Gene linked to de­pres­sion

The Denver Post - - NATION & WORLD - By Car­rie Wells

BAL­TI­MORE» Although there are med­i­ca­tions to treat de­pres­sion, many sci­en­tists aren’t sure why they’re ef­fec­tive and why they don’t work for ev­ery­one.

Re­searchers at the Univer­sity of Mary­land School of Medicine be­lieve they may have found a key to the puz­zle of ma­jor de­pres­sion that could lead to ther­a­pies for those who don’t re­spond to med­i­ca­tions al­ready on the mar­ket.

A study by the re­searchers has iden­ti­fied the cen­tral role a gene known as Sl­c6a15 plays in ei­ther pro­tect­ing from stress or con­tribut­ing to de­pres­sion, de­pend­ing on its level of ac­tiv­ity in a part of the brain as­so­ci­ated with mo­ti­va­tion, plea­sure and re­ward seek­ing.

Pub­lished in the Jour­nal of Neu­ro­science in July, the study is the first to il­lu­mi­nate in de­tail how the gene “works in a kind of neu­ron that plays a key role in de­pres­sion,” the ac­cord­ing to the med­i­cal school.

Specif­i­cally, the re­searchers found that mice with de­pres­sion had re­duced lev­els of the gene’s ac­tiv­ity, while those with high lev­els of the gene’s ac­tiv­ity han­dled chronic stress bet­ter.

Although se­nior re­searcher Mary Kay Lobo’s pri­mary stud­ies were done with mice, she also ex­am­ined the brains of peo­ple who had com­mit­ted sui­cide and found re­duced lev­els of the gene’s ac­tiv­ity, con­firm­ing a likely link.

She hopes now that drugs could be de­vel­oped that would en­cour­age the gene’s ac­tiv­ity.

“I thought it was fas­ci­nat­ing we had this sys­tem in place that al­lows us to go af­ter things or be mo­ti­vated or have plea­sure and I was in­ter­ested in how it be­comes dys­func­tional in cer­tain diseases like de­pres­sion,” Lobo said. “I hope that we can iden­tify mol­e­cules that could po­ten­tially be ther­a­peu­ti­cally treated or tar­geted to treat de­pres­sion.”

Lobo and her col­leagues have been ex­am­in­ing the gene for years. In 2006, they dis­cov­ered that it was more com­mon among spe­cific neu­rons in the brain that they later learned were re­lated to de­pres­sion. Five years later, other re­searchers learned that the gene played a role in de­pres­sion, and Lobo and her re­search col­leagues de­cided to in­ves­ti­gate what that role is in those spe­cific neu­rons.

About 15 mil­lion adults, or 6.7 per­cent of all U.S. adults, ex­pe­ri­ence ma­jor de­pres­sion in a given year, ac­cord­ing to the Anx­i­ety and De­pres­sion As­so­ci­a­tion of Amer­ica. It is the lead­ing cause of dis­abil­ity for Amer­i­cans ages 15 to 44. It is more preva­lent in women and can de­velop at any age, but the me­dian age of on­set is 32.5.

David Di­etz, an as­so­ciate pro­fes­sor in the Depart­ment of Phar­ma­col­ogy and Tox­i­col­ogy at the State Univer­sity of New York-Buf­falo, said lit­tle was known pre­vi­ously about the bi­o­log­i­cal ba­sis of de­pres­sion in the brain. Many drugs used to treat de­pres­sion were dis­cov­ered “serendip­i­tously,” he said, and it wasn’t clear why they worked.

“We’re start­ing to re­ally get an idea of what does the de­pressed brain look like,” Di­etz said. “When you put the whole puz­zle to­gether, you see where the prob­lem is. For too long we’ve been throw­ing things at in­di­vid­ual pieces. It’s so com­plex and we have so lit­tle in­for­ma­tion that it was al­most bound to be that way. For the first time this is one of those big­ger pieces you can slide into the jig­saw puz­zle.”

Lobo said it’s not clear yet how Sl­c6a15 works in the brain, but she be­lieves it may be trans­port­ing three types of amino acids into a sub­set of neu­rons called D2 neu­rons in a part of the brain called the nu­cleus ac­cum­bens. The nu­cleus ac­cum­bens and D2 neu­rons are known to play a role in plea­sure, ac­ti­vat­ing when one eats a de­li­cious meal, has sex or drinks al­co­hol.

The amino acids would then be syn­the­sized into neu­ro­trans­mit­ters. De­pres­sion pre­vi­ously has been linked to im­bal­ances of the neu­ro­trans­mit­ters sero­tonin, nor­ep­i­neph­rine and dopamine.

So even though peo­ple may have proper lev­els of amino acids in their bod­ies, the neu­rons in their brains that need them may not be get­ting enough if the trans­porter is not work­ing as it should.

“This gene is crit­i­cal for putting very spe­cific amino acids in the right place so that neu­ro­trans­mit­ters can be syn­the­sized,” said A.J. Ro­bi­son, an as­sis­tant pro­fes­sor in the Depart­ment of Phys­i­ol­ogy at Michi­gan State Univer­sity. “It’s the lo­ca­tion, lo­ca­tion, lo­ca­tion idea. It’s not the amino acids; it’s where they’re at and in which cells.”

Ro­bi­son said Lobo’s next step would be dis­cov­er­ing more about how the trans­porter gene works.

“The fact that this trans­porter seems to be im­por­tant is what the pa­per shows and how it does it is not shown, and that’s a chal­lenge for her,” he said. “Fig­ur­ing out the how of it is the next step, and Dr. Lobo is par­tic­u­larly po­si­tioned to do it.”

Lobo’s team was able to use gene ther­apy, a form of ther­apy in the early stages of be­ing stud­ied in hu­mans, in the mice to boost the gene’s ac­tiv­ity.

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