The effects of THC on the developing postnatal hippocampus

Cannabis has recently gained attention in the publics political debate due to its medical potential, legalization and new ways of consumption. While cannabis use in adults is considered to be safe, new clinical reports are published on its toxicity and its involvement in newly described diseases, such as cannabinoid hyperemesis syndrome (HES). It is particularly notable that cannabis consumption during pregnancy changes the embryonic brain leading to problems with learning and memory persisting into the adulthood of affected offspring. However, if cannabis exposure through recreational use, or when used as medication, during childhood and adolescence can affect brain function is currently unknown. The human brain is developing until the mid 20s, allowing for a long developmental window for drugs to change the structural basis of cognition: the underlying neuronal network operations. Understanding how cannabis can affect the developing brain during this time is thus important, since 1) cannabis potency is increasing, 2) cannabis is becoming more and more available due to legalization and 3) cannabis use is highest in young adolescents. Therefore, the aim of this proposal is to investigate the underlying changes that cannabis produces to the young adolescent brain. For this project, we will focus on the hippocampus, a brain structure particularly sensitive to cannabis. We will clarify which proteins are changed due to cannabis exposure in the young adolescent hippocampus, and how these changes affect the survival and network connectivity of neurons. We will focus our protein findings on neuron energy production to see how cannabis use during childhood/adolescence can permanently change neuron function. In sum, our experimental methodology will show cannabis induced changes in the developing hippocampus and deliver a database with druggable targets that can be used to either prevent or improve brain functioning after cannabis exposure.

In this project, we have mainly addressed how cannabis affects the fetal and postnatal developing brain. We found that THC exposure during pregnancy and after birth resulted in the misplacement of certain cell types in the hippocampus and cortex regions of the brain. We also found that brain circuitry was changed after cannabis exposure, indicating that care should be taken when consuming cannabis during pregnancy and that young children should not be exposed to cannabis either. We additionally discovered that THC interacts with (S)-ketamine in the adult brain leading to strong physiological reactions and the prevention of the therapeutic effects of (S)-ketamine on behavior and hormone levels. Our data experimentally confirmed the already proposed contraindication of both drugs during psychiatric treatment, helping clinicians to understand why the two drugs should not be used together. Finally, the funding for this project allowed us to investigate hypothalamic development, and develop new tools that target important signaling systems in health and disease. We invented fluorescent tracers that can be used to visualized receptors as an alternative to antibodies, so that changes in receptor expression patterns can be detected in specific diseases, including autism and ADHD.