The hippocampus, a small structure in the brain, plays a vital role in memory storage and formation. For instance, the hippocampus participates in “spatial memory,” which enables us to remember and navigate our environment, and “contextual memory,” which involves remembering specific details of past experiences. Hippocampal memory formation and recall involve a process called synaptic plasticity, which describes the ability of synapses, otherwise known as connections between neurons, to increase or decrease in strength based on their frequency of use. Increasing the strength of synapses typically occurs through a process called long-term potentiation, and is important in creating new memories, while weakening synapses occurs through long-term depression, and is involved in forgetting information.

Prof. Reed’s research focuses on how prenatal cannabinoid exposure (or PCE for short) affects hippocampal synaptic plasticity and resulting memory formation. The research team exposed pregnant rats to synthetic cannabinoids to model the effects of human cannabis use during pregnancy. As the rodent offspring grew into adolescents, the researchers assessed them to determine their abilities to form memories and learn. These tests involved determining if the rats would remember an unpleasant stimulus in the form of a small electric shock to assess contextual memory. The rats also completed a water maze task to assess spatial memory.

Strikingly, adolescent rats that had been exposed to synthetic cannabinoids prenatally demonstrated appreciable deficits in hippocampal-dependent memory. So, how did this occur? Cannabinoids interact with the brain through tiny structures called cannabinoid receptors, such as the CB1 receptor, which is found throughout the brain, including in the hippocampus. When a woman uses cannabis during pregnancy, cannabinoids such as THC can travel across the placenta to the delicate foetal brain. Here, they can affect brain development.

A central finding of the study involved the neurotransmitter glutamate, which is heavily involved in learning and memory. Neurotransmitters are typically released into synapses, where they help to transmit signals between neurons in the brain. Glutamate is a common excitatory neurotransmitter, meaning that it typically increases activity in the neurons it interacts with. In the hippocampus, glutamate receptors are heavily involved in synaptic plasticity, such as the GluN2A and GluN2B receptors. In essence, maintaining an appropriate balance between GluN2A and GluN2B receptors in the hippocampus is important for normal memory function.

The study showed that PCE in the rats disrupted this delicate balance, whereby cannabinoid exposure changed GluN2A and GluN2B receptor activity, which in turn affected synaptic transmission. Put simply, the brain’s ability to strengthen synaptic activity, a key process in learning and memory, was compromised. Ultimately, this disrupted glutamate signalling in PCE rat adolescents helped to explain their memory impairments.

Strikingly, PCE also appeared to alter the structure of the affected neurons. The PCE rats also demonstrated reduced levels of a protein called polysialylated-neural cell adhesion molecule (or PSA-NCAM for short), which is a protein that affects synaptic growth and structure, and plays an important role in how the hippocampus grows during foetal development. PSA, otherwise known as polysialic acid, is a special component of NCAM proteins that greatly affects their function. With lower levels of PSA-NCAM in the brains of the PCE rats, their synapses were less adept at reinforcing neural activity through synaptic plasticity, reducing their ability to form new memories.

Happily, the researchers found that it may be possible to treat PCE-mediated memory deficits, despite the fact that the relevant neural changes likely began long before the rodents reached adolescence. The researchers showed that treating the rats with PSA helped to restore their memory function, suggesting that treatments that could increase levels of PSA-NCAM in the hippocampus may represent a viable treatment option in children who were exposed to cannabis in the womb.

Assuming that similar mechanisms are relevant in humans, such treatments might one day help such children to regain some cognitive abilities. However, much more research is needed to determine whether these processes are identical in humans, and how these mechanisms can be safely targeted using drug treatments.

Whether PCE-mediated cognitive impairment is ultimately treatable or not, this study serves as a warning for pregnant women who consider using cannabis. Prenatal exposure can have potentially significant and enduring effects on memory and learning. As with any intoxicating substance, cannabis has risks that should be understood before making the choice to consume it.

Prof. Reed and colleagues have shown that cannabis exposure can deeply impact the developing brain’s ability to create and retain memories. Excitingly, by revealing some of the complex molecular mechanisms behind these phenomena, the study also offers hope for future treatments. Of particular note, PSA-NCAM emerged as a key participant in both PCE-mediated memory impairment and in the potential recovery of cognitive function as a treatment modality.

As cannabis use becomes more common globally, it is essential that research continues to investigate its effects on vulnerable populations, so that potential users can make informed decisions about their own health, and that of their children. The work of Prof. Reed and colleagues is a crucial step in this journey.