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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
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