Puberty represents a time of chaos, when emotions, appearance and internal chemistry are changing like at a frantic pace. And so, it is no wonder that this developmental period is also time of high anxiety that occasionally can lead to the all-too-common teenage angst as well as panic and suicidal tendencies.

Now, researchers at the State University of New York Downstate Medical Center in New York City have found the switch that transforms quiescent children into raging, hormonal teens. The team reports in Nature Neuroscience that allopregnanolone (THP), a chemical that normally helps soothe the activity of brain cells in adults and children by binding to receptors that inhibit accelerating electrical activity, actually becomes an antagonist during puberty.

"Puberty is certainly a time when there are huge changes in hormones," senior study author Sheryl Smith says. "When we looked at the time of puberty, we found that the steroid THP completely flipped to the opposite effect."

THP is a steroid created in the body when progesterone, the female sex hormone, is metabolized. Typically, THP is released in the brain in response to stress, and quiets the neural system within 30 minutes of escalation. THP works by binding to so-called GABA receptors on the surfaces of neurons, or nerve cells. Smith notes that GABA (gamma-aminobutyric acid) is the primary inhibitory neurotransmitter in the brain, and that "any sedative like tranquilizers, anesthetics and alcohol all act on the GABA receptor."

To determine why the system goes haywire during puberty, the team homed in on the CA1 region of the hippocampus, a curved slice in the center of the brain that regulates emotion. The CA1 has been implicated in controlling anxiety. The team was searching for a specific type of GABA receptor known as alpha4-beta2-delta, known to be particularly sensitive to steroids.

Using a female mouse model—because, Smith notes, girls are twice as likely as boys to experience anxiety disorders during puberty—the team initially tried to determine the number of such GABA receptors present in the CA1 in both young and pubertal animals.

They discovered three times the amount of the alpha4-beta2-delta receptors in the adolescent mice than in the youngsters; they were located in the neurons' dendrites, the tips, through which the neurons receive messages from other nerve cells. "Before puberty in the CA1 hippocampus there is [practically] nothing," Smith says, adding that previous research showed there is also a dearth of these receptors in the adult brain.

To determine if the special receptors were linked to behavioral differences, the researchers stressed out young, pubescent and adult mice by trapping them in a plastic tube for 45 minutes. They then removed them and gave them 20 minutes to settle down before placing them in another stressful situation—a maze that is known to make the animals anxious. The 20 minutes of downtime was enough time for the young and adult mice to relax but the adolescents remained hyped up.

The team later determined in vitro that the alpha4-beta2-delta receptors in the CA1 behave differently than normal GABA receptors, absorbing a current of chloride ions, rather than expelling them. "Normally, chloride is flowing out," Smith explains, "and THP enhances the GABA receptors which enhance [the] inhibition" of out-of-control neural activity. During puberty, THP instead slows desensitizes GABA receptors, allowing spiking brain activity to carry on unchecked.

Smith says that her group's mouse model faithfully emulates the conditions in humans. "We know that the human alpha4-beta2-delta GABA receptor is also inhibited [during puberty] as it is in the mouse," she says. "This suggests a biological basis for these changes in mood and amplified responses in stress."

She notes that this newly discovered nexus could pave the way for new treatments for depression in teen girls. This suggests that the research community can "develop strategies either targeting [THP]," or the receptors, she says.

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