Washington: A recent study has offered a promising entry point for attacking a near-universal and debilitating symptom of schizophrenia, memory deficits, which has thus far withstood all forms of treatment.
The Columbia scientists found that disruptions to the brain's centre for spatial navigation, its internal GPS, result in some of the severe memory deficits seen in schizophrenia. The study in mouse models of the disorder marks the first time that schizophrenia's effects have been observed in the behaviour of living animals and at the level of individual brain cells with such high-resolution, precision and clarity.
"An almost intractably complex disorder, schizophrenia is nearly impossible to fully treat in large part because it acts as two disorders in one," said co-senior author Joseph Gogos from Columbia's Mortimer B. Zuckerman Mind Brain Behaviour Institute. "On one hand, you have paranoia, hallucinations and delusions; while on the other you have severe memory deficits. Antipsychotic drugs, which treat the first class of symptoms, are entirely ineffective when dealing with the second. The reasons for this are simple: we do not yet understand what happens in the brains of schizophrenia patients."
Cracking schizophrenia's code must therefore start with deciphering its biological origins, noted Gogos. For this study, the team focused on a brain region called CA1, located in the hippocampus, which plays a role in both navigation and in episodic memory. Physical alterations to CA1 have been previously reported among schizophrenia patients.
They developed experiments to record CA1 activity in mice that were genetically modified to mimic schizophrenia, and compared them to normal, healthy mice. The researchers placed both groups of animals on a treadmill under a high-resolution, two-photon microscope, where they were exposed to a variety of sights, sounds and smells (including a water reward placed at unmarked locations on the treadmill). These experiments were designed to test the animals' ability to navigate a new environment, remember how to navigate a familiar one and adapt quickly when that environment was altered.
The two groups of mice showed striking differences in behaviour and in cell activity. While both groups could successfully navigate a new environment, the schizophrenia-like mice had more trouble remembering familiar environments from day to day, as well as adapting when aspects of that environment changed. By simultaneously tracking the animals' place cells via the two-photon microscope, the team spotted the difference.
"When the healthy mice approached something familiar, such as water, their place cells fired with increasing intensity, and then quieted down as the animals moved away," explained senior author Attila Losonczy. "And when we moved the location of the water, and gave the animals a chance to relearn where it was, the activity of their place cells reflected the new location."
But the brains of the schizophrenia-like mice were different. Their place cells did not shift when the water reward was moved. The brain cells' lack of adaptability, the scientists argue, could reflect a key and more general mechanism of memory deficits in schizophrenia. It could also represent a new target for drug intervention.
The results are published in Nature Neuroscience.