Penetrating Spider Bites and Neuropsychiatric Insights

Penetrating Spider Bites and Neuropsychiatric Insights

Black Widow Spider. Photo Courtesy of National Park Service.

The female black widow spider is notorious for both her venomous bite and her reputation for using it on her own partner after mating. Her venom contains latrotoxin, among other toxins, which is a small protein that for years has been used in biochemical research to study cell signaling and neurotransmitter release in neurons. It places the black widow at the center of a fascinating web - one connecting its neurotoxin to attention deficit hyperactivity disorder (ADHD).

An individual's susceptibility to latrotoxin results from specific receptors on the neuron's surface. The major receptor that binds latrotoxin is called latrophilin (LPHN). This receptor belongs to a superfamily of proteins known as G protein-coupled receptors, which are currently the subject of intense research by the pharmaceutical industry. Three LPHNs have been identified so far — LPHN1, 2 and 3 — and each have a different tissue distribution, but are alike in their ability to bind to the latrotoxin in black widow venom.

When latrotoxin binds to latrophilin in the cell surface, two things happen. The toxin uses the receptor as an anchor to insert itself into the cell membrane, opening a channel for a massive influx of calcium into the cell. As a result, there is an uncontrolled release of neurotransmitters from the cell, which is what causes the effects of latrotoxin. The venom also acts at the nerve ends to prevent muscle relaxation, causing constant, strong and painful contractions.

Most people rarely die from a black widow's bite, but small children and the elderly can have life-threatening reactions. Although the spider tale ends there, the story of biochemical and genetic discovery moves into even more interesting territory.

In February 2010, National Human Genome Research Institute (NHGRI) researchers in the Medical Genetics Branch participated in the discovery of a common variant in the LPHN3 gene that confers susceptibility to ADHD. The common neuropsychiatric disorder affects 8 to 12 percent of children worldwide, and 60 percent of children have symptoms that persist into adulthood. In preliminary studies, the researchers found that the incidence of ADHD in the general population would be reduced by about 9 percent if the effect of the LPHN3 gene variant that confers susceptibility to ADHD were controlled.

In November 2010, the NHGRI group published an article reviewing what scientists have learned about the LPHNs and their impact on psychiatric disorders, drawing attention again to the association they found between LPHN3 gene variations and ADHD. The article appeared online in the American Journal of Medical Genetics Part B: Neuropsychiatric Genetics and will soon appear in the journal's print issue.

In the review article, the NHGRI researchers note that LPHN3, with its particular brain-specific distribution and involvement in brain activity, is a potential target for devleoping new drugs to treat ADHD.

"If we are able to identify a mutation in the LPHN3 protein that affects its function in people with ADHD, we will have a promising candidate for drug development," said Ariel Martinez, a biochemist in the NHGRI Medical Genetics Branch and lead author of the review article.

Rat studies referenced in the review article showed that different organ tissues produce levels of the various LPHNs in a discernible distribution. LPHN1 is produced predominantly in the brain, but in lower levels in most other tissues. LPHN2 primarily is found outside the brain, especially in the liver and lung. LPHN3 is detectable only in the brain. Another animal study cited by the authors found that mice deficient in LPHN1 attend poorly to their offspring, suggesting that a deficiency of LPHN1 does not affect brain function so much as it does some behaviors.

Their own studies conducted on human tissue offer an even greater specificity about the parts of the brain where various levels of LPHN3 are produced, with high levels in such brain structures as the amygdala, cerebellum and prefrontal cortex, and lower levels in the corpus callosum, hippocampus and occipital, frontal and temporal lobes. These data strongly implicate LPHN3 in brain development in childhood when ADHD usually appears.

"It is not a coincidence that LPHN3 is present at high levels in brain structures implicated in the dopamine systems, which are the ones affected in ADHD patients," explained Martinez. "LPHN3 seems to be a promising gene in the study of ADHD and other neurodevelopmental disorders."

In their review article, NHGRI researchers discuss a secondary impact of LPHN3 variants associated with ADHD, which is an increased risk for substance use disorder. The lifetime risk for this secondary behavioral disorder is approximately 50 percent in subjects whose ADHD persists into adulthood. The researchers will provide an in-depth analysis of the role for the LPHN3 variant and the risk for substance use disorder and disruptive behaviors in an upcoming article.