11 Apr 2017
by Hakon Heimer
It is often suggested that schizophrenia represents not a single disease process but the common final pathway for many different avenues involving a host of genetic, biological, and environmental causes. A new study led by Jordan Hamm and Rafael Yuste at Columbia University in New York City supports this notion of many paths to symptoms of schizophrenia.
In an article published online in Neuron on April 5, 2017, Hamm and colleagues write that they have found similar patterns of cortical activity abnormality in two very different models for psychosis research: a 22q11 deletion syndrome mouse model and the chronic ketamine exposure model. In both cases, the researchers found that groups of visual cortex neurons that fire together―called “ensembles”―were less consistent in this activity than corresponding ensembles in control animals.
These stable or semi-stable emergent activity patterns correspond to the “attractors” hypothesized to be the building blocks of memory, thoughts, perception, and action. Rolls and colleagues have proposed that schizophrenia is an attractor disease, wherein ensembles of cells don’t fire in harmony (Rolls et al., 2008).
“We’re suggesting that the point at which all the diverse, low-level pathophysiologies of schizophrenia converge is at the initial ensemble level in local territories of the brain,“ said Hamm. These hypothesized breakdowns of local cortical ensembles might then underlie larger-scale disruptions in connectivity seen on functional MRI.
“One of the really nice things, and one of the rare things, about this paper is that they looked across animal models,” said Philip Corlett of Yale University in New Haven, Connecticut, who was not involved in the study.
Hamm and colleagues studied visual cortex activity by several methods in two mouse models: mice that had been exposed to chronic ketamine infusions, blocking NMDA-type glutamate receptors to create a pharmacological model of schizophrenia (as reported by SRF from the 2015 SfN meeting; see also SRF glutamate hypothesis), and Df(16)A+/- mice developed by co-author Joseph Gogos to recapitulate a version of the human 22q11 deletion syndrome, which confers a high risk for schizophrenia (see SRF news here and here).
The mice were first studied with standard single-electrode electrophysiology, both at rest and during visual stimulation, and the authors report that they saw alterations in gamma-band dynamics and signal-to-noise ratio recapitulating data from human schizophrenia subjects.
The researchers then employed two-photon calcium imaging, which Yuste helped pioneer, to visually track the firing of individual and local populations of hundreds of neurons in awake animals. They found some differences between the models at the single-cell level: The chronic ketamine-treated mice, but not the Df(16)A+/- mice, had more active neurons. But those single neurons were, when averaged across trials, responding appropriately to the visual stimuli.
This was not the case at the level of local circuits. “Ensembles in both of these low-level models of schizophrenia are disrupted, both at rest and during stimulus-induced activity,” said Hamm.
While visual cortex is not a traditional hotspot for schizophrenia research, there is evidence that neurons in many different brain regions behave differently in the disorder.
“I think it’s good that we’re moving the lamp post outside of prefrontal cortex,” said Corlett. “There’s certainly evidence that it’s relevant to patients. I think about work by Dan Javitt showing early visual perturbations, particularly in first-episode patients.” (See SRF news story.)
Two control experiments did not produce the ensemble dysfunction. Both acute treatment with ketamine to block NMDA receptors and acute pharmacogenetic suppression of parvalbumin-containing interneurons produced recordable, though different, alterations at the level of single cells, yet neither manipulation produced ensemble-level changes.
“We’re providing an umbrella for all these separate findings that converge once you move from the molecular and cellular levels to the circuit level,” said Yuste.
Hamm said that they have not tried normalizing the faulty attractors with current antipsychotic drugs, though he thinks it could be informative.
"Based on the fact that first- and second-generation antipsychotic medications, acting primarily via the midbrain-striatal dopamine system, do not completely ameliorate cognitive and negative symptoms, one could expect that treatments targeting cortical circuits directly may have a more robust effect on cortical ensembles," he said. "Alternatively, one could imagine that restabilizing striatal-pallidal-thalamic dynamics via typical/atypical antipsychotics could partially recover thalamic reticular nucleus control over thalamocortical input, gradually reinforcing externally driven ensembles in a feedforward manner."
One model to explain, and treat, them all?
The authors suggest that these abnormalities could underlie different facets of schizophrenia: positive symptoms arising from inconsistent or unreliable attractors and cognitive symptoms from unstable attractors.
Corlett agrees about the potential to explain different aspects of schizophrenia, adding negative symptoms to the mix.
“I think it provides to a nice motif for both the positive symptoms of schizophrenia, wherein the network is responding to information that isn’t present, and also some of the negative symptoms, wherein it’s hard to bring the network out of what’s called a basin of attraction, to get enough energy to move to a new state,” he said.
For his part, Yuste is engaged in thought experiments beyond mere explanations. “This provides a conceptual framework to attack the pathophysiology of schizophrenia and correct it,” he said.
Last year, Yuste’s group published a study in which they used optogenetics to create artificial ensembles in mouse visual cortex, without disrupting pre-existing ones. He proposes the possibility of using optogenetics, or a related method called optochemistry, to strengthen weak attractors in patients.
Such a Star Trek medicine scenario (which Yuste and George Church sketched out in a Scientific American article; see Yuste and Church, 2014) will depend on future advances in mapping the activity of circuits to function and then identifying faulty attractors in patients.