New discoveries are being made about changes in the brain during depression. Dr. Mia Lindskog of the Karolinska Institute, Sweden, and her team say that two separate mechanisms cause the emotional symptoms and the deficits in memory and learning seen in depression.
Dr. Lindskog explains that depression “is characterized by both emotional and cognitive symptoms.” However, she adds, “the relationship between these two symptoms of depression is poorly understood.”
The team compared ordinary rats against a strain of rats that had been bred with a disposition toward depression. This strain of rats has recently been found to have decreased emotional memory, impaired brain plasticity, and a smaller hippocampus.
The idea was to investigate the glutamatergic system, which is a system of amino acids vital for information processing in the hippocampus, in order to “reveal the mechanisms underlying the emotional and cognitive aspects associated with the disease.”
Clinical studies have shown abnormalities in the glutamatergic system in depressed people, but it is not yet clear how this affects the brain and contributes to depression symptoms.
All of the rats were injected with D-serine, a substance secreted by support cells for brain neurons called astrocytes. The “depressed” rats showed an improvement in their previously impaired brain plasticity and on memory tests.
Apathy was tested by releasing the rats into a container of water and observing whether they immediately tried to climb out or stayed floating in the container. The “depressed” rats showed no improvement in their level of apathy following the injection with D-serine.
“We have shown that there are two symptoms that can be influenced independently of one another, which means they could be treated in tandem in patients with depression,” said Dr. Lindskog. She added, “It’s likely that astrocytes perform a very important function in the brain.”
The researchers also found that the hippocampus in the brains of depressed rats had a lower plasticity that left them unable to increase neuron activity when needed. But after being soaked in D-serine, the plasticity of the hippocampus in brain samples improved.
A reduction in the size of the hippocampus is one of the most common findings in depressed patients and in this depressed strain of rats. It has a “prominent role” in memory and a potential role in emotional symptoms, say the authors.
Reporting the findings in the journal Molecular Psychiatry, the authors state, “Both synaptic plasticity and memory impairments were restored by administration of D-serine.”
Dr. Lindskog says, “D-serine doesn’t pass the blood-brain barrier particularly well, so it’s not really a suitable candidate on which to base a drug. But the mechanism that we’ve identified, whereby it’s possible to increase plasticity and improve memory, is a feasible route that we might be able to reach in a way that doesn’t involve D-serine.”
She believes it is crucial to learn more about this process. “These findings open up new brain targets for the development of more potent and efficient antidepressant drugs,” Dr. Lindskog says.
In their journal paper, the team explains that current antidepressant drugs sometimes resolve emotional symptoms without benefiting depression-linked deficits in memory and learning. This discrepancy “suggests the involvement of different mechanisms in the origin of these two key aspects of depression,” they write.
Perhaps this study holds the key to these different mechanisms. As the researchers say, “Based on our results, we propose a mechanism in which dysfunctional astrocytic regulation of glutamate affects glutamatergic transmission, causing memory deficits that can be restored independently of the emotional aspects of depression.”
They can also account for the lower D-serine level in the hippocampus of depressed rats: it is due to changes in the shape and function of astrocyte neurons.
“In summary,” they write, “our data describe interactions within the glutamatergic system that should be considered when designing new therapies for depression.” Several different aspects of the system should be targeted “to effectively treat both the cognitive and emotional symptoms that are associated with depression,” they add.
More recently it has been confirmed that, as Dr. Lindskog suspected, astrocytes are of major importance in depression. Dr. Boldizsar Czeh of the Max-Planck-Institute of Psychiatry, Munich, Germany, and colleagues took a further look at astrocytes.
They report that astrocytes “are regarded as the most abundant cell type in the brain,” but it seems they also regulate synapses, that is, the area that allows communication between neurons. They appear to control neuron development in the hippocampus.
In the journal European Neuropsychopharmacology, the team sums up all the evidence that antidepressant drugs affect astrocytes. “We propose here a hypothesis that antidepressant treatment activates astrocytes, triggering the reactivation of cortical plasticity.”
They believe that these astrocyte-specific changes probably contribute to the effectiveness of currently available antidepressant drugs, but they add that “better understanding of these cellular and molecular processes could help us to identify novel targets for the development of antidepressant drugs.”
Dysfunctional Astrocytic Regulation of Glutamate Transmission in a Rat Model of Depression. Gomez-Galan, M. et al. Molecular Psychiatry February 28, 2012 doi: 10.1038/mp.2012.10
Czeh, B. and Di Benedetto, B. Antidepressants act directly on astrocytes: Evidences and functional consequences. European Neuropsychopharmacology Volume 23 Issue 3 pp. 171-85 March 2013.