Mitochondrially Mediated Plasticity in the Pathophysiology and
Treatment of Bipolar Disorder
Jorge A Quiroz1, Neil A Gray1,2, Tadafumi Kato3,4and Husseini K Manji*,1,2,4
1Laboratory of Molecular Pathophysiology, Department of Health and Human services, National Institute of Mental Health, National Institutes of
Health, Bethesda, MD, USA;2College of Physicians and Surgeons, Columbia University, New York, NY, USA and3Laboratory for Molecular
Dynamics of Mental Disorders, RIKEN Brain Science Institute, Saitama, Japan
Bipolar disorder (BPD) has traditionally been conceptualized as a neurochemical disorder, but there is mounting evidence for
impairments of cellular plasticity and resilience. Here, we review and synthesize the evidence that critical aspects of mitochondrial
function may play an integral role in the pathophysiology and treatment of BPD. Retrospective database searches were performed,
including MEDLINE, abstract booklets, and conference proceedings. Articles were also obtained from references therein and personal
communications, including original scientific work, reviews, and meta-analyses of the literature. Material regarding the potential role of
mitochondrial function included genetic studies, microarray studies, studies of intracellular calcium regulation, neuroimaging studies,
postmortem brain studies, and preclinical and clinical studies of cellular plasticity and resilience. We review these data and discuss their
implications not only in the context of changing existing conceptualizations regarding the pathophysiology of BPD, but also for the
strategic development of improved therapeutics. We have focused on specific aspects of mitochondrial dysfunction that may have major
relevance for the pathophysiology and treatment of BPD. Notably, we discuss calcium dysregulation, oxidative phosphorylation
abnormalities, and abnormalities in cellular resilience and synaptic plasticity. Accumulating evidence from microarray studies, biochemical
studies, neuroimaging, and postmortem brain studies all support the role of mitochondrial dysfunction in the pathophysiology of BPD.
We propose that although BPD is not a classic mitochondrial disease, subtle deficits in mitochondrial function likely play an important role
in various facets of BPD, and that enhancing mitochondrial function may represent a critical component for the optimal long-term
treatment of the disorder.
Neuropsychopharmacology (2008) 33, 2551–2565; doi:10.1038/sj.npp.1301671; published online 30 January 2008
Keywords: bipolar disorder; mitochondria; synaptic plasticity; bcl-2; lithium; calcium regulation
Despite the fact that bipolar disorder (BPD) is a common,
severe, often life-threatening illness, the biochemical
abnormalities underlying the predisposition to, and the
pathophysiology of, this complex and intriguing neuropsy-
chiatric disorder have yet to be fully elucidated (Goodwin
and Jamison, 2007). The brain systems that have heretofore
received the greatest attention in neurobiological studies of
BPD have been the monoaminergic neurotransmitter
systems, which are extensively distributed throughout the
network of limbic, striatal, and prefrontal cortical neuronal
circuits thought to support the behavioral and visceral
manifestations of the disease (Drevets, 2000). Neurobiolo-
gical studies of mood disorders over the last 40 years have
primarily focused on abnormalities of these systems, on
characterizing alterations of individual neurotransmitters in
disease states, and on assessing response to mood stabilizer
and antidepressant medications. Studies of cerebrospinal
fluid chemistry, neuroendocrine responses to pharmaco-
logical challenge, and neuroreceptor and transporter bind-
ing have demonstrated a number of abnormalities in
monoaminergic neurotransmitter and neuropeptide sys-
tems in mood disorders (Goodwin and Jamison, 2007).
Unfortunately, these observations have not yet greatly
advanced our understanding of the underlying biology of
recurrent mood disorders, which must include an explana-
tion for the predilection to episodic, and often profound,
mood disturbance that can become progressive over time.
BPD likely arises from the complex interaction of multiple
susceptibility (and protective) genes and environmental
factors, and the phenotypic expression of the disease
includes not only mood disturbance, but also a constellation
of cognitive, motor, autonomic, endocrine, and sleep/wake
Received 18 September 2007; revised 15 December 2007; accepted
15 December 2007
*Correspondence: Dr HK Manji, Mood and Anxiety Disorders
Program, National Institute of Mental Health, National Institute of
Health, Department of Health and Human Services, Building 35, 1C-
912, 35 Convent Drive, Bethesda, MD 20892, USA, Tel: +1 301 496
9802, Fax: +1 301 480 0123; E-mail: firstname.lastname@example.org
4These authors contributed equally to this work
Neuropsychopharmacology (2008) 33, 2551–2565
& 2008 Nature Publishing GroupAll rights reserved 0893-133X/08 $30.00
abnormalities. Furthermore, while most antidepressants
exert their initial effects by increasing intrasynaptic levels
of serotonin and/or norepinephrine, their clinical antide-
pressant effects are observed only after chronic adminis-
tration (over days to weeks), suggesting that a cascade of
downstream events is ultimately responsible for their
therapeutic effects. These observations have led to the idea
that while dysfunction within the monoaminergic neuro-
transmitter systems is likely to play an important role in
mediating some facets of the pathophysiology of BPD, it
likely represents the downstream effects of other, more
primary abnormalities in signaling pathways.
Plasticity, the ability to undergo and sustain change, is
essential for the proper functioning of our nervous system.
This capacity for change allows organisms to adapt to
complex alterations in both their internal and external
environments, a feature fundamentally important for
survival and reproduction. The biological basis of this
capacity to adapt encompasses a diverse set of cellular and
molecular mechanisms that fall under the general term
‘neuroplasticity’; in this paper, we make the distinction
between synaptic plasticity and neuroplasticity.
Synaptic plasticity refers to the cellular process that
results in lasting changes in the efficacy of neurotransmis-
sion. More specifically, the term synaptic plasticity refers to
the variability of the strength of a signal transmitted
through a synapse. The regulation of transmission at the
synapse may be mediated by changes in neurotransmitter
levels, receptor subunit phosphorylation, surface/cellular
levels of receptors, and conductance changes, among others.
Neuroplasticity is a broader term that encapsulates
changes in intracellular signaling cascades and gene
regulation, modifications of synaptic number and strength,
variations in neurotransmitter release, modeling of axonal
and dendritic architecture and, in some areas of the CNS,
the generation of new neurons. Modifications arising from
neuroplastic mechanisms can be of short duration or long
lasting, and this is determined by the qualitative, quanti-
tative, and temporal characteristics of the precipitating
Research on the biological underpinnings of mood
disorders has therefore moved away from focusing on
absolute changes in neurochemicals such as monoamines
and neuropeptides, and instead has begun highlighting the
role of neural circuits and synapses, and the plastic
processes controlling their function. Thus, these illnesses
can best be conceptualized as genetically influenced
disorders of synapses and circuits rather than simply as
(Bachmann et al, 2005; Schloesser et al, 2007). Most
germane to the present discussion is the fact that it is
now clear that mitochondria regulate not only long-term
cell survival/cell death, but also immediate synaptic
functionFboth of which are clearly very relevant for
BPD. Indeed, Kato and co-workers had anticipated some
of the recent developments in the field when they first
proposed that mitochondrial dysfunction might play an
important role in the pathophysiology of BPD (Kato and
Kato, 2000; Kato et al, 2001; Murashita et al, 2000).
It is important to emphasize at the outset that it is not our
contention that BPD is necessarily a classic mitochondrial
disorder. Indeed, the vast majority of BPD patients do
not show the symptoms of classic mitochondrial disorders
(eg, optic and retinal atrophy, seizures, dementia, ataxia,
myopathy, exercise intolerance, cardiac conduction defects,
diabetes, and lactic acidosis; Fadic and Johns, 1996).
Instead, emerging data suggest that upstream abnormalities
(likely encoded in the nucleus) converge on mitochondrial
function, leading to altered synaptic plasticity and impaired
cellular resilience. In this paper, we synthesize and focus on
the emerging data that support the contention that
mitochondrial dysfunction may play a role in the impair-
ments of cellular plasticity and resilience manifest in the
context of BPD. It should be noted that it is beyond the
scope of this paper to discuss in detail the myriad functions
performed by mitochondria. Thus, we limit ourselves to a
discussion of those facets most likely to play a role in the
pathophysiology and treatment of BPD, namely intracellular
calcium regulation, cytoprotection, and synaptic plasticity.
MITOCHONDRIA PLAY CRITICAL ROLES IN INTRA-
CELLULAR Ca2+REGULATION, CYTOPROTECTION,
AND REMODELING NEUROPLASTICITY
Mitochondrial physiology has the well-known function of
energy production through the Krebs tricarboxylic acid
cycle and oxidative phosphorylation. One byproduct of
oxidative phosphorylation is the production of reactive
oxidative species (ROS) that are capable of reacting with a
wide variety of biological substrates, including protein thiol
groups, membrane lipids, and nucleic acids, leading to cell
damage and mutations.
However, mitochondria have additional important roles
in the regulation of intracellular calcium (Ca2+), cytopro-
tection, and synaptic plasticity. Mitochondrial Ca2+uptake
from and release into the cytosol has important conse-
quences for neuronal and glial activity, modulating both
physiological and pathophysiological intracellular res-
ponses (Simpson and Russell, 1998). Calcium ions influence
the synthesis and release of neurotransmitters, receptor
signaling, the action potential, and neuronal periodicity
(Kandel et al, 2000; Torok, 1989; Wolff et al, 1977). The
diffusion of free Ca2+ion in subcellular regions is normally
discrete and short-lived (it is estimated to be free for
B50ms before encountering a Ca2+-binding protein); it is
then sequestered in the mitochondria and endoplasmic
A large movement of positively charged Ca2+into the
mitochondrion will exert a depolarizing effect; most
importantly for the present discussion, this increase can
surpass mitochondrial capacity to export protons (as well as
other cations), and it has the potential to lead to the
cessation of ATP synthesis and the initiation of the
apoptotic (programmed cell death) process (see below).
On N-methyl-D-aspartate(NMDA) glutamate receptor
activation, channel opening allows a rapid influx of Ca2+
into the cytosol and mitochondria that are able to rapidly
buffer this load (Nicholls and Ward, 2000; Stout et al, 1998).
Ca2+uptake into mitochondria may activate the permea-
bility transition pore (PTP, a channel crossing the outer and
inner mitochondrial membranes) independently of ROS
production (Chalmers and Nicholls, 2003; Figure 1).
Mitochondrial dysfunction in Bipolar Disorder
JA Quiroz et al
The opening of the PTP has a number of important
consequences including not only contributions to learning
and synaptic plasticity (Weeber et al, 2002), but also cell
death (Bernardi et al, 1998). Mitochondria immediately
depolarize (stopping or reversing ATP synthesis) and a
number of proteins are released from the intermembrane
space. These include the proteins cytochrome c and
apoptosis-inducing factor (AIF), which are known to lead
to the activation in the cytosol of proteases (caspases). It is
believed that this release is the first irreversible step of
apoptosis, after which the cell is committed to undergo
programmed cell death. Intriguingly, mounting evidence
suggests that activation of mitochondrial apoptotic cascades
may lead to a process of ‘synaptic apoptosis’ activated in a
highly localized manner (Culmsee and Mattson, 2005).
Subsequently, individual synapses or neurites may selectively
undergo atrophy and provide a mechanism for synapse loss
in both physiological and pathophysiological processes.
Apoptotic signaling in the synaptic compartment appears
to have some synapse-specific effects, such as the degrada-
tion of certain glutamate receptors (Glazner et al, 2000).
Importantly, a growing body of evidence suggests
mitochondria may be integrally involved in the general
processes of synaptic plasticity (Yang et al, 2003). The
depolarization of presynaptic mitochondria has been shown
to impair neurotransmitter release following tetanic stimu-
lation (likely through the disruption of intracellular Ca2+
buffering; Billupsand Forsythe,
increased synaptic activity has been shown to induce the
expression of mitochondrial-encoded genes, suggesting
that a long-lasting upregulation of energy production may
be triggered by synaptic activity itself, thereby playing a role
2002). In addition,
exert their action through G protein-coupled receptors associated with PLC, which is involved in the PIP2 intracellular pathway; IP3 and DAG acting on the
endoplasmic reticulum modify the intracellular concentration of Ca2+. Glutamate activation of NMDA receptors also induces a rapid influx of Ca2+into the
cytosol and subsequently, mitochondria. A large movement of positively charged Ca2+into the mitochondrion will exert a depolarizing effect, surpassing
mitochondrial capacity to export protons (as well as other cations), potentially leading to the cessation of ATP synthesis and the activation of the
permeability transition poreFindependently of ROS productionFinitiating apoptotic processes. The figure also depicts the neuroprotective role of the
activation of G protein-coupled receptors associated with the activation of the PKA intracellular pathway, which mediates the phosphorylation and activation
of CREB and upregulates bcl-2Fan antiapoptotic protein that acts by increasing the stability of the PTP. Similar upregulation of bcl-2 occurs through the
activation of Trk-B receptor by BDNF, through the MAP/ERK pathway, in addition to the interference against propapototic mitochondrial proteins (such as
Bad). AC, adenylyl cyclase; AIF, apoptosis-inducing factor; Akt, protein kinase that inactivate GSK; ATP, adenosine triphosphate; Bad, pro-apoptotic protein
regulated by RSK; Bag-1, bcl-2-binding antiapoptotic protein; bcl-2, antiapoptotic protein B-cell leukemia/lymphoma; BDNF, brain-derived neurotrophic
factor; Ca2+, calcium; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein; Cyt c, cytochrome C; DAG, diacylglycerol;
E Ret, endoplasmic reticulum; GC, glucocorticoid; Glu, glutamate; GR, glucocorticoid receptor; Gs, protein G stimulatory of adenylyl cyclase; GSK, glycogen
synthase kinase; Gq, protein G stimulatory of phospholipase C; IP3, inositol 4,5-trisphosphate; IP3r, inositol triphosphate receptor; MAP/ERK, mitogen-
activated protein kinase (MAP) pathway also referred to as extracellular signal-regulated kinase (ERK) pathway; NMDAr, N-methyl-D-aspartate receptor; NT,
neurotransmitter and its G protein-coupled receptor; P, phosphate group; PIP2, phosphatidylinositol biphosphate; PI-3K, phosphatidylinositol 3-kinase; PKA,
protein kinase A; PLC, phospholipase C; PTP, permeability transition pore; ROS, reactive oxidative species; RSK, kinase of ERK-MAP kinase cascade that
downregulates Bad; TCF/LEF, transcription factors for specific genes; Trk-B, tyrosine kinase receptor.
Intracellular signaling pathways relevant to the pathophysiology of BPD and its role in synaptic and neuronal apoptosis. Several neurotransmitters
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