P. 2. c. 011 Overexpression of the homeobox Otx2 gene leads to spontaneous fluctuations in manic-and depressive-like behaviour

M Jukic, A Avin, M Bar, T Baron, K Zega, O Novikov, O Kofman, G Agam, C Brodski

Research output: Contribution to journalMeeting Abstract


Objectives: Changes in mood which are not correlated to apparent
exogenous events are an integral part of normal behavior. In
bipolar disorder, fluctuations of manic- and depressive behavior,
which are often not associated with obvious external events, play
a critical role. Despite the importance for normal and pathological
behavior, the mechanisms underlying endogenous fluctuations in
mood are virtually unknown. A major obstacle preventing progress
of our understanding of this behavior has been the lack of
appropriate animal models [1]. Previously, we demonstrated that
the transcription factor Otx2, which has been suggested as a susceptibility gene for bipolar disorder, orchestrates the development
of monoaminergic neurons [2].
P.2.c. Mood disorders and treatment − Bipolar disorders (basic) S361
Mutants overexpressing Otx2 show a subtle, but significant
increase of midbrain dopaminergic neurons and a substantially
decrease in serotonergic neurons. A reduction of noradrenergic
neurons is also present in the locus coeruleus. Moreover, transmitter measurements, transporter binding assays and autoradiography experiments indicate in mutants a subtle increase in striatal
dopaminergic innervation and a marked decrease of serotonergic
innervation in all tested brain areas.
Results: Here we use mouse mutants overexpressing Otx2,
to study endogenous fluctuations in manic- and depressive-like
behavior. We found that Otx2 mutants show in their home cage,
extended periods of hyperactivity spontaneously alternating with
periods of reduced activity.
This observation was quantified by assessing the coefficient of
variance which we calculated by dividing the standard deviation
of the mean activity of individual animals by their mean activity.
Mutants showed a significantly higher value compared to controls
(t10 = 2.462, p = 0.034). Repeated measurements in the open field
demonstrated for Otx2 mutants increased intra-individual fluctuations in locomotor activity (t18 = 3.029, p = 0.007), habituation
(t18 = 2.38, p = 0.027) and different risk-taking behavioural parameters related to the presence in the center of the open field
(t18 = 2.482, p = 0.028, t18 = 2.864, p = 0.014). In the sugar preference test, which was used as a measure for hedonic-like behavior
Otx2 mutants showed increased intra-individual changes in sweet
preference (t18 = 2.897, p = 0.01) and sugar intake (t10 = 3.057,
p = 0.008).
Lithium and olanzapine, which are used for the treatment of bipolar disorder as well as drugs interfering with
monoaminergic neurotransmission reversed behavioural alterations of Otx2 mutants. Acute olanzapine treatment selectively
reduced in mutants risk taking behaviour in the elevated plus maze
Genotype×TreatmentF1,40 = 4.663, p = 0.038) and in the dark light box
Genotype×TreatmentF1,40 = 2.886, p = 0.098).
Chronic lithium treatment reduced the distance traveled in
the center of the open field (Treatment×GenotypeF1,210 = 8.525, p = =
The Coefficient of variance of the frequency of entries in the
open field was also reduced in mutants after lithium treatment
Treatment×GenotypeF1,210 = 7.231, p = 0.008).
Conclusions: We conclude that a dysfunction of Otx2 could
play a critical role in the fluctuation of manic- and depressive
behaviour by altering normal monoaminergic neurotransmission.
[1] Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders.
Nat Neurosci. 2010 Oct; 13: 1161−9.
[2] Brodski C, Vogt Weisenhorn D, Signore M, Sillaber I, Oesterheld M,
Broccoli V, Acampora D, Simeone A, Wurst W. Location and size of
dopaminergic and serotonergic cell populations are controlled by the
position of the mid-hindbrain organizer Journal of Neuroscience, 2003,
23(10): 4199–207.
Disclosure statement: The National Insitute for Psychobiology in Israel −
Founded by the Charles E. Smith Family (grant 209−11−12 to C.B.) and
The Israeli Ministry of Health, Chief Scientist Office (grant 3–7433 to
Original languageEnglish GB
Pages (from-to)S360-S361
JournalEuropean Neuropsychopharmacology
Issue number23
StatePublished - 2013


Dive into the research topics of 'P. 2. c. 011 Overexpression of the homeobox Otx2 gene leads to spontaneous fluctuations in manic-and depressive-like behaviour'. Together they form a unique fingerprint.

Cite this