Kainate receptor auxiliary subunit NETO2 is required for normal fear expression and extinction
Neuropsychopharmacol.. 2019-02-15; 44(11): 1855-1866
DOI: 10.1038/s41386-019-0344-5
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Mennesson M(1)(2), Rydgren E(1), Lipina T(3)(4)(5)(6), Sokolowska E(1),
Kulesskaya N(1), Morello F(1), Ivakine E(7), Voikar V(8), Risbrough V(9)(10),
Partanen J(1), Hovatta I(11)(12).
Author information:
(1)Molecular and Integrative Biosciences Research Program, University of
Helsinki, Helsinki, Finland.
(2)Department of Psychology and Logopedics, Medicum, University of Helsinki,
Helsinki, Finland.
(3)Lunenfeld Tanenbaum Research Institute at Mount Sinai Hospital, Toronto, ON,
Canada.
(4)Federal State Budgetary Scientific Institution, Scientific Research Institute
of Physiology and Basic Medicine, Novosibirsk, Russia.
(5)Novosibirsk State University, Novosibirsk, Russia.
(6)Department of Pharmacology and Toxicology, University of Toronto, Toronto,
ON, Canada.
(7)Program of Genetics and Genome biology, Hospital for Sick Children, Toronto,
ON, Canada.
(8)Neuroscience Center, University of Helsinki, Helsinki, Finland.
(9)Veterans Affairs, La Jolla, CA, USA.
(10)Department of Psychiatry, University of California, San Diego, CA, USA.
(11)Molecular and Integrative Biosciences Research Program, University of
Helsinki, Helsinki, Finland. .
(12)Department of Psychology and Logopedics, Medicum, University of Helsinki,
Helsinki, Finland. .
Comment in
Neuropsychopharmacology. 2019 Oct;44(11):1841-1842.
NETO1 and NETO2 are auxiliary subunits of kainate receptors (KARs). They
interact with native KAR subunits to modulate multiple aspects of receptor
function. Variation in KAR genes has been associated with psychiatric disorders
in humans, and in mice, knockouts of the Grik1 gene have increased, while Grik2
and Grik4 knockouts have reduced anxiety-like behavior. To determine whether the
NETO proteins regulate anxiety and fear through modulation of KARs, we undertook
a comprehensive behavioral analysis of adult Neto1-/- and Neto2-/- mice. We
observed no differences in anxiety-like behavior. However, in cued fear
conditioning, Neto2-/-, but not Neto1-/- mice, showed higher fear expression and
delayed extinction compared to wild type mice. We established, by in situ
hybridization, that Neto2 was expressed in both excitatory and inhibitory
neurons throughout the fear circuit including the medial prefrontal cortex,
amygdala, and hippocampus. Finally, we demonstrated that the relative amount of
synaptosomal KAR GLUK2/3 subunit was 20.8% lower in the ventral hippocampus and
36.5% lower in the medial prefrontal cortex in Neto2-/- compared to the Neto2+/+
mice. The GLUK5 subunit abundance was reduced 23.8% in the ventral hippocampus
and 16.9% in the amygdala. We conclude that Neto2 regulates fear expression and
extinction in mice, and that its absence increases conditionability, a phenotype
related to post-traumatic stress disorder and propose that this phenotype is
mediated by reduced KAR subunit abundance at synapses of fear-associated brain
regions.
DOI: 10.1038/s41386-019-0344-5
PMCID: PMC6784901
PMID: 30770891 [Indexed for MEDLINE]