What Are NMDA Receptors?
NMDA receptors are important for brain development and function. They help communicate between brain cells and are crucial for learning and memory. The brain undergoes significant changes during adolescence, and NMDA receptors play a key role in this process. If these receptors are blocked or disrupted during this critical period, it can lead to long-term problems, including symptoms seen in schizophrenia.
Schizophrenia is a serious mental illness that affects how a person thinks, feels, and behaves. It often starts in late adolescence or early adulthood and can cause problems with memory, thinking, and social interactions. Scientists are constantly looking for ways to understand and treat this condition. Our recent study from the University of Haifa has found a promising new approach using chemogenetic techniques to help restore memory deficits caused by disruptions during brain development.
Adolescence is a time of intense brain remodeling, especially in the prefrontal cortex (PFC), a region crucial for decision-making, memory, and social behavior. The study focused on what happens when this process goes awry. By injecting young rats with a drug called MK-801, which blocks NMDA receptors (key players in brain signaling), mimicked a neurodevelopmental disruption linked to schizophrenia. This blockade, administered during early adolescence (postnatal days 30–44), led to long-term changes in the adult brain.
Key Findings:
In the initial experiment, we employed electrophysiology—a method for assessing electrical activity in neurons—to investigate the pyramidal neurons of the PFC, which are essential for information processing in the brain. The findings revealed that rats treated with MK-801 experienced an imbalance in excitatory and inhibitory signals, referred to as E/I balance. Notably, inhibitory signals (sIPSCs), which function as brakes on brain activity, were diminished, leading to increased overexcitation. This disruption is characteristic of conditions such as schizophrenia, where the brain fails to filter and process information effectively.
Could this imbalance be corrected to restore normal behaviour? That’s where the second experiment comes in, and it’s where things get exciting. We used a cutting-edge technique called chemogenetics, which allows one to control specific neurons with a drug, much like flipping a switch. The rats were injected with a virus (hM4Di) into the PFC to target pyramidal neurons, making them responsive to a compound called clozapine N-oxide (CNO). When CNO was administered, it dampened the activity of these neurons, effectively turning down the volume on their overexcited chatter.
Novel Object Recognition (NOR): This task checks if rats can remember a familiar object versus a new one—a test of recognition memory. MK-801-treated rats normally struggle here, showing poor memory. Remarkably, when their PFC neurons were quieted with CNO, these rats performed as well as healthy controls, suggesting their memory deficits were reversed.
Social Interaction Test (SIT): This measures how much rats prefer socializing with another rat over an empty space. Unfortunately, calming the PFC neurons didn’t improve social behavior, as MK-801-treated rats still showed reduced sociability.
Restoring recognition memory by taming PFC pyramidal neurons highlights the role of E/I imbalance in memory deficits and suggests that targeting overactive neurons could be a therapeutic strategy. However, the lack of improvement in social behavior tells us that social deficits might involve other brain regions or circuits, which is a critical clue for future research.
Check out the full study by Bauminger et al. in Progress in Neuropsychopharmacology & Biological Psychiatry https://www.sciencedirect.com/science/article/pii/S0278584625001137 for all the nitty-gritty details, including the electrophysiological data and behavioral protocols.
References:
1. Coyle, J. T. NMDA Receptor and Schizophrenia: A Brief History. Schizophr. Bull. 38, 920–926 (2012).
2.Insel, T. R. Rethinking schizophrenia. Nature 468, 187–193 (2010).
3. Bauminger, H. & Gaisler-Salomon, I. Beyond NMDA Receptors: Homeostasis at the Glutamate Tripartite Synapse and Its Contributions to Cognitive Dysfunction in Schizophrenia. Int. J. Mol. Sci. 23, 8617 (2022).