For some years, scientists have had evidence that in schizophrenia, communication between the brain’s PFC, or prefrontal cortex (the seat of higher cognitive function) and the thalamus (a kind of signal-relay station) is in some way disturbed. Now, a team led by two-time NARSAD grantee Bo Li, Ph.D., of Cold Spring Harbor Laboratory, has traced a circuit between those brain areas, providing new clues about what goes wrong in schizophrenia.

Their research was published on April 8th in the Journal of Neuroscience.

The circuit is an inhibitory one––that is, it regulates the timing of information flow from various parts of the brain into the PFC. Dr. Li and colleagues focused on connections between a section of the PFC called the medial prefrontal cortex and a section of the thalamus called the mediodorsal thalamus. They observed a process called feedforward inhibition. Via this mechanism, one neuron excites the next neuron “downstream” in a circuit (called the target neuron), and also recruits a third neuron to tamp down or inhibit the downstream target, after a delay.

Dr. Li, recipient of a Young Investigator grant in 2010 and an Independent Investigator grant in 2015, notes that this mechanism limits the window of time within which the target neuron can be activated. Placed in the context of the PFC-thalamus circuit, this is the significance: when the thalamus transmits a bit of information gathered by the senses, the inhibitory process the team discovered acts to filter out “noise” not directly related to the sensory information. When the system is working properly, this makes available to an individual (or a rodent, in the case of these experiments) precise sensory information.   

When the system is not working properly, it stands to reason that cognition––the ability to correctly process data from our senses––is disturbed. This has not been shown in either mice or people in the context of schizophrenia symptoms, but the discovery by Dr. Li’s team makes this a plausible theory and a potential basis for new treatment approaches. In part, this is because the team’s experiments identified two neuronal types in the PFC, which signals from the thalamus activate. The circuit consists of excitatory pyramidal neurons (neurons whose branches are in the shape of a pyramid), carrying the signal from the thalamus, and inhibitory neurons that tamp down and regulate the signal from pyramidal neurons.

“The current problem for treating schizophrenia is the lack of drugs that work,” Dr. Li said. “So the discovery of this mechanism for the disease is exciting. But this is just the beginning of efforts to specify a neural pathway implicated in schizophrenia and what changes occur in the pathway.”

Read the abstract.