Adolescent cannabinoid exposure delays development of prefrontal cortex perineuronal nets and inhibitory interneurons

Maturation of inhibitory signaling during critical period development depends on neural activity driven by experience. Parvalbumin positive (PV+) interneurons, the dominant type of inhibitory interneuron in prefrontal cortex (PFC), undergo critical period development during adolescence. Their maturation is supported by perineuronal nets (PNNs), lattice-like extracellular matrix structures that surround PV+ cells and regulate their synaptic inputs and activity. The endocannabinoid system also regulates excitatory-inhibitory balance by providing negative feedback that reduces presynaptic excitatory drive under conditions of elevated glutamatergic activity. To test the effect of pharmacological stimulation of cannabinoid receptors on the development of inhibitory signaling in PFC, male and female rats were treated with the synthetic cannabinoid WIN 55, 212-2 (WIN) from postnatal day (PD) 35-45. We observed an increase in PNNs and PV+ cells from the juvenile period (PD24) to adolescence (PD36 and 46), followed by a leveling off or reduction in early adulthood (PD71). WIN-treatment reduced PNNs in PFC and delayed the emergence of PV+ cells. These changes occurred earlier in female animals than males but persisted into adulthood in males, potentially impairing inhibitory signaling. Functionally, we observed a disinhibition of PFC neural activity recorded in awake-behaving adult animals following adolescent WIN treatment, which also was stronger in males. Together, these findings indicate that cannabinoid exposure during the vulnerable developmental period of adolescence may alter PNN development, leading to functional changes in PFC inhibitory signaling that may ultimately have long-lasting impact on executive control of behavior.