Brain Networks Strengthened By Closing Ion Channels

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.


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 may 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 stress
exposure. "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.


Yale University School of Medicine

med.yale/ysm