Sleep and Circadian Rhythm Disruption in Social Jetlag and Mental Illness - Progress in Molecular Biology and Translational Science - page 338

brain. 65 NRG1 is expressed in the SCN and retinal ganglion cells, 66,67 con-
sistent with its proposed involvement in circadian function.
4.2. Genes that generate and regulate sleep and circadian
rhythms that also play a role in normal mental health
At the level of genetic association, several studies have identified associations
between schizophrenia and clock genes (reviewed in Ref. 68 ). There is some
evidence of an association with Per3 and Tim with schizophrenia and
schizoaffective disorder, and Cry1 has been suggested as a candidate gene
for schizophrenia based on its location near a linkage hot spot for schizo-
phrenia on chromosome 12q24. A transmission bias for the Clock
3111C/T polymorphism has been suggested in a population of 145 Japanese
schizophrenia patients. This polymorphism has been associated with aber-
rant dopaminergic neurotransmission to the SCN. Elevated Per1 expression
has also been shown in the temporal lobe of postmortem schizophrenic
brains. 68
Mechanistic evidence also exists for a link between the circadian system
and bipolar disorder. First, the serine/threonine protein kinase GSK3B is
known to phosphorylate elements of the transcriptional-translational feed-
back loop (TTFL) and is a target of the mood-stabilizer lithium. 69 Additional
evidence has come from behavioral phenotyping of Clock mutant mice.
Mice carrying a mutation of the TTFL component Clock show hyperactiv-
ity, reduced sleep, lower anxiety, increased risk-taking behavior, and
increased reward value for cocaine, sucrose, or medial forebrain stimulation.
Chronic administration of lithium returned these responses to wild-type
levels. These behaviors are analogous to those seen in patients with mania.
The Clock mutant animals also showed elevated dopamine function in the
ventral tegmental area (VTA), and the behavioral phenotype could be res-
cued by expressing functional CLOCK protein in this region alone. 70 More-
over, in vivo gene silencing in the VTA alone has been shown to produce
such mania-related behaviors. 71 It is possible that the role of CLOCK in
the VTA that gives rise to the mania phenotype described in these studies
may occur as a result of a deficit in circadian function, but could also occur
via an unrelated role of this protein in the VTA. Certainly, silencing this
gene in the VTA results in changes in the expression of other genes, includ-
ing ion channels and genes involved in dopamine synthesis. 71 Further evi-
dence comes from the Myshkin mouse mutant, which is caused by a
mutation in the neuron-specific sodium, potassium ATPase a 3( Atp1a3 ).
Similar to Clock mutant mice, these animals, both a mania and SCRD