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Neurology Today:
doi: 10.1097/01.NT.0000411143.58747.83
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News from the Society for Neuroscience Meeting: New Evidence for the Distinct Brain Pathophysiology of Mood Disorders

Valeo, Tom

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ARTICLE IN BRIEF

Investigators discuss research implicating neural pathways in mood disorders.

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WASHINGTON, DC—Mood disorders, once ascribed to the mind, are now recognized as the product of genetic and biochemical processes in the brain that may be modified by both experience and medications, according to Huda Akil, PhD, senior research scientist and co-director of the Molecular & Behavioral Neuroscience Institute at the University of Michigan.

In a talk here at the Society for Neuroscience meeting in November, Dr. Akil described how genome-wide association studies (GWAS) have been identifying genes that each confer a small additional risk of bipolar disorder.

“The idea is to look at commonly occurring variants,” she said during a special lecture on the neurobiology of mood. “If it's overrepresented in bipolar illness, you suspect it contributes to it.”

DR. HUDA AKIL said, ...
DR. HUDA AKIL said, ...
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GENOME-WIDE ANALYSIS

Dr. Akil was one of more than 250 scientists who participated in the Psychiatric GWAS Consortium Bipolar Disorder Working Group, which performed a GWAS analysis involving 11,974 people with bipolar disorder, and 51,792 controls. The analysis, which was published in the Sept. 18 online edition of Nature Genetics, revealed several genes that confer a small risk. A study on the downstream effects of gene expression is currently underway.

Four of the genes are involved with either channel signaling or cell morphology: CACNA1C, which codes for a calcium channel subunit; ANK3, which codes for a cytoskeleton binding protein important for organizing the nodes of Ranvier and the initial axon segment; SYNE1, which codes for a synaptic envelope protein; and ODZ4, which is important in neurite growth, cell adhesion, and cortical patterns.

While all are clearly implicated in bipolar disorder, they each confer a tiny additional risk. “The odds are if you have these genes, your risk might go from about 1 percent to about 1.3 percent,” she said.

But that's not a discouraging finding, according to J. Raymond DePaulo Jr., MD, Henry Phipps Professor and chairman of the department of psychiatry and behavioral science at Johns Hopkins University School of Medicine.

“These genes appear to account for a very small variance in the illness, but they may be important in helping us understand the central pathway to bipolar disorder,” said Dr. DePaulo, author of Understanding Depression: What We Know and What You Can Do About it (Wiley). “Finding genes associated with bipolar disorder is so important because right now we have no other way to understand this disease. When the amyloid precursor protein [APP] mutation was discovered, people initially didn't think much of it because it accounted for only about 1 percent of the illness, but then they found two other mutations in the presenilins that changed the way the APP protein was cut up and managed by the body, and that turned out to give us a central theory of Alzheimer's. That's exactly what we need for bipolar disorder — a central thesis that would enable us to look at things in a different way, and potentially draw fairly dramatic conclusions.”

Many genes appear to be involved in the etiology of bipolar disorder, and the same clinical manifestation of bipolar disease may result from different, non-overlapping genetic causes, according to Dr. Akil. Also, the disease may reflect a breakdown not of one group of brain cells, but of brain circuits, or what Dr. Akil calls the “neural choreography” that integrates various brain regions. “The problem is not one dancer or the other,” she said, referring to mood disorders. “The problem is that the integration of the dance has fallen apart.”

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POSTMORTEM ANALYSIS

With fellow researchers who collaborate through the Pritzker Neuropsychiatric Disorders Research Consortium at the University of Michigan; the University of California, Stanford; Cornell; and the HudsonAlpha Institute, Dr. Akil has participated in autopsies that reveal striking differences in brains from people with depression or bipolar disorder. [For more detailed analysis on the methodology and results, see Figure 1.]

“We thought their brains would look alike since both the bipolar and depressed subjects died while depressed, but they did not,” Dr. Akil said. “In depression, the biggest changes were in the hippocampus. In bipolar disorder, the biggest changes were in the nucleus accumbens. You can see a signature of each disease.”

By comparing the brains they were able to detect hundreds of genes expressed differently in the amygdala of depressed people who committed suicide but were not treated for their depression. In suicide patients who had been treated, however, gene expression in the amygdala was no different from the control brains.

“So we concluded that there was in fact an impact of the treatment on the amygdala since it reversed the differences,” she told Neurology Today. “So the drug did something. However, this was not the case in the hippocampus. There you see residual changes in gene expression that are not touched by the drug. While the treatment did reverse some of the differences, many deviations from the control hippocampuses remained in the suicide group that had been treated. Since these people went on to commit suicide, we suggest they were treatment resistant, and what we are looking at are potential genes that are targets for gene resistance, genes that remain disruptive in spite of treatment.”

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THE ROLE OF FIBROBLAST GROWTH FACTORS

The genes that showed the most alteration in the depressed brains were for fibroblast growth factors (FGFs). Since these are influenced by antidepressants, they provide another possible pathway for altering mood disorders, judging from recent research with rats that Dr. Akil has conducted. Male rats become lethargic and exhibit brain changes that coincide with depression when they are repeatedly defeated by territorial rats. These brain changes include alterations in FGF2 and FGF receptor R1 in the hippocampus, and large decreases of FGF2 in the dentate gyrus, Dr. Akil and her colleagues found. The changes parallel what is observed in the brain of depressed humans.

And as Dr. Akil and colleagues reported in a March 2011 issue of Biological Psychiatry, inhibiting FGF2 produces increased anxiety behavior, which is often comorbid with clinical depression.

In contrast, administering FGF2 works like an antidepressant. “It doesn't just do remodeling of the brain,” Dr. Akil said. “It's online, doing a job. If you blocked it in this instant, it would change your behavior immediately.”

To test this effect more carefully Dr. Akil and her colleagues bred two strains of rats — high responders that eagerly explore a new space and novel objects, and low responders that tend to hug the wall and appear more fearful.

“High responders have higher levels of FGF2, whereas low responders have low levels of FGF, including in the hippocampus,” Dr. Akil said. “This led us to the idea that perhaps FGF2 has a role not just in depression, but in anxiety behavior as well.”

Putting low responders into an enriched environment full of objects to explore boosts brain levels of FGF2 and alleviates their depression-like behavior. “When you increase FGF2 by enriching the environment, you raise FGF2 and decrease anxiety and depression,” Dr. Akil said. “When you stress animals, you decrease FGF2.”

Also, when one of Dr. Akil's colleagues, Cortney A. Turner, PhD, gave one shot of FGF2 to low responding rat pups two days after birth, they grew up more willing to explore their environment, according to results they published in the May 10 Proceedings of the National Academy of Sciences.

The next step, according to Dr. Akil, will involve discovering the targets affected by FGF2, as well as other brain mechanisms involved in mood disorders.

“The brain is in the middle of our business whether we like it or not,” she said. “There is a distinct signature of brain pathophysiology that is behind what the clinician is seeing in depression.”

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MORE ON THE GENETIC UNDERPINNINGS OF MOOD

Like Huda Akil, PhD, presenters at a Society for Neuroscience nanosymposium on the neurological basis of individual susceptibility for mental illness are also investigating the genetic underpinnings of mood.

David T. Hsu, PhD, of the Molecular and Behavioral Neuroscience Institute at the University of Michigan in Ann Arbor, genotyped 22 unmedicated patients with major depressive disorder (MDD) and 128 healthy controls to test his hypothesis that variations in the corticotropin-releasing hormone receptor gene rs110402, a single nucleotide polymorphism in the CRH receptor 1 (CRHR1) gene, interact with early life stress to influence the severity of MDD. “A dysregulated CRH system is associated with major depressive disorder,” he said. However, previous studies have shown that the A allele for CRHR1 rs110402 appears to have a protective effect against developing MDD after childhood abuse.

Sixteen of the patients with MDD and 83 of the controls underwent an fMRI scan while viewing blocks of positive, negative, and neutral words. Blood-oxygenation-level dependent (BOLD) signals in healthy A carriers were significantly more robust in the right and middle temporal/angular gyrus, an area important for processing emotional stimuli. Among GG carriers, the BOLD signals in the subgenual cingulate cortex were greater in people with MDD compared to healthy controls. (Signals in that area often are increased in people with MDD.) Conversely, carriers of one or two A alleles showed lesser responses than carriers of homozygous GG alleles. (Hypothalamic activity is often increased in depression.) This suggests that activity in these regions may contribute to the vulnerability of GG-homozygous individuals to mood disorders.

Jonathan Oler, PhD, an associate scientist in the department of psychiatry at the University of Wisconsin, Madison, also focused on the CRHR1 gene, which he and his colleagues previously associated with “anxious temperament” (AT), a tendency, beginning early in life, toward extreme shyness and increased bodily reactions to even mildly threatening stimuli. Although a risk factor for anxiety disorders, depression, and substance abuse later in life, little is known about the genetics of AT, but Dr. Oler identified a SNP in exon 6 of CRHR1 predictive of AT and AT-associated brain metabolism.

One of Dr. Oler's colleagues, Andrew S. Fox, a PhD candidate in the Waisman Laboratory for Brain Imaging and Behavior at the University of Wisconsin, presented evidence that gene expression patterns in the primate amygdala are linked to the neural substrate of anxious temperament. Fox and his colleagues used 18F-labellled deoxyglucos positron-emission tomotraphy (FDG-PET) to determine that the central nucleus region of the amygdala and the anterior hippocampus of 238 young rhesus monkeys with anxious temperament are key regions in the generation of the anxiety. They also used genetic analysis to detect a significant genetic basis for the metabolic activity in the hippocampus characteristic predictive of anxious temperament. Activity in the amygdala predictive of anxious temperament, however, did not appear to be significantly heritable.

In a poster presentation at the meeting Dr. Oler and Fox, along with other members of the lab headed by Ned H. Kalin, MD, Hedberg Professor and chairman of the department of psychiatry at the University of Wisconsin School of Medicine and Public Health, reported the results of mRNA expression studies on the central nucleus of the amygdala of 24 of the monkeys. They found 140 transcripts that reflect diverse mechanisms predictive of anxious temperament. Their findings, they say, suggest that genes involved with neuroplasticity and brain maturation appear to be related to maladaptive responses to novelty and threat in individuals with extreme anxious temperament.

Oler JA, Fox AS, Kalin NH, et al. Amygdalar and hippocampal substrates of anxious temperament differ in their heritability. Nature 2010;466:864-868.

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REFERENCES:

Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature Genet 2011;43:977–983.

Eren-Koçak E, Turner CA, Watson SJ, Akil H. Short-hairpin RNA silencing of endogenous fibroblast growth factor 2 in rat hippocampus increases anxiety behavior. Biol Psychiatry 2011;69(6):534-540.

Turner CA, Clinton SM, Akil H, et al.Fibroblast growth factor-2 (FGF2) augmentation early in life alters hippocampal development and rescues the anxiety phenotype in vulnerable animals. Proc Natl Acad Sci 2011;108(19):8021-8025.

©2012 American Academy of Neurology

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