Summary: Researchers report a group of neurons that fire haphazardly in mouse models of schizophrenia could underlie the psychosis that is symptomatic of the disorder.
Source: Columbia University.
Haphazard activity could underlie psychosis, say researchers.
Researchers at Columbia University have discovered that a small group of neurons fired haphazardly in mice with signs of schizophrenia. The findings suggest that a breakdown in the synchronized behavior of these brain cells could produce the classic disordered thinking and perceptions associated with the disease.
The study, which may be the first to test the idea that schizophrenia arises from disruptions in small networks of neurons, was published today in Neuron.
Affecting about one percent of the population, schizophrenia is marked by a range of distinct symptoms, from hallucinations and delusions, to memory problems and social withdrawal. It also comes in a variety of forms, which has hindered researchers in finding a unifying explanation for the disease that could improve diagnosis and treatment.
“If you think of the neurons in the schizophrenic mice as pixels on a TV screen, it’s as if most of the pixels have been scrambled,” said the study’s lead author, Jordan Hamm, a postdoctoral researcher at Columbia University. “Each pixel no longer relates to its neighbor to form a coherent, stable picture.”
The researchers chose to focus on the visual cortex because impaired visual processing is one of schizophrenia’s defining traits. Using calcium-imaging techniques, they recorded flashes of light emitted by individual neurons as each fired off an electric signal. In healthy mice, they found that groups of 60 to 120 neurons flashed in a consistent pattern, as if following a choreographed arrangement. The neurons in the mice with signs of schizophrenia, by contrast, fired more randomly as if working in isolation.
The researchers tested two mouse models of the disease, genetic and chemical, and found similar results. Mice given regular doses of ketamine, an anesthetic that acts on glutamate receptors and can produce psychotic behavior, showed erratic neural activity, as did mice bred with a genetic mutation associated with a high risk of developing schizophrenia in humans.
“The pattern emerging from this analysis is one of profound disorganization, as though neurons were acting on their own rather than as a coherent group,” said study coauthor Dr. Joseph Gogos, a neuroscientist at Columbia University Medical Center and Columbia’s Zuckerman Institute who studies underlying mechanisms of schizophrenia in genetic models of the disorder.
In a related study published in Science last year, the researchers showed that repeatedly stimulating a small group of neurons in the same region of the mouse brain, the visual cortex, caused the neurons to fire together, as if their respective connections had been strengthened by use. Dr. Rafael Yuste, the study’s senior author and a neuroscientist at Columbia, has suggested that this process could explain how memories and thoughts form, and how neural circuits might be reprogrammed through artificial manipulation.
Both studies suggest new avenues for treating schizophrenia, the researchers say, through the manipulation of genes, genetic pathways, and even individual neurons, to restore disrupted neural units to their normal functioning.
“I’ve experienced deep frustration in trying to treat schizophrenic patients without understanding how this disease works,” said Yuste. “I’m excited by the possibility of reversing some of schizophrenia’s symptoms by reprogramming neurons to fire in a more coordinated fashion.”
Funding: This research was supported by the NIH/National Institute of Mental Health, NIH/National Eye Institute, DARPA SIMPLEX, Brain and Behavior Research Foundation.
Source: Kim Martineau – Columbia University
Image Source: NeuroscienceNews.com image is credited to Nicoletta Barolini/Columbia University.
Original Research: Abstract for “Altered Cortical Ensembles in Mouse Models of Schizophrenia” by Jordan P. Hamm, Darcy S. Peterka, Joseph A. Gogos, and Rafael Yuste Neuron. Published online April 5 2017 doi:10.1016/j.neuron.2017.03.019
Altered Cortical Ensembles in Mouse Models of Schizophrenia
•Neuronal ensemble activity is less reliable in mouse chronic ketamine model
•Ensembles are affected in mouse genetic model of schizophrenia
•Abnormal ensembles are found in both spontaneous and sensory-evoked activity
•Data are consistent with schizophrenia being a disease of cortical attractors
In schizophrenia, brain-wide alterations have been identified at the molecular and cellular levels, yet how these phenomena affect cortical circuit activity remains unclear. We studied two mouse models of schizophrenia-relevant disease processes: chronic ketamine (KET) administration and Df(16)A+/−, modeling 22q11.2 microdeletions, a genetic variant highly penetrant for schizophrenia. Local field potential recordings in visual cortex confirmed gamma-band abnormalities similar to patient studies. Two-photon calcium imaging of local cortical populations revealed in both models a deficit in the reliability of neuronal coactivity patterns (ensembles), which was not a simple consequence of altered single-neuron activity. This effect was present in ongoing and sensory-evoked activity and was not replicated by acute ketamine administration or pharmacogenetic parvalbumin-interneuron suppression. These results are consistent with the hypothesis that schizophrenia is an “attractor” disease and demonstrate that degraded neuronal ensembles are a common consequence of diverse genetic, cellular, and synaptic alterations seen in chronic schizophrenia.
“Altered Cortical Ensembles in Mouse Models of Schizophrenia” by Jordan P. Hamm, Darcy S. Peterka, Joseph A. Gogos, and Rafael Yuste Neuron. Published online April 5 2017 doi:10.1016/j.neuron.2017.03.019