Dendritic Spine Loss Reported in Schizophrenia and Bipolar Disorder

Golgi-stained human brain tissue from the dorsolateral prefrontal cortex.

Golgi-stained human brain tissue from the dorsolateral prefrontal cortex.

Schizophrenia and bipolar disorder are very different mental illnesses, but researchers are discovering evidence that the two disorders have some common pathologies. According to a recent study, a shared characteristic appears to be dendritic spine loss.

The researchers used Neurolucida to study pyramidal cells in human brain tissue from individuals with schizophrenia (n=14), individuals with bipolar disorder (n=9) and unaffected control participants (n=19). The pyramidal cells were located in the dorsolateral prefrontal cortex – a region that plays a key role in working memory. Bipolar patients showed significantly reduced spine density (10.5 percent) compared to control. Schizophrenic patients also showed lower spine density (6.5 percent), but this number just missed significance when compared to control patients. Individuals with both illnesses showed a lower number of spines per dendrite, as well as reduced dendritic length compared to controls.

To obtain these results, researchers analyzed 15 Golgi-stained pyramidal cells in each tissue sample. They used Neurolucida to reconstruct the longest dendrite on the pyramidal cells and to mark spines. After the researchers finished reconstructing the cells, Neurolucida provided them with important data about the dendrites and spines.

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Hawaii Scientists Measure Density of Parvalbumin-Interneurons With Stereo Investigator

Reduced density of PV-interneurons in Sepp1-/- mice. (A) Representative images showing PV expression in the hippocampus (left column) and inferior colliculus (middle and right columns) of WT Sepp1+/+ (top row) and Sepp1-/- (bottom row) mice. Higher magnification images of the inferior colliculus (far right) (B), Mean density of PV-interneurons per mm3 (+-SEM, n=6 per genotype) in brain regions investigated: SC; MS; DG, CA1, and CA2/3 of the hippocampus; IC. * P<0.01. Figure courtesy of Matthew W. Pitts, Ph.D.

Reduced density of PV-interneurons in Sepp1-/- mice. (A) Representative images showing PV expression in the hippocampus (left column) and inferior colliculus (middle and right columns) of WT Sepp1+/+ (top row) and Sepp1-/- (bottom row) mice. Higher magnification images of the inferior colliculus (far right) (B), Mean density of PV-interneurons per mm3 (+-SEM, n=6 per genotype) in brain regions investigated: SC; MS; DG, CA1, and CA2/3 of the hippocampus; IC. * P<0.01. Figure courtesy of Matthew W. Pitts, Ph.D.

Foods like tuna fish and Brazil nuts are rich in selenium, a mineral that scientists say has antioxidant effects, keeping the brain healthy and free of clutter so cells can work smoothly together. A key element of this process is Selenoprotein P (Sepp1) – a protein that delivers selenium to neurons by binding with another protein – ApoER2. Neuroscientists at the University of Hawaii say Sepp1 plays a critical role in brain function, and deficits may play a part in mental illnesses like schizophrenia.

In their study published in Neuroscience, the researchers investigate the relationship between Sepp1 and parvalbumin (PV)-interneurons – a class of brain cell that controls firing rates and synchronizes spiking activity among other groups of neurons. Previous research shows that these cells need selenium to develop properly, so the scientists set out to find out what affect a Sepp1 deficit would have on the mouse brain.

Led by Dr. Matthew W. Pitts, the research team compared the brains of wild type mice with Sepp1 deficient mice. They used a Zeiss Axioskop microscope equipped with Stereo Investigator to conduct a stereological analysis of PV-interneurons in several different regions of the mouse brain. Using Stereo Investigator’s optical fractionator probe, they observed reduced numbers of PV-interneurons along with elevated oxidative stress in the inferior colliculus of Sepp1 deficient mice, a region involved in processing auditory information.

“Stereo Investigator was particularly useful for estimating cell density in larger brain structures, such as the inferior colliculus,” said Dr. Pitts.

Since scientists speculate that dysfunctional PV-interneuron networks may be involved in neuropsychiatric conditions, the researchers conducted behavioral tests that showed impairments in contextual fear extinction, latent inhibition, and sensorimotor gating in the Sepp1 deficient mice – behaviors observed in some mental illnesses.

“Previous studies (Valentine et al., 2008) and our findings together indicate that ApoER2- mediated uptake of Sepp1 serves an important neuroprotective role in the inferior colliculus,” the authors say in their paper. “These findings may have relevance to neuropsychiatric conditions in which dysfunc- tional PV-interneuron networks have been implicated, such as epilepsy and schizophrenia.”

Pitts M.W., Raman A.V., Hashimoto A.C., Todorovic C., Nichols R.A., Berry M.J. Deletion of selenoprotein P results in impaired function of parvalbumin interneurons and alterations in fear learning and sensorimotor gating. Neuroscience. 2012 Apr 19;208:58-68. doi: 10.1016/j.neuroscience.2012.02.017.

 

Dr. Eric Kandel Studies Schizophrenia with a Transgenic Mouse and a Neuroanatomical Eye

A crux of Dr. Eric Kandel’s career has been the integration of psychiatric with biological research. After earning a degree in psychiatry from NYU Medical School, he turned his attention to the brain’s molecular structure, and later pioneered a reductionist approach to neurobiology by using the Aplysia sea slug as his model organism.

An MBF Bioscience customer for many years, Dr. Kandel’s research on learning and memory helped give rise to the notion of plasticity in the brain. Recently, the octogenarian Nobel Prize Laureate, Columbia University professor, Kavli Institute for Brain Science director, and Howard Hughes Medical Institute senior investigator began focusing on schizophrenia with the transgenic mouse as a model.

“Transgenic mouse models may be just one impetus pushing psychiatry toward a needed paradigm shift, one that integrates psychiatry, neurobiology, and cognitive psychology,” he told Psychiatric News, the newspaper of the American Psychiatric Association.

The article reports that Dr. Kandel’s lab developed a mouse model with schizophrenic symptoms based on the genetic structures of a human schizophrenic brain. The transgenic mouse overexpressed the D2 receptor in the striatum and also expressed a regulatory gene that could be used to control the receptor gene. According to the article, the researchers found that the experimental mice mimicked the behavior of humans with schizophrenia in tests of motivation and hedonic reactions.

Read more about the Schizophrenia research being conducted at Dr. Kandel’s lab at psychnews.psychiatryonline.org; and learn about his experience as a Jewish child in Vienna in the 1930s, what sparked his interest in psychoanalysis, and why he decided to study Aplysia sea slug at Nobelprize.org.

Photo of Dr. Kandel via Columbia University.

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Swiss Scientists Use Stereo Investigator to Study Schizophrenia

There may be more evidence that schizophrenia results from a combination of genetic and environmental factors. One of these hereditary influences may be an impaired ability to synthesize the antioxidant glutathione (GSH), which results in oxidative stress, according to a study conducted by scientists at the University of Lausanne in Switzerland.

By observing mice with a GSH deficit, Dr. Kim Q. Do and her team determined that the inability to synthesize GSH led to “inadequate responses to stress and fear,” while the capacity for spatial learning and spatial memory remained intact. Thus, they concluded that a deficiency of GSH results in a “selective decrease of PV-IR interneurons in CA3 and dentate gyrus (DG) of the ventral but not dorsal hippocampus.”

The research group quantified the density of GABAergic interneurons in various subregions of the mouse hippocampus with Stereo Investigator.

“Each stereological session started at low magnification with the identification of the boundaries of the region of interest on two sections from each animal,” Dr. Do explained.

Boundaries between the hippocampal regions were traced and an intermediate zone was created between the CA1 and CA3 to ensure these regions did not overlap. The counting and analysis of neurons was performed with the aid of an optical dissector, at a 40x magnification.

“We found Stereo-Investigator user-friendly and adaptable to the requirements of our study, ” said Dr. Do. “We plan to continue using this software to quantify in our animal model the density of neurons in other candidate brain regions implicated in schizophrenia.”

Access the article abstract and full text (by subscription) at jneurosci.org.

Pascal Steullet, Jan-Harry Cabungcal, Anita Kulak, Rudolf Kraftsik, Ying Chen, Timothy P. Dalton, Michel Cuenod, and Kim Q. Do (2010), “Redox Dysregulation Affects the Ventral But Not Dorsal Hippocampus: Impairment of Parvalbumin Neurons, Gamma Oscillations, and Related Behaviors” The Journal of Neuroscience, 30(7):2547-2558

{Image of Dr. Kim Q. Do courtesy of the University of Lausanne}

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