GABA(A)alpha1 knockout (KO) mice express transiently the alpha3 subunit, leading to the assembly of functional GABA(A) receptors and initial normal formation of inhibitory synapses, that are retained until adulthood. Subsequently, down-regulation of the alpha3 subunit causes a complete loss of GABAergic postsynaptic currents, resulting in a decreased rate of inhibitory synaptogenesis and formation of mismatched synapses between GABAergic axons and PC spines. Notably, the postsynaptic adhesion molecule neuroligin-2 (NL2) is correctly targeted to inhibitory synapses lacking GABA(A) receptors and the scaffold molecule gephyrin, but is absent from mismatched synapses, despite innervation by GABAergic axons. Our data indicate that GABA(A) receptors are dispensable for synapse formation and maintenance and for targeting NL2 to inhibitory synapses. However, GABAergic signaling appears to be crucial for activity-dependent regulation of synapse density during neuronal maturation.
Patrizi
Annarita
A
Department of Anatomy, Pharmacology, and Forensic Medicine, and National Institute of Neuroscience-Italy, C.so Massimo d'Azeglio, 52, I-10126 Turin, Italy.
Scelfo
Bibiana
B
Viltono
Laura
L
Briatore
Federica
F
Fukaya
Masahiro
M
Watanabe
Masahiko
M
Strata
Piergiorgio
P
Varoqueaux
Frédérique
F
Brose
Nils
N
Fritschy
Jean-Marc
JM
Sassoè-Pognetto
Marco
M
D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D021381:Protein Transport; D011689:Purkinje Cells / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D011963:Receptors, GABA-A / Q000172:deficiency* / Q000378:metabolism; D013569:Synapses / Q000378:metabolism* / Q000648:ultrastructure
D015816:Cell Adhesion Molecules, Neuronal; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011963:Receptors, GABA-A; C098003:neuroligin 2