Researchers identify brain circuit behind schizophrenia-linked memory loss

- Korean Brain Research Institute finds weakened thalamus-prefrontal synapses during adolescence trigger short-term memory impairment

- Artificially boosting damaged circuit activity in mice restores memory to normal levels, pointing to new treatment target

South Korean researchers have identified a neural circuit abnormality responsible for the short-term memory impairment seen in schizophrenia — and found that artificially boosting the weakened circuit's activity can restore memory to normal levels.

The Korea Brain Research Institute announced Monday that a research team led by Principal Researcher Ra Jong-cheol of the institute's neuroscience division has uncovered the mechanism by which synapses connecting the thalamus and the prefrontal cortex selectively weaken during adolescence, triggering short-term memory deficits.

Schizophrenia is a psychiatric disorder marked not only by hallucinations and delusions but also by a range of cognitive impairments, including memory loss and difficulty concentrating. Short-term memory deficits in particular are considered a leading cause of reduced daily functioning and social ability. Whether these changes directly cause memory decline — and when they first emerge — had not been clearly established.

The research team focused on reduced NMDA receptor function, one of the mechanisms implicated in the onset of schizophrenia. NMDA receptors are proteins that play a key role in transmitting information between neurons and in learning and memory.

The team repeatedly administered ketamine, an NMDA receptor blocker, to adolescent mice over two weeks, then analyzed changes in memory and neural circuitry.

The mice showed a marked decline in performance on the Y-maze test, a standard measure of short-term memory. The memory impairment persisted even 28 days after drug treatment was stopped.

Adult mice, by contrast, showed no lasting memory deficits — confirming that the adolescent brain is particularly vulnerable to reduced NMDA receptor function.

Detailed analysis of the neural circuitry revealed a selective decrease in neurotransmitter release efficiency at the synapses carrying signals from the thalamus to the prefrontal cortex. Synapses connecting neurons within the cerebral cortex itself showed no notable changes.

This indicates that reduced NMDA receptor function does not affect the brain broadly, but selectively weakens specific neural circuits critical to memory.

Measurements of prefrontal cortex neuron activity in living mice showed that animals with weakened thalamus-prefrontal connections also had a diminished ability to distinguish and process directional information — confirming that synaptic abnormalities translate into impaired information processing.

The research team then went a step further, conducting experiments to restore function to the damaged brain circuit.

Korea Brain Research Institute researchers Yoo Jin-seon (from left), Choi In-seon and Ra Jong-cheol. [Provided by Korea Brain Research Institute]

Using chemogenetic technology to modulate the activity of specific neurons, the team artificially increased activity in the circuit linking the thalamus and the prefrontal cortex. Both the prefrontal cortex's information-processing capacity and the mice's short-term memory performance recovered to normal levels.

The findings go beyond establishing a correlation between weakened circuit connectivity and memory decline — they demonstrate through animal experiments a direct causal link between circuit dysfunction and memory impairment.

The study is significant for suggesting that cognitive impairment in schizophrenia may stem from abnormalities in a specific brain circuit, and that targeting that circuit could offer a path to improving memory. However, further validation will be needed before the findings can be applied to human patients, given that the research was conducted in mice.

"Previous brain imaging studies in schizophrenia patients had only reported a correlation between weakened thalamus-prefrontal connectivity and short-term memory decline," Ra said. "This research demonstrates in an animal model the causal relationship — that reduced NMDA receptor function during adolescence weakens specific synapses, and that reactivating that circuit can restore memory."

The findings were published in the international journal Science Advances.

nbgkoo@heraldcorp.com