Understanding Mechanisms of Vulnerability During Adolescence: A Role for Perineuronal Nets

A hallmark of adolescent brain development is the establishment of a finely-tuned excitatory-inhibitory (E-I) balance in the prefrontal cortex (PFC). This balance, which comes online as inhibitory signaling is refined, helps regulate neuron activity and is essential for the acquisition of higher cognitive function, such as decision-making, in adulthood. It is widely accepted that the maturation of parvalbumin-containing (PV+) interneurons is critical for developing E-I balance, as PV+ interneurons are known to regulate excitability of other cells. Interestingly, approximately 70% of PV+ interneurons in PFC are surrounded by perineuronal nets (PNNs), a lattice-like structure that forms around them during critical periods of development and regulates their plasticity. Drugs of abuse are known to affect PNNs in adulthood, but few researchers have studied the impact of drug use on PNNs during development. Cannabis, the most commonly used illicit drug among adolescents, is known to alter E-I balance by disrupting the development of PV+ cells, so we began by investigating whether cannabis might be exerting its effects by disrupting PNN development and making PV+ cells vulnerable to insult. Addiitionally, this work explored whether disruptions in PFC PNNs would lead to functional deficits in decision-making, a PFC dependent behavior. If this is the case, then PNNs may be one neurobiological mechanism that underlies the effects of cannabis on the developing brain. Enhancing our understanding of both the immediate and lasting effects of cannabinoids on the developing brain will elucidate the consequences of substance use during adolescence, with implications for the study of addiction and adolescent-onset psychiatric disorders, as well as cannabis policy.