February 28, 2005

Working memory: a new target?

Selective alterations in prefrontal cortical GABA neurotransmission in schizophrenia: a novel target for the treatment of working memory dysfunction.

Lewis DA, Volk DW, Hashimoto T.

Psychopharmacology (Berl). 2004 Jun;174(1):143-50. Epub 2003 Dec 09.

This article is about research being done to identify other potential targets in the brain for medications for schizophrenia. The authors focus on an aspect of schizophrenia that is often overlooked, but is of paramount importance in understanding the disorder fully. Namely, the loss of working memory and deficit in executive function that is associated with schizophrenia often can be severely limiting when people with schizophrenia are attempting to reintegrate into society. Working memory refers to what is needed to remember and complete a task. Executive function regards the mental processes involved in planning and executing a task. Both of these are often disturbed in schizophrenia. The parts of the brain that are typically considered important for these processes is called the DLPFC or dorsolateral prefrontal cortex. That breaks down to dorsolateral (dorso = back, lateral=side) prefrontal (just behind the frontal lobe) cortex (outer layers of the brain matter). There have been many studies that have demonstrated a decrease in blood flow to the DLPFC in people with schizophrenia, particularly in these types of memory tasks. The neurons thought to be responsible for these changes utilize a neurotransmitter called GABA (gamma aminobutyric acid). This is a neurotransmitter that is utilized by the brain for inhibitory functions and it can control the on/off switch of important cells called pyramidal cells. These cells are vital for the processing of these types of memory. The GABA neurons are themselves turned on or off by receptors that respond to local conditions. To make it even more complicated, there are several parts of the receptor that finesse the neuron to respond in different ways. The subunit that has been shown to be most critical for this process is the GABA-A receptor. Therefore, the authors postulate that action at that part of the receptor may be able to alter how those neurons fire and by doing that may alter the dysfunctional cells that are in the DLPFC that causes the functional impairment in working memory and executive function.

While this paper delves into many complex issues regarding the genetics of the receptors, the proteins that may/may not be involved, I will discuss the possible pharmacological implications that they discuss rather than focusing on the complex basic science.

The chandelier cell (named for its chandelier-like appearance) is a cell that responds to the GABA-A subunit and is responsible for impacting the initial segments of the pyramidal cells. Brain cells, or neurons, work by an electrical impulse that is generated at the beginning of the cell (axon initial segment) and that moves quickly to the end (synapse) where it releases neurotransmitter that impacts and starts the process in the next neuron. Since these chandelier cells work in the important initial segment, they are of particular interest. The authors postulate, and are studying, whether a medication that works at the GABA-A receptor (an agonist or drug that increases activity at the receptor) would be beneficial in working memory and may impact this core schizophrenia symptom. In particular, there is a subunit of the subunit called the alpha-2 subunit that is even more specific for this process and that is what the authors are testing with a new medication. It should be noted that medications called benzodiazepines (like ativan/lorazepam, klonipin/clonazepam or valium/diazepam) work more generally on the GABA system. The medication being proposed would be like a cousin of these but much more specific (hopefully.) The research on such a medication is being done now, and it remains to be seen if it will have the theorized benefit in actuality, but the results should be available in the not too distant future though it might be a much longer time until such a medication is available widely on the market.

Click here for the article on PubMed

Original Author: Jacob


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