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.