Schizophrenia Linked To Loss Of Cells In Hippocampus

Deficits in social memory may be due to a decrease in the number of a particular class of brain cells, called inhibitory neurons, in a little-explored region within the brain’s memory center, scientists at Columbia University’s Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University Medical Center (CUMC), and the Université Paris Descartes have found.

Social memory deficits are an important yet little understood feature of psychiatric disorders such as schizophrenia.

The findings explain some of the underlying mechanisms that lead to the more difficult-to-treat symptoms of schizophrenia, including social withdrawal, reduced motivation and decreased emotional capacity.

Scientists have long speculated that schizophrenia, which affects about 1 in every 100 adults worldwide, originates in part in the hippocampus, the brain’s headquarters for memory and spatial navigation. As a result, nearly every region of the hippocampus has been studied extensively in the hopes of gaining insight into the disorder.

Unexplored Island

One notable exception is a tiny region of the hippocampus known as CA2. Explained Vivien Chevaleyre, PhD, group leader in neuroscience at the Université Paris Descartes and a lead author of the paper:

“Smaller and less well-defined than other parts of the hippocampus, CA2 was like a small island that was depicted on old maps but remained unexplored.”

Several discoveries have focused attention on a possible association between CA2 and schizophrenia. This region of the hippocampus is associated with vasopressin, a hormone that plays a role in sexual bonding, motivation and other intensely social behaviors, which become impaired in people with the disorder.

In addition, postmortem examinations of people with schizophrenia have revealed a marked decrease in the number of CA2 inhibitory neurons, while the rest of the hippocampus remained largely unaffected. However, the significance of this loss had remained unclear.

Reduced Social Memory

In this study, the researchers performed a series of electrophysiological and behavioral experiments on a mouse model of schizophrenia developed at CUMC.

By examining the brains of these mice, the researchers observed a substantial decrease in inhibitory CA2 neurons, as compared to a control group of normal, healthy mice. This is a change remarkably similar to that previously observed in postmortem examinations of people with schizophrenia.

Moreover, the team discovered that the modified mice had a significantly reduced capacity for social memory compared with the controls. This raises the hypothesis that changes to CA2 may account for some of the social behavioral changes that occur in individuals with the disorder.

Said Joseph Gogos, PhD, a professor of physiology and neuroscience at CUMC, a principal investigator at the Zuckerman Institute and a lead author of the paper:

“Even the timing of the emergence of symptoms in the mice, during young adulthood, parallels the onset of schizophrenia in humans.”

Added Steven Siegelbaum, PhD, chair of the Department of Neuroscience at CUMC, a principal investigator at the Zuckerman Institute and a co-author of the paper:

“We can now examine the effects of schizophrenia at the cellular level and at the behavioral level. This essentially opens up a whole new avenue for research that could lead to earlier diagnosis and more effective treatments for schizophrenia.”

Rebecca A. Piskorowski, Kaoutsar Nasrallah, Anastasia Diamantopoulou, Jun Mukai, Sami I. Hassan, Steven A. Siegelbaum, Joseph A. Gogos, Vivien Chevaleyre
Age-Dependent Specific Changes in Area CA2 of the Hippocampus and Social Memory Deficit in a Mouse Model of the 22q11.2 Deletion Syndrome
Neuron, Vol. 89, Issue 1, p163–176

Photo: mouse hippocampus, with CA2 inhibitory neurons stained in light blue. In the researchers’ mouse model of schizophrenia, this region showed significant depletion of neurons and was accompanied by a deficit in social memory. Credit: Vivien Chevaleyre

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