title: Unexpected association of the "inhibitory" neuroligin 2 with excitatory PSD95 in neuropathic pain.
abstract: In the spinal nerve ligation (SNL) model of neuropathic pain, synaptic plasticity shifts the excitation/inhibition balance toward excitation in the spinal dorsal horn. We investigated the deregulation of the synaptogenic neuroligin (NL) molecules, whose NL1 and NL2 isoforms are primarily encountered at excitatory and inhibitory synapses, respectively. In the dorsal horn of SNL rats, NL2 was overexpressed whereas NL1 remained unchanged. In control animals, intrathecal injections of small interfering RNA (siRNA) targeting NL2 increased mechanical sensitivity, which confirmed the association of NL2 with inhibition. By contrast, siRNA application produced antinociceptive effects in SNL rats. Regarding NL partners, expression of the excitatory postsynaptic scaffolding protein PSD95 unexpectedly covaried with NL2 overexpression, and NL2/PSD95 protein interaction and colocalization increased. Expression of the inhibitory scaffolding protein gephyrin remained unchanged, indicating a partial change in NL2 postsynaptic partners in SNL rats. This phenomenon appears to be specific to the NL2(-) isoform. Our data showed unexpected upregulation and pronociceptive effects of the "inhibitory" NL2 in neuropathic pain, suggesting a functional shift of NL2 from inhibition to excitation that changed the synaptic ratio toward higher excitation.
authors.affiliation: CNRS, UMR5297, IINS, F-33077 Bordeaux, France Université de Bordeaux, F-33077 Bordeaux, France Inserm, U862, Neurocentre Magendie, F-33077 Bordeaux, France Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montréal (IRCM), QC H2W 1R7, Canada.
authors.forename: Tiphaine
authors.initials: T
authors.lastname: Dolique
authors.forename: Alexandre
authors.initials: A
authors.lastname: Favereaux
authors.forename: Olivier
authors.initials: O
authors.lastname: Roca-Lapirot
authors.forename: Virginie
authors.initials: V
authors.lastname: Roques
authors.forename: Claire
authors.initials: C
authors.lastname: Léger
authors.forename: Marc
authors.initials: M
authors.lastname: Landry
authors.forename: Frédéric
authors.initials: F
authors.lastname: Nagy
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000502:physiology*; D059350:Chronic Pain / Q000503:physiopathology; D000076122:Disks Large Homolog 4 Protein; D006930:Hyperalgesia / Q000503:physiopathology; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D008026:Ligation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D036421:Nerve Fibers, Unmyelinated / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009437:Neuralgia / Q000503:physiopathology* / Q000523:psychology; D010812:Physical Stimulation; D020671:Posterior Horn Cells / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D013127:Spinal Nerves / Q000502:physiology
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C098003:neuroligin 2
keywords: Dorsal horn; Neuroligin; Neuropathic pain; Painful sensitization; Spinal cord
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