Schizophrenia is
a difficult disorder to study because it is so complex. There are many symptoms
and patients show different combinations of them. To study the neurobiological
aspects of schizophrenia, researchers use animals, including rodents like rats
and mice. Because of its complexity, it is impossible to recreate the disorder
in an animal but there are ways to mimic certain aspects. One of the pharmacological
ways of doing so is by using the drug ketamine.
Ketamine is a
dissociative anesthetic, which means it can create feelings of unreality and
hallucinations similar to some symptoms of schizophrenia. Because of this
similarity, ketamine is also expected to have an effect on the number of
parvalbumin (PV) interneurons in the brain. PV interneurons are decreased in
number in patients with schizophrenia, as assessed by post-mortem samples.
Jennifer
Corriveau, a PhD candidate in Dr. James Chrobak’s lab at the University of
Connecticut, uses ketamine in a rat model of schizophrenia to assess PV
interneuron number. Past studies using ketamine in rodents had conflicting
findings: in some, PV interneuron number was decreased and in others, it was
increased. To complicate matters, the past studies used animals of different
ages. Jennifer thought the variations in PV interneuron number after ketamine
treatment might be due to age.
To test this
hypothesis, she assessed PV interneuron numbers in rats at 1 mo and 6 mo of
age. When compared to the 1 mo old rats, the brains of 6 mo old animals had
50-90% fewer PV interneurons in the CA1 and dentate gyrus regions of the
hippocampus, an area of the brain involved in learning and memory. In 24 mo old
rats extensively trained in a learning and memory task, the number of PV cells
was increased. Jennifer thought the increase might be due to the training.
In her next
experiment, she trained rats in a radial water maze and assessed their memory
during and after a 14-day ketamine administration. By day 6, the rats receiving
ketamine were making more errors in the maze than the rats who received only
saline. After stopping ketamine administration, the error rate returned to baseline
slowly over a few days. Ketamine leaves the body quickly so the slow return to
baseline suggested its effect lasted even after ketamine was gone.
After behavioral
testing, there was no difference in PV cell number between the ketamine and
saline groups. Jennifer thinks maybe cognitive training can reduce the negative
impact of ketamine has on PV cell number. Alternatively, the 10-day wait
between the end of testing and tissue harvest may have been enough time for any
changes in PV expression levels to return to baseline. Jennifer says she has
plans for a similar study where she will harvest the tissue on the last day of
behavioral testing to see if there are differences in PV cell number.
As for the
increase in PV interneuron number in the older rats, Jennifer thinks the
expression level of PV in interneurons is variable and highly dynamic. The
expression may increase during aging or after cognitive training. She plans to
continue investigating PV protein expression after ketamine administration. Jennifer
emphasizes how important animal age, type of, and length of behavioral testing
are when assessing PV expression.
Yes, it has been used as a general anesthetic. It is a dissociative anesthetic and can induce psychosis and confusion in humans. Due to this, it has been used a model of schizophrenia in animal research.
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