Featured Research

from universities, journals, and other organizations

Brain Networks Strengthened By Closing Ion Channels, Research Could Lead To ADHD Treatment

Date:
April 23, 2007
Source:
Yale University
Summary:
Yale School of Medicine and University of Crete School of Medicine researchers report the first evidence of a molecular mechanism that dynamically alters the strength of higher brain network connections. This discovery may help the development of drug therapies for the cognitive deficits of normal aging, and for cognitive changes in schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder (ADHD).

Yale School of Medicine and University of Crete School of Medicine researchers report in Cell April 20 the first evidence of a molecular mechanism that dynamically alters the strength of higher brain network connections.

Related Articles


This discovery may help the development of drug therapies for the cognitive deficits of normal aging, and for cognitive changes in schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder (ADHD).

"Our data reveal how the brain's arousal systems influence the cognitive networks that subserve working memory-which plays a key role in abstract thinking, planning, and organizing, as well as suppressing attention to distracting stimuli," said Amy Arnsten, lead author and neurobiology professor at Yale.

The brain's prefrontal cortex (PFC) normally is responsible for so-called executive functions. The ability of the PFC to maintain such memory-based functions declines with normal aging, is weakened in people with ADHD, and is severely disrupted in disorders such as schizophrenia and bipolar disorder.

The current study found that brain cells in PFC contain ion channels called hyperpolarization-activated cyclic nucleotide-gated channels (HCN) that reside on dendritic spines, the tiny protrusions on neurons that are specialized for receiving information. These channels can open when they are exposed to cAMP (cyclic adenosine monophosphate). When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. Arnsten said inhibiting cAMP closes the channels and allows the network to reconnect.

The study also found alpha-2A adrenergic receptors near the channels that inhibit the production of cAMP and allow the information to pass through into the cell, connecting the network. These receptors are stimulated by a natural brain chemical norepinephrine or by medications like guanfacine.

"Guanfacine can strengthen the connectivity of these networks by keeping these channels closed, thus improving working memory and reducing distractibility," she said. "This is the first time we have observed the mechanism of action of a psychotropic medication in such depth, at the level of ion channels."

Arnsten said the excessive opening of HCN channels might underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC neurons with cAMP, which opens HCN channels, temporarily disconnects networks, and impairs higher cognitive abilities.

There is also evidence that this pathway may not be properly regulated with advancing age, resulting in destruction of cAMP. The dysregulation of the pathway may contribute to increased forgetfulness and susceptibility to distraction as we grow older.

The research is also relevant to common disorders such as ADHD, which is associated with weaker regulation of attention and behavior. ADHD is highly heritable, and some patients with ADHD may have genetic changes in molecules that weaken the production of norepinephrine. Treatments for ADHD all enhance stimulation of the norepinephrine receptors.

These new data also have important implications for the researchers' studies of more severe mental illnesses like schizophrenia and bipolar disorder, which can involve mutations of a molecule called DISC1 (Disrupted in Schizophrenia) that normally regulates cAMP. Loss of function of DISC1 in patients with schizophrenia or bipolar disorder would increase vulnerability to cortical network disconnection and profound PFC deficits. This may be especially problematic during exposure to even mild stress, which may explain the frequent worsening of symptoms following exposure to stress. "We find it remarkable to relate a genetic mutation in patients to the regulation by an ion channel of PFC neuronal networks," said Arnsten.

Co-authors include Min Wang, Brian Ramos, Yousheng Shu, Arthur Simen, Alvaro Duqye, Avis Brennan, Susheel Vijayraghavan, Anne Dudley, Eric Nou, David McCormick, James Mazer and Constantinos Paspalas, who also has an appointment at the University of Crete School of Medicine in Heraklion, Greece.

The work was supported by research grants from the National Institute on Aging and the National Institute of Mental Health, as well as from Shire Pharmaceuticals Group plc and an award from the Kavli Institute of Neuroscience at Yale.

Arnsten and Yale have a license agreement with Shire Pharmaceuticals for the development of guanfacine for the treatment of patients with ADHD. Yale has submitted a patent application on the use of HCN blockers for the treatment of PFC cognitive deficits based on the data reported in the Cell paper.

Cell 129: 1-14 (April 20, 2007)


Story Source:

The above story is based on materials provided by Yale University. Note: Materials may be edited for content and length.


Cite This Page:

Yale University. "Brain Networks Strengthened By Closing Ion Channels, Research Could Lead To ADHD Treatment." ScienceDaily. ScienceDaily, 23 April 2007. <www.sciencedaily.com/releases/2007/04/070420143324.htm>.
Yale University. (2007, April 23). Brain Networks Strengthened By Closing Ion Channels, Research Could Lead To ADHD Treatment. ScienceDaily. Retrieved November 28, 2014 from www.sciencedaily.com/releases/2007/04/070420143324.htm
Yale University. "Brain Networks Strengthened By Closing Ion Channels, Research Could Lead To ADHD Treatment." ScienceDaily. www.sciencedaily.com/releases/2007/04/070420143324.htm (accessed November 28, 2014).

Share This


More From ScienceDaily



More Mind & Brain News

Friday, November 28, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Are Female Bosses More Likely To Be Depressed?

Are Female Bosses More Likely To Be Depressed?

Newsy (Nov. 24, 2014) — A new study links greater authority with increased depressive symptoms among women in the workplace. Video provided by Newsy
Powered by NewsLook.com
Winter Can Cause Depression — Here's How To Combat It

Winter Can Cause Depression — Here's How To Combat It

Newsy (Nov. 23, 2014) — Millions of American suffer from seasonal depression every year. It can lead to adverse health effects, but there are ways to ease symptoms. Video provided by Newsy
Powered by NewsLook.com
Could Your Genes Be The Reason You're Single?

Could Your Genes Be The Reason You're Single?

Newsy (Nov. 21, 2014) — Researchers in Beijing discovered a gene called 5-HTA1, and carriers are reportedly 20 percent more likely to be single. Video provided by Newsy
Powered by NewsLook.com
Milestone Birthdays Can Bring Existential Crisis, Study Says

Milestone Birthdays Can Bring Existential Crisis, Study Says

Newsy (Nov. 21, 2014) — Researchers find that as people approach new decades in their lives they make bigger life decisions. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

Strange & Offbeat Stories

 

Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins