Published in Volume
119, Issue 4
(April 1, 2009)J Clin Invest.
Copyright © 2009, American Society for Clinical
Bipolar disorder: from genes to behavior pathways
Mood and Anxiety Disorders Program, National Institute of Mental Health,
NIH, Bethesda, Maryland, USA.
Address correspondence to: Husseini K. Manji, Johnson & Johnson
Pharmaceutical Research and Development, 1125 Trenton-Harbourton Road, E32000,
Titusville, New Jersey 08560, USA. Phone: (609) 730-2968; Fax: (609) 730-2940;
Published April 1, 2009
Bipolar disorder (BPD) is a devastating illness that is characterized by recurrent
episodes of mania and depression. In addition to these cyclic episodes, individuals
with BPD exhibit changes in psychovegetative function, cognitive performance, and
general health and well being. In this article we draw from neuroimaging findings in
humans, postmortem data, and human genetic and pharmacological studies as well as
data from animal models of behavior to discuss the neurobiology of BPD. We conclude
with a synthesis of where the field stands and with suggestions and strategies for
future areas of study to further increase our conceptual understanding of this
Bipolar disorder (BPD), classified as a mood disorder in the Diagnostic and
statistical manual of mental disorders (4th edition), is a common, chronic,
and recurring medical disorder that is characterized by episodes of mania —
extremely elevated mood, energy, unusual thought patterns, and sometimes psychosis
— and depression. Although these episodes are usually interspersed with
periods of relatively normal mood, BPD is the cause of significant suffering for both
patients and their families. BPD leads to limited functioning, which often results in
decreased productivity in both the personal and the professional arenas of the
patient’s life. The prognosis for patients with BPD is poor, with high rates
of relapse, lingering residual symptoms, cognitive impairments, and diminished well
being (1). Moreover, individuals with BPD
frequently have coexisting medical conditions, such as obesity, cardiovascular disease,
diabetes mellitus, and thyroid dysfunction, all of which are exacerbated by their BPD
The prevalence of BPD was thought to be around 1%, but current reported diagnoses
indicate that this figure may be closer to 5%. This increased prevalence is mainly
accounted for not by an increase in diagnosis of full-blown BPD (which is known as BPD
I), but by various softer (i.e., less severe) conditions that fall
under the BPD spectrum. Disorders under the BPD spectrum have been grouped based on some
overlap in clinical manifestations; however, whether they share the same underlying
genetics and pathophysiology is uncertain. Therefore, we focus on the emerging
neurobiology surrounding BPD I, referred to herein simply as BPD (3).
Because of the elevated morbidity and mortality suffered by individuals with the
disorder, BPD has been increasingly recognized as a major health problem. Despite
advances in its diagnosis and recognition, the underlying neurobiology of BPD remains
largely unknown. It is thought that BPD is a multifactorial disease that results from a
combination of different genetic profiles, characterized by the presence of various
protective and/or preventive genes relative to susceptibility and/or risk genes as well
as environmental influences, including chronic stressors and traumatic experiences.
Historically, the brain systems receiving the greatest attention in neurobiological
studies of BPD have been the monoaminergic neurotransmitter systems, i.e., the
serotonergic, noradrenergic, and dopaminergic neurotransmitter systems. These
neurotransmitter systems are extensively distributed throughout the brain’s
network of limbic, striatal, and prefrontal cortical neuronal circuits and are thought
to support the behavioral and visceral manifestations of mood disorders (Figure 1). Despite evidence showing that many of these
circuits are likely to be involved, no obvious degeneration or complete dysfunction of
any single neurotransmitter system has been identified. In this regard, the biological
underpinnings of BPD appear to differ from classic neurodegenerative disorders such as
Parkinson disease and Alzheimer disease, where clear deficits can be traced to the
dopaminergic and cholinergic pathways, respectively. However, as we discuss here, many
researchers believe that BPD arises from modulation of synaptic and neural plasticity in
critical circuits mediating affective and cognitive function. Thus, BPD may represent a
disorder of altered synapses and circuits, rather than being the result of imbalances in
Locations of the monoaminergic nuclei within the brain as well as the
projections from these nuclei throughout the brain. Nuclei as well as their projections are color coded: yellow, cholinergic; green,
dopaminergic; blue, noradrenergic; red, serotonergic.
In this Review, we discuss how the currently employed research strategies have furthered
our understanding of the underlying neurobiology of BPD. We have broadly categorized
these strategies into three main areas: patient-based research including neuroimaging,
postmortem tissue analyses, and genetic association studies; analysis of pre-clinical
animal models of BPD, such as models of stress and/or depression, models of mania, and,
more recently, genetic models that resemble specific facets of BPD symptomatology; and
molecular and cellular pharmacologic studies that attempt to identify the cellular and
molecular effects of validated mood-stabilizing drugs (MSDs). We end with a conclusion
about where the field stands, both clinically and pre-clinically, and discuss what we
believe is necessary to make the next steps forward. Clearly, we are at the early stages
of understanding the neurobiology of this complicated and multi-factorial disease.
However, better understanding of the underlying biology is critical for the future
development of targeted therapies that are both more effective as well as free from
harmful and/or intolerable side effects.
Neuroimaging. Functional neuroimaging studies have identified abnormalities in the brains of
individuals with BPD, which may be indicative of dysfunction in key neural circuits
(4). These circuits are distributed
throughout a wide array of neuronal structures, including the amygdala and related
limbic nuclei, the orbital and medial prefrontal cortex (PFC), the anterior
cingulate, the medial thalamus, and related regions of the basal ganglia (Figure
It is plausible that dysfunction or modulation of these circuits may predispose an
individual toward manifestation of the symptoms of BPD. For example, studies have
shown reduced activity in the right PFC during episodes of mania (6), and dysfunction of the right PFC is thought to
contribute to a disinhibited profile, including poor impulse control, risk taking,
distractibility, poor sustained attention, and delusions, all of which resemble the
symptoms of mania (4, 7).
Schematic of neuroanatomical regions implicated in affective processes. Neuroimaging studies, observations from patients with selective CNS lesions, as
well as data from animal behavioral studies have implicated several regions
throughout the brain in the control of mood states and emotions. These regions are
located throughout the limbic, striatal, and frontal regions. Adapted with
permission from Neuropsychopharmacology (24).
Researchers using CT and MRI have identified structural changes in the brains of
patients with mood disorders, including patients with BPD. Overall, gray matter
volume is not substantially different in patients with BPD compared with normal
healthy individuals (8–10). However, several studies have found
region-specific reductions in gray matter volume, including increased ventricular
size and decreased frontal cortical volume (11, 12). Specifically, volumetric
decreases have been identified in the anterior cingulate cortex (13), and other studies have indicated gray matter
loss in the left dorsolateral PFC (DL-PFC) (14), the ventral PFC, and the orbital PFC (15). Temporal lobe regions, including the hippocampus and the amygdala, have
not been as well studied. However, one study found more prevalent volumetric
decreases in the right hippocampal formation of the affected twin in monozygotic twin
sets discordant for BPD (16).
White matter hyperintensities (WMHs) around the ventricles and in the subcortical
white matter have consistently been found in the brains of depressed elderly persons
as well as in the brains of patients with BPD (17, 18). Although the functional and
pathological relevance of WMHs has not been fully determined, WMHs have been
associated with cerebrovascular accidents (stroke and transient ischemic attacks),
ischemia, axonal loss, increased perivascular space, minute brain cysts, and necrosis
(19). Recent data suggest that a
substantial proportion of individuals with BPD, including children diagnosed with
BPD, exhibit WMHs more frequently than the general population. The incidence of WMHs
is higher in children with neuropsychiatric disorders, including children with BPD
(20, 21). In addition, WMHs are associated with poor treatment outcome in patients
with mood disorders, particularly when localized to the subcortical rather than the
periventricular areas (22, 23). Combined studies on the increased incidence
of WMHs in affective disorders suggest that these lesions could indicate some type of
damage to brain tissue, which could result in disruption of the neuronal connections
necessary for normal behavioral functioning (24).
Imaging studies using magnetic resonance spectroscopy (MRS) led to the notion that
BPD may be associated with mitochondrial dysfunction (25, 26). In particular,
high-resolution 1H-MRS imaging studies conducted to quantitatively assess
concentrations of N-acetyl-aspartate (NAA), a predominant
neurochemical in the human brain that is localized to mature neurons and synthesized
within mitochondria, found decreased concentrations of NAA in the hippocampus, the
DL-PFC, the orbitofrontal cortex, and the basal ganglia in various patient
populations, including patients with BPD (27–32). In addition,
studies using 31P-MRS, which allows examination of energy metabolism in
the brain, showed a decrease in phosphocreatine and/or ATP levels in patients with a
mood disorder, including patients with BPD (33–35). Consistent with
these findings, low brain pH levels, as measured indirectly by 31P-MRS,
have also been identified in patients with a mood disorder (33–35).
While it is clear that BPD is not a mitochondrial disorder per se, some data suggest
that cellular and molecular abnormalities present in the brain of patients with BPD
may be associated with alterations in normal mitochondrial function (36). Evidence from microarray, biochemical,
neuroimaging, and postmortem studies support the role of mitochondrial dysfunction in
BPD (37). In addition to energy production,
neuronal mitochondria play an important role in regulating apoptosis, intracellular
calcium levels, and synaptic plasticity (24).
Mitochondrial dysfunction may also be involved in the calcium signaling abnormality
found in BPD (37). Regulation of intracellular
calcium levels may be particularly important in the context of the CNS, since fast
changes in the levels of calcium are responsible for mediating actions associated
with the release of, and response to, neurotransmitters. Changes in calcium levels
are also crucial for initiating transcription events at several genes whose
transcription is dependent on increases in neuronal activity. One of these neuronal
activity–dependent genes, brain-derived neurotrophic factor
(BDNF), has been implicated in the etiology of several mood
disorders (38). Furthermore, it is known that
mitochondria are involved in the initiation of apoptotic processes (39), and newer evidence has suggested that proper
mitochondrial function may be important for the regulation of synaptic plasticity.
For example, increased neural activity has been shown to induce transcription of
genes encoded by mitochondrial DNA, suggesting that increases in energy production
may play a role in the regulation of synaptic strength (40).
A role for the glutamatergic system in mood disorders, including BPD, has also been
supported by neuroimaging data. In a proton MRS study of children with BPD, patients
were shown to have increased levels of glutamate in the frontal lobes and basal
ganglia (41), while another study identified
increased glutamate levels in the occipital cortex of depressed adult patients (42). Although current data from neuroimaging
studies are interesting, their interpretation remains incomplete and often
controversial. Despite finding differences in specific locations and deficits in
biochemical markers, it is not yet understood what these findings represent or how
they may affect the function of various circuits in the brain. In addition, it is not
yet known whether the abnormalities that have been discovered represent developmental
problems that confer vulnerability to severe mood disorders, compensatory mechanisms
for other related pathogenetic processes, or the continual recurrence of affective
Analysis of postmortem human tissue. Studies of postmortem brain tissue from patients with recurrent mood disorders,
including some with BPD, have found reduced subcortical nuclei volumes (43). Various other studies have shown
differential neuronal densities and morphologies that appear to be layer and
cell-type specific in both patients with BPD and patients with major depressive
disorder. For example, the density of neurons containing large cell somas, which are
likely to correspond to glutamatergic pyramidal neurons, was decreased in layers III
and V of the DL-PFC of individuals with recurrent mood disorders (44). Furthermore, the size of DL-PFC neurons in
layers V and VI was also reduced (45). In
patients with BPD, the size of the cell soma of pyramidal neurons in the CA1 region
of the hippocampus has been found to be decreased (46), as have cell densities in layers III–VI in different regions
of the anterior cingulate (24, 36). Interestingly, cell densities of
nonpyramidal neurons were decreased in layer II, and neuron size was increased in
layers II and V of these anterior cingulate regions (24, 36).
In addition, decreased levels of calbindin- and parvalbumin-expressing neurons, both
of which are subtypes of GABAergic interneurons, have been identified in the anterior
cingulate cortex, the hippocampus, and the entorhinal cortex of patients with BPD
(47, 48). These data, in combination with studies showing decreased hippocampal
expression of glutamic acid decarboxylase 67 (GAD67) and somatostatin in the
hippocampus of patients with BPD, have led to the hypothesis that a subset of
hippocampal interneurons may be abnormal in BPD (49).
In addition to changes in the size and density of neuronal cell types, changes in
glial cell biology have also been observed in studies of postmortem tissue from
patients with BPD. The density of glial cells seems to be decreased in frontal
cortical areas, while the nucleus size increases (44, 50–52). Moreover, a proteomics study using brains
from individuals with BPD and individuals with major depressive disorder found
disease-specific alterations in levels of glial-fibrillary acidic protein (GFAP), an
abundantly expressed astrocyte-specific protein (53). Additional studies have found reductions in oligodendrocyte number and
in the expression of genes that are related to oligodendrocyte differentiation and
myelin production in the DL-PFC of individuals with BPD (54). The recurrent theme of decreased cell density and number may
represent cell loss and atrophy in these patients over the course of disease
progression. It is presently unknown whether this type of brain atrophy is one of the
underlying causes of the disease, or whether it contributes to illness pathology by
disrupting the normal circuitry that is key to normal affective and cognitive
As discussed above, neuroimaging studies have provided suggestive evidence for
abnormalities in mitochondrial function and energy production in BPD. Analysis of
expression levels of key mitochondrial-related genes in the postmortem human brain
has provided additional evidence to support this idea. A recent microarray study
comparing postmortem hippocampal tissue from individuals with BPD and individuals
with schizophrenia as well as normal healthy controls revealed that the expression of
43 genes was decreased in patients with BPD compared with those with schizophrenia
(49). Furthermore, 42% of these genes
encoded mitochondrial proteins.
In addition to the prominent findings of altered expression of genes encoding
mitochondrial proteins, substantial changes have been observed in the level of
expression of proteins implicated in synaptic function. These findings suggest
alterations in synaptic plasticity mechanisms in individuals with BPD. The neuronal
plasticity marker GAP-43 is highly expressed in axonal growth cones during
development and is implicated in regulation of axonal morphology and synaptic
plasticity in the mature brain (55). In
patients with BPD, it has been reported that levels of GAP-43 are reduced in both the
cingulate cortex and the hippocampus (56,
57). The synapsin family of proteins binds
synaptic vesicles to the cytoskeleton, preventing their transport to the presynaptic
membrane and subsequent neurotransmitter release (58). Docking of synaptic vesicles and neurotransmitter release are regulated
by a complex of proteins that includes SNAP-25, syntaxin, synaptobrevin, and
synaptophysin. In postmortem brains from individuals with BPD, a reduction in the
levels of synapsin family members has been found in the hippocampus (59). However, increases in the levels of SNARE
complex proteins, which are responsible for mediating the fusion of synaptic vesicles
with the cell membrane, have been observed in the DL-PFC (60). An additional study showed decreased levels of synaptobrevin
and synaptophysin in the visual association cortex of patients with BPD (61). The levels of mRNAs encoding netrins, a
family of proteins important in regulating axon guidance, have also been shown to be
reduced in the CA3 region of the hippocampus and entorhinal cortex of patients with
Genetic studies. Combined evidence from family, twin, and adoption studies suggests that BPD has a
strong genetic component. Twin studies show a highly elevated concordance rate in
monozygotic twins when compared with dizygotic twins (63, 64), and BPD is more likely to
occur in biological parents of adopted children than in the adoptive parents (65). Strategies for detecting the genetics of BPD
include both linkage and association studies. Linkage methods test the loci of
vulnerability genes by studying co-inheritance of chromosomal fragments in specific
illnesses, whereas association studies test whether a specific gene variant is
associated with a given disorder. A list of genes, including their known functions
and potential role in the etiology of BPD, that have been implicated via both linkage
and association studies is lengthy and beyond the scope of this review (see ref.
66 for an in-depth discussion). Of the
implicated genes, most attention has been given to those that encode proteins known
to interact with signaling pathways previously implicated in BPD. For example,
several of the risk genes that have been identified are known to interact with the
PKC and glycogen synthase kinase 3β (GSK3β) signaling
pathways (67, 68). In addition, other putative susceptibility genes, including glutamate
receptor, metabotropic 3 (GRM3) and GRM4; glutamate
receptor, ionotropic, N-methyl-d-aspartate 2B
(GRIN2B); D–amino acid oxidase
(DAO); and DAO activator (DAOA, also known as
G72), encode proteins involved in glutamatergic signaling (68, 69).
In addition, a number of genes encoding proteins involved in circadian biology,
including ARNT-like protein 1, brain and muscle (BmaL1), TIMELESS, and PERIOD3, have
been implicated as susceptibility genes for BPD (68). These genes are of interest because virtually all patients with BPD have
alterations in circadian function, including alterations in sleep patterns, activity,
hormonal secretions, and appetite.
Beyond the older linkage and association studies, recent advances in technology have
allowed researchers to study the genetic component of BPD using genome-wide
association studies (GWASs). Four groups have recently performed independent GWASs of
BPD (67, 70–72). However, the
significance of these findings is unclear, since very few findings have been
replicated from sample to sample and there is the possibility of multiple false
positives due to the substantial number of comparisons. In one study using 1,233
patients with BPD and 1,439 control subjects, Baum and colleagues identified a SNP in
diacylglycerol kinase h (DGKH) as being associated with BPD (67). The Wellcome Trust Case Control Consortium
(WTCC) analyzed 1,868 individuals with BPD and 2,938 control subjects and identified
a locus in a gene rich region of high linkage disequilibrium on chromosome 16p12 as
being associated with BPD (70). Sklar et
al.’s study of 1,461 patients with BPD and 2,008 control subjects found
their strongest result in myosin 5B (MYO5B) (71). The most recent GWAS, by Ferreira et al., used a new sample
with 1,098 individuals with BPD and 1,267 control subjects and found the strongest
results in ankyrin G (ANK3) and calcium channel, voltage-dependent,
L-type, α 1C subunit (CACNA1C) (72). A broad comparison of the WTCC and the Sklar study also
confirmed the CACNA1C results, identifying CACNA1C
as showing a consistently strong signal in individuals with BPD (72). More studies are clearly necessary before
any consensus can be made as to the significance of these recent findings.
Analysis of pre-clinical animal models of BPD
While considerable caution undoubtedly needs to be taken in applying animal models to
complex neuropsychiatric disorders, animal models can be valuable tools for exploring
the underlying pathologies of human diseases and developing better therapies. An ideal
animal model for BPD should show face validity, i.e., it should include spontaneous and
progressive behavior that oscillates between increased and decreased manifestations of
the behavior being modeled, which should be similar to a behavior characteristic of
either human mania or depression. Moreover, the modeled behavior should show predictive
validity, i.e., it can be normalized by treatment with MSDs (36). The progressive and cyclic nature of BPD presents a unique
challenge for modeling in rodents. Indeed, as discussed in detail below, most models
have tended to focus on either mania or depression, rather than modeling both behaviors,
which both occur in individuals with BPD (36,
73). Currently, more models of depressive
illness exist than of mania or of the cyclical nature of BPD (73). Increasing the difficulty of developing animal models of BPD is
the hypothesis that an interaction between both genes and the environment are needed in
order to manifest symptoms of the illness. Determining what types of environmental
disturbances to pair with the various genetic alterations is difficult, but may be
critical in effecting useful models.
Models of stress and/or depression. A commonly used line of research for those studying BPD using animal models is to
examine the relationship between cellular and molecular characteristics of animals
and behavior in laboratory situations that replicate environments thought to
predispose humans toward depression. Some of the more commonly used models have been
maternal separation and various chronic stress paradigms including psychosocial
stress, mild unpredicted stress, and restraint/immobilization stress (36, 74).
Another model used to induce a depression-like state is the learned helplessness
model (73, 75). In this model, animals are administered an inescapable aversive
stimulus, frequently an electric foot shock. Following the inescapable portion of the
paradigm, animals are again administered the aversive stimulus, but in an environment
where they are capable of escaping the aversive stimulus. Longer latencies or a lack
of any response is seen as indicative of “learned
helplessness” (73, 75). The forced swim test is the most commonly
used animal model in depression research, and more specifically has been widely used
as a screen for antidepressant treatments (74,
76). These models have been useful thus far
in helping to screen for potential therapeutic candidates. Further, studies with
genetically modified animals using these paradigms have helped to identify candidate
molecular and genetic signaling pathways that may be involved in the development of
behavioral attributes that mirror disease symptomatology. However, we have yet to be
able to adequately model the diseases well enough to determine anything conclusive
about the overall etiology of the disorder.
Models of mania. Hyperactivity is one of the more simple behaviors to detect and quantify in animals.
Thus, many models of mania that have been developed have focused on this aspect as
the core of their modeling (36, 77). Acute treatment with psychostimulants such
as methamphetamines and cocaine can produce a wide range of mania-like behaviors,
including hyperactivity, heightened awareness and alertness, insomnia, and changes in
sleep patterns (78, 79). Psychostimulant-induced hyperactivity is sensitive to
lithium treatment and possibly to other anticonvulsants that have been used as MSDs.
Sleep deprivation has also been used with some success as a model for mania. Rats
exposed to 72 hours of sleep deprivation exhibit a variety of behaviors that show
face validity for modeling human mania. These behaviors include insomnia,
hyperactivty, irritability, aggressive behavior, and hypersexuality (78, 79).
Furthermore, in terms of predictive validity, lithium has been shown to alleviate
some of these mania-like behaviors.
Genetic models of BPD. Numerous genetic modifications, most of which have been engineered in the mouse
species (Table 1), show increased
depressive-like symptoms and alterations in affective behavior in various behavioral
tests. As previously discussed, depressive-like behavior is often measured as the
extent of behavioral desperation in the forced swim test or as increased
susceptibility toward learned helplessness. In addition, genetic animal models have
been developed that do not confer susceptibility to depression per se but do render
the animals unresponsive to antidepressants (Table 2). These models have been useful in helping to identify various genes and
signaling pathways that may be involved in the development of depressive symptoms
and, importantly, in the response to antidepressant drugs. Here we highlight several
findings that have produced much interest and stimulated continued research in the
Important genetically engineered mice that model BPD behaviors
Genetically engineered mice important to BPD research
The neurotrophic hypothesis of depression posits that growth factors, in particular
BDNF, play a key role in regulating mood (38).
This hypothesis arose from several observations: first, that the amount of BDNF is
decreased in the hippocampus of animals showing abnormalities in depressive- and
anxiety-like behavior (80); second, that
chronic but not acute antidepressant usage increases BDNF levels (81); and third, that acute application of BDNF,
via intrahippocampal injection, has an antidepressant effect (82). However, the neurotrophic hypothesis of depression has been
complicated by various genetic manipulations within the BDNF signaling pathway, which
show complex, region-specific effects. For example, it has now been shown that
contrary to its antidepressant effect in the hippocampus, administration of BDNF in
the ventral tegmental area (VTA) results in pro-depressive behaviors (83). Conditional deletion of
BDNF in the forebrain does not seem to confer depression per se but
does seem to be important in the ability to respond to antidepressants (84). Interestingly, the inability to respond to
antidepressants has also been observed in mice that lack adult hippocampal
neurogenesis (85). A number of investigators
have produced results suggesting that creation of new neurons in the dentate gyrus of
the hippocampus is involved in mood regulation (86). Since BDNF has been implicated in regulation of complex mood-related
behavior as well as the proliferation and survival of new neurons in the dentate, it
has been postulated that BDNF signaling may be an important component in adult
neurogenesis and that this pathway may be uniquely involved in the regulation of
mood-related behavior (86). However, it is
clear that the story is not completely straightforward, and further research is
necessary to elucidate the effects of BDNF in the etiology of depression, the role of
BDNF in the response to antidepressant treatment, and how these effects may be
related to adult hippocampal neurogenesis.
Two recent reports of mutant mice resembling behavioral facets of mania have
reinvigorated interest in animal models of BPD (Table 1). In the first report, McClung and colleagues found that mutant mice
carrying a Clock gene mutation that encodes a
dominant-negative CLOCK protein are hyperactive, need less sleep, and show an
increased propensity for stimulants and reward (87). These mutant mice exhibit less depressive- and anxiety-like behavior
and, remarkably, chronic administration of lithium reduced many of the behavioral
features reminiscent of mania. These results are particularly interesting since
circadian rhythms and the genes that underlie the molecular clock have been highly
implicated in BPD and because patients with BPD show marked behavioral impairments in
their circadian rhythms. A second report of interest concerns the gene encoding
glutamate receptor 6 (Glur6) (101). As
GLUR6 resides in a genetic linkage region (6q21) associated with
BPD, the demonstration that Glur6-deficient mice exhibit behavior related to symptoms
of mania is very exciting (88). Specifically,
Glur6-deficient mice exhibit less anxious behavior, more risk-taking behavior, less
despair-type manifestations, and increased aggressive displays. Further, chronic
lithium treatment in these mice reduces hyperactivity, aggression, and some
risk-taking behavior (88). Future studies
similar to these should begin to shed light on the etiology of BPD as well as provide
various genetic and behavioral models that can be used to dissect the underlying
neurobiological mechanisms associated with particular deficits in BPD.
Recent studies have identified a molecule that may be associated with affective
resilience and enhanced recovery from depressive-like and manic-like states (89). The molecule, Bcl-2–associated
athanogene (Bag1), interacts with Hsp70, glucocorticoid receptors (GRs), Bcl-2, and
Raf, thereby regulating intracellular signal transduction, nuclear hormone receptors,
gene transcription, and cell survival. Microarray studies identified Bag1 as a target
for the actions of MSDs (90), and analysis of
neuron-selective Bag1 transgenic mice indicated a beneficial role for the protein in
depressive-like and manic-like behaviors (102). Specifically, Bag1 transgenic mice showed less anxious-like behavior
and had higher spontaneous recovery rates following analysis in the learned
helplessness model of stress and/or depression. On mania-related tests, Bag1
transgenic mice recovered much faster in the amphetamine-induced hyperlocomotion test
and displayed a clear resistance to cocaine-induced behavioral sensitization.
Molecular and cellular pharmacologic studies
Despite substantial advances in pharmacotherapeutics, lithium remains the gold standard
therapy for BPD. Valproic acid (VPA), which was first used therapeutically as an
anticonvulsive, has become an additional mainstay for treating BPD (36). Current research on understanding the actions
of lithium and VPA assumes that these drugs do not have major direct interactions with
cell surface receptors and are more likely to exert their effects directly or indirectly
through modulation of intracellular targets. Although several targets and mechanisms of
these drugs have been identified, precisely which effects are responsible for specific
facets of the therapeutic response remains to be fully elucidated. Since the chemical
structures of lithium, which is a monovalent cation, and VPA, which is a fatty acid, are
highly dissimilar, identifying common targets for these two effective MSDs could be
potentially important, as shared biochemical targets would be more likely to represent
targets underlying their therapeutic value. It is beyond the scope of this article to
review all the molecular and cellular pharmacologic studies; the reader is referred to
other reviews (91, 92). Here, we evaluate the most extensively studied and highly
Lithium at therapeutically relevant concentrations functions as a direct inhibitor of a
limited number of enzymes because it acts as a competitor for magnesium (93, 94). The
enzymes known to be inhibited by lithium include inositol monophosphatase (IMPase);
inositol polyphosphate 1–phosphatase (IPPase); bisphosphate
3′-nucleotidase; fructose 1,6-bisphosphatase; GSK3β; and
phosphoglucomutase (reviewed in refs. 95–97). The signaling
pathways that involve IMPase and GSK3, the phosphoinositol signaling cascade and the Wnt
signaling pathway, respectively, have received the greatest attention and interest
Overview of the PI and Wnt/GSK3 signaling pathways in the neuron. (A) Lithium directly inhibits key enzymes including IPPase and IMPase
that regulate inositol-1,4,5-triphosphate (IP3) recycling.
IMPase–mediated catalysis represents the final step in the conversion
of inositol monophosphate (IMP) to myoinositol. Thus, inhibiting IMPase can reduce
myoinositol levels. The inositol depletion hypothesis proposes that IMPase
inhibition interferes with PI synthesis. The PI signaling cascade starts with
surface receptor activation, shown here as GPCR-mediated activation of PLC.
Activated PLC catalyzes the hydrolysis of PI biphosphate (PIP2) to diacylglycerol
(DAG) and IP3. DAG activates PKC, which, among many other functions, activates
myristoylated, alanine-rich C-kinase substrate (MARCKS). The antimanic drugs
lithium and VPA both decrease levels of phosphorylated and total MARCKS. Molecules
in red depict enzymes, while molecules in blue depict second messengers. PI
signaling modulates other second messenger proteins including the small GTPase,
Ras, and phosphatidylinositol-4-phosphate (PIP4). (B) Overview of the
Wnt and GSK3 signaling pathways. Both lithium and Wnt signaling can inhibit GSK3.
In the Wnt signaling pathway, Wnt glycoproteins interact with the frizzled family
of receptors to stimulate the dishevelled-mediated (not shown) inactivation of
GSK3. Inhibition of GSK3 prevents β-catenin phosphorylation, which
inhibits its degradation and allows it to act as a transcription factor. Wnt
proteins have been implicated in the regulation of neuron morphology,
neurotransmission, and synaptogenesis. GSK3 is also inhibited by AKT (also known
as PKB), which is activated downstream of the tropomyosin receptor B (TrkB), whose
ligand is BDNF. In addition to inhibiting β-catenin, GSK3 has numerous
other targets including microtubule-associated proteins, tau, GSK, and rev-erb
α. Adapted with permission from
The phosphoinositol signaling cascade mediated by G protein activation of PLC-B is one
of the most extensively studied pathways in BPD research (Figure 3A). The direct inhibition of IMPase and IPPase by lithium suggests
that it may decrease the bioavailability of myoinositol. This inositol depletion
hypothesis posits that lithium interferes with the regeneration of inositol and, under
conditions where inositol limits phosphatidylinositol (PI) synthesis, depletes the cell
of PI. Because PI is an obligate precursor of PI biphosphate (PIP2), the hypothesis
suggests that inhibition of IMPase could disrupt PIP2/IP3-mediated signaling (98, 99).
Although the inositol depletion hypothesis provides an elegant potential mechanism to
explain the actions of lithium, several important issues remain unresolved, and recent
data have challenged some of the predilections to the model. For example, therapeutic
levels of lithium do not deplete PIP2 in vivo, and this phenomenon is an essential
component of the hypothesis (100). Moreover,
although the in vivo inhibition of IMPase is incomplete, it is not clear whether this
modest reduction in inositol is sufficient to impair PI or PIP2 synthesis (101). Research has therefore moved to more
downstream targets in the PI signaling cascade. It has been demonstrated that lithium
reduces the levels of specific PKC isozymes in limbic and limbic-related areas of the
brain. Notably, VPA also exerts similar attenuating effects on PKC signaling, whereas
agents capable of triggering mania exert the opposite effects. One of the genes emerging
as a risk factor for BPD in GWASs, DGKH, encodes a protein that is an
upstream regulator of PKC signaling. These findings on the PKC pathway have led to the
use of tamoxifen, as high concentrations directly inhibit PKC, with promising
preliminary results in the treatment of mania (102). These data suggest that direct, centrally acting PKC inhibitors may
represent novel therapeutics for the treatment of mania (92, 103).
GSK3 antagonizes both the insulin and Wnt signaling pathways and has recently been
demonstrated to regulate synaptic plasticity (104–112). Many of the
known effects of lithium can theoretically be explained in terms of GSK3 inhibition. For
example, lithium increases neuronal growth cone area (104, 105), alters synaptogenesis
(106, 107), and stimulates hippocampal neurogenesis (108). All of these effects mimic Wnt signaling (107, 109, 110). However, inhibition of GSK3 is achieved at
the higher end of the therapeutic range of lithium, raising some questions about whether
this level of inhibition is sufficient to have strong biological effects. However,
secondary inhibition modes have been proposed, which may enhance direct inhibition of
GSK3 by lithium (111, 112). Pharmacologic and genetic approaches that regulate GSK3 have
behavioral effects that suggest utility in the treatment of BPD. For example, two
structurally dissimilar GSK3 small molecule inhibitors and a peptide inhibitor reduce
immobility in the forced swim test and attenuate amphetamine-induced hyperactivity
In addition to its direct effects on GSK3, chronic lithium administration at
therapeutically relevant concentrations induces prominent neuroprotective and
neurotrophic proteins, including Bcl-2 (115) and
BDNF (116), in rodents and cultured neurons.
Bcl-2 is not only a major antiapoptotic protein, but also stimulates axonal regeneration
following injury (reviewed in ref. 117).
Consistent with its effects on GSK3, BDNF, and Bcl-2, lithium has been demonstrated to
exert robust neuroprotective properties against various insults both in vitro and in
vivo (reviewed in ref. 118). Notably, several
independent studies demonstrated that lithium has neuroprotective effects in animal and
cellular models of Alzheimer disease, Huntington disease, Parkinson disease, retinal
degeneration, spinal cord injury, and HIV infection (119). Finally, human neuroimaging data have shown that chronic lithium
treatment in patients with BPD increases NAA levels (a putative marker of neuronal
viability) as well as regional gray matter volumes (120, 121). These human data suggest that
activation of neurotrophic cascades may underlie the mechanisms by which this simple
monovalent cation exerts major effects in the treatment of BPD.
VPA has clear effects on high-frequency sodium channel firing and GABA function, effects
that are likely to contribute to its effects as an anticonvulsant and potentially to its
effects as a mood stabilizer (91). Its ability to
function as a histone deacetylase (HDAC) inhibitor has received a great deal of
attention, as the role of epigenetic modification and transcription regulation in the
control of mood behaviors has garnered increased visibility (122). Recent research has fostered the idea that epigenetic
mechanisms, exerting long-lasting control over gene expression, could mediate stable
changes in brain function in individuals with BPD. Acetylation of histone tail lysines
is a major epigenetic mechanism that is generally associated with transcriptional
activation. Recently, Weaver and colleagues showed that the epigenomic state of the
GR gene could be established via behavioral programming in rats
(123). Remarkably, this epigenomic state
could be reversed with an HDAC inhibitor (124).
Thus, it has been postulated that early-life environmental stressors contributing to the
development of or predisposition to BPD, might be responsive to HDAC inhibitors.
Conclusions and strategies for the future
The large body of literature about the development and underlying neurobiology of BPD
indicates a potential role for a multitude of different signaling pathways and
neuroendocrine systems. As we have reviewed here, there is an emerging body of evidence
suggesting that abnormalities in the regulation of signaling and neural plasticity are
integral to the underlying neuropathology of BPD. A correction of dysregulated
trans-synaptic signaling by MSDs represents a physiological process that curtails the
major oscillations in behavioral states associated with BPD. However, determining which
abnormalities actually mediate predisposition to the disease and which are merely
factors that are along for the ride seems difficult with so many different pathways and
genes being implicated. Although recent research has made great strides toward a better
understanding of the illness, continued technological progression in genetic studies and
animal models of behavior hold promise for extending our knowledge in the future.
An important question to address in future research concerns the distinction between
acute, subchronic, and chronic effects of MSDs and the environmental stressors that
serve to predispose to or contribute to illness development. A clear understanding of
the timeline under which stressors and MSDs mediate their effects will help guide future
studies, enabling researchers to develop hypotheses to test the mechanisms underlying
known effects. For example, acute and subchronic effects are most likely to be mediated
by regulation of neurotransmission, kinase activity, and enzyme inhibition or
facilitation. On the other hand, chronic effects are most likely to be mediated by more
stable, long-lasting changes rooted in changes in gene transcription, likely as a result
of epigenetics and chromatin remodeling or changes to signaling loops as a result of
continual feedback pressure.
As discussed above, a wealth of neuroimaging, neuropathological, biochemical, and
behavioral studies over the course of the past decade have suggested numerous candidates
for impairments in BPD, including a preponderance of components of various cellular
plasticity cascades. These results highlight the potential importance of neuroprotective
and neurotrophic effects in the etiology and treatment of BPD. A growing list of genes
that confer susceptibility to BPD have been identified, a number of which have been
implicated in the cellular or molecular pathophysiology of the disease. These data and
the promise of future technological advances hold much promise for the potential
discovery of novel therapeutics for BPD.
Authorship note: Keri Martinowich and Robert J. Schloesser contributed
equally to this work.
Conflict of interest: The authors have declared that no conflict of
Nonstandard abbreviations used: BAG, Bcl-2–associated
athanogene; BDNF, brain-derived neurotrophic factor; BPD, bipolar disorder; DL-PFC,
dorsolateral PFC; GSK3β, glycogen synthase kinase 3β; GWAS,
genome-wide association study; IMPase, inositol monophosphatase; IPPase, inositol
polyphosphate 1–phosphatase; MRS, magnetic resonance spectroscopy; MSD,
mood-stabilizing drug; NAA, N-acetyl-aspartate; PFC, prefrontal
cortex; PI, phosphatidylinositol; VPA, valproic acid.
Citation for this article:J. Clin. Invest.119:726–736 (2009). doi:10.1172/JCI37703
H.K. Manji’s present address is: Johnson & Johnson
Pharmaceutical Research and Development, Titusville, New Jersey, USA.
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