Schizophrenia-Related Memory Decline: Clues to Its Cause Found in Brain Circuit [Reading Science]

Korea Brain Research Institute Confirms Weakened Thalamus-Prefrontal Cortex Connection in Adolescent Mice
Activating the Circuit Restores Short-Term Memory, Offering a Potential New Treatment Target

Researchers in South Korea have identified how a brain circuit works in a way that could explain the short-term memory deficits seen in people with schizophrenia. They found that weakening the neural circuit connecting the thalamus and prefrontal cortex in adolescent mice impaired memory, while reactivating the circuit restored memory function. The findings are expected to offer clues for identifying new targets to treat cognitive impairment in schizophrenia.

The Korea Brain Research Institute said on October 19 that a team led by Principal Researcher Ra Jongcheol of its Department of Brain and Neuroscience had identified the synaptic mechanism through which NMDA receptor hypofunction, associated with schizophrenia, leads to short-term memory impairment. The findings were published in the international journal Science Advances.

Schematic of thalamo-prefrontal synaptic weakening caused by NMDA receptor hypofunction during adolescence and its chemogenetic restoration. Reduced NMDA receptor function during adolescence lowers neurotransmitter release efficacy at thalamo-prefrontal synapses, resulting in short-term memory impairment (center). Strengthening this circuit through chemogenetics restores both release efficacy and short-term memory (right). Image provided by the research team.

NMDA receptors are proteins involved in signal transmission between neurons and in learning and memory. Hypofunction of these receptors is being studied as one factor related to the pathogenesis of schizophrenia. Previous brain imaging studies of people with schizophrenia found that weaker connections between the thalamus and prefrontal cortex tended to be associated with poorer short-term memory, but the causal relationship between the two was unclear.

The research team repeatedly administered ketamine, an NMDA receptor blocker, to adolescent mice for two weeks and then analyzed changes in their memory and brain circuits. In a Y-maze test assessing short-term memory, the mice performed worse, and their performance had not recovered even 28 days after the drug was discontinued. By contrast, adult mice did not show this persistent memory impairment.

An examination of the brain circuits found that the efficiency of neurotransmitter release was selectively reduced at synapses along the pathway from the thalamus to the prefrontal cortex. No notable changes were observed at synapses connecting neurons within the same cerebral cortex. This means that NMDA receptor hypofunction does not affect all neural circuits equally, but instead weakens specific circuits.

The synaptic changes also affected the ability to process information. When the team measured prefrontal neuron activity in live mice, it found that mice with a weakened circuit were less able to distinguish and process information about the direction of movement.

Activating Weakened Brain Circuit Restores Memory Function

The team then strengthened the circuit between the thalamus and prefrontal cortex using a chemogenetic technique to artificially regulate the activity of specific neurons. Both the impaired ability to process directional information and short-term memory performance returned to normal levels. The animal experiments confirmed that dysfunction in a specific circuit can cause memory impairment.

Photo of the joint research team. Provided by KBRI.

However, this study modeled some cognitive impairments associated with schizophrenia in mice treated with ketamine. Further research is needed to determine whether the same mechanism applies to people with schizophrenia and whether activating the circuit would lead to therapeutic benefits.

“This study shows that hypofunction of NMDA receptors during adolescence reduces synaptic release efficiency and weakens this circuit, and that artificially strengthening the circuit restores memory. In doing so, it demonstrates causation beyond correlation in an animal model,” said Ra Jongcheol, principal researcher at the Korea Brain Research Institute.

Researchers from the Daegu Gyeongbuk Institute of Science and Technology (DGIST), Seoul National University, Hanyang University Hospital and Yonsei University also participated in the study.

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