April 23, 2007

Research Progress in Countering Cognitive Deficits of Schizophrenia

Researchers at Yale Medical School and the University of Crete School of Medicine report the first evidence of a molecular mechanism that dynamically alters the strength of higher brain network connections.

They hope their discovery will lead to the development of drug therapies for the cognitive deficits seen in schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder (ADHD) as well as the cognitive deficits that can accompany normal aging.

They were able to study the molecular workings of memory and cognition in the prefrontal cortex, a portion of the brain involved in memory, and planning. They saw disruptions in the molecular underpinnings in this area involving the tiny "ion channels" which allow brain cells to communicate with each other.

One disruption was in an important molecule involved in normal cellular functioning - cAMP (cyclic adenosine monophosphate). This molecule is regulated by a gene called DISC1, which has been shown to be disrupted in some cases of schizophrenia. When disrupted, it can lead to profound deficits in this area of the brain, and the disruption in this case would be especially affected during exposure to even mild stress.

The ion channels can open when they are exposed to cAMP. When open, the information can no longer flow into the cell, and thus the network is effectively disconnected. The study's lead author, Dr. Amy Arnsten, (neurobiology professor at Yale), said that inhibiting cAMP closes the channels and allows the network to reconnect.

The excessive opening of HCN channels may underlie many lapses in higher cognitive function. Stress, for example, appears to flood PFC (prefrontal cortex)neurons with cAMP, which opens HCN (hyperpolarization-activated cyclic nucleotide)-gated channels, temporarily disconnects networks, and impairs higher cognitive abilities.

Yale has submitted a patent application, based on the data found, using "HCN blockers" (which help keep the channels of brain-cell communication open) for the treatment of cognitive deficits in the prefrontal cortex.

Read the full article: Brain Networks Strengthened by Closing Ion Channels Original Source: Cell 129: 397-410 (April 20, 2007)

Additional Reading:
Genetic Studies Show DISC1 Gene Likely a Player in Schizophrenia

UCLA Schizophrenia Genetics Discoveries

Damaged gene & Schizophrenia Predisposition (DISC1)

Stress and the Cellular Response to Dopamine


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