Abstract
(from Importin a5 Regulates Anxiety through MeCP2 and Sphingosine Kinase 1, Panayotis et al, 2018)
Importins mediate transport from synapse to soma and from cytoplasm to nucleus, suggesting that perturbation of importin-dependent pathways should have significant neuronal consequences. A behavioral screen on five importin a knockout lines revealed that reduced expression of importin a5 (KPNA1) in hippocampal neurons specifically decreases anxiety in mice. Re-expression of importin a5 in ventral hippocampus of knockout animals increased anxiety
behaviors to wild-type levels. Hippocampal neurons lacking importin a5 reveal changes in presynaptic plasticity and modified expression of MeCP2- regulated genes, including sphingosine kinase 1 (Sphk1). Knockout of importin a5, but not importin a3 or a4, reduces MeCP2 nuclear localization in hippocampal neurons. A Sphk1 blocker reverses anxiolysis in the importin a5 knockout mouse, while pharmacological activation of sphingosine signaling has robust anxiolytic effects in wild-type animals. Thus, importin a5 influences sphingosine-sensitive anxiety pathways by regulating MeCP2 nuclear
import in hippocampal neurons.
Method
Hippocampal slice preparation
Hippocampal slice recordings were used to investigate the impact of importin a5 deletion at the circuit level. To do so, 8-10 week-old mice were deeply anesthetized with isoflurane, followed by decapitation. The brains were removed and the horizontal hippocampal slices (300-350 mm) were prepared with a Vibratome (Ci 7000 smz, Campden instruments Ltd.) in the ice-cold cutting ACSF solution.
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