Unexpected association of the “inhibitory” neuroligin 2 with excitatory PSD95 in neuropathic pain.

Tiphaine Dolique, Alexandre Favereaux, Olivier Roca-Lapirot, Virginie Roques, Claire Léger, Marc Landry, Frédéric Nagy
Pain. 2013-11-01; 154(11): 2529-2546
DOI: 10.1016/j.pain.2013.07.035

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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

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