Abstract Converging human association studies link cannabis abuse during adolescence with an increased likelihood of developing cognitive and emotional regulation deficits later in life, many of which are refined and dependent on prefrontal cortex (PFC) maturation during adolescence. However, the neurobiology underlying this adolescent vulnerability remains unclear due to our limited knowledge on how adolescent cannabis exposure impacts the maturation of neural circuits. Our long-term goal is to identify sensitive neurodevelopmental processes that are vulnerable to repeated cannabis exposure, with emphasis on PFC neuronal circuits that undergo functional remodeling during adolescence. Data from our recent studies revealed that a hallmark of PFC maturation is the re-calibration of an excitatory-inhibitory (E-I) balance during adolescence that is required for sustaining proper PFC-mediated behaviors in adulthood. Our data also indicate that it is the maturation of GABA function that renders the PFC labile during adolescence, a developmental process that is intimately linked to the activity of afferent transmission from the ventral hippocampus. Similarly, adolescent, but not adult, exposure to THC impaired the maturation of PFC GABA function. This raises the exciting possibility that the PFC deficit resulting from adolescent THC exposure is mechanistically linked to the disruption of specific inputs driving PFC maturation. Based on our preliminary data, we will test the central hypothesis that the developing PFC GABA circuit during adolescence is highly sensitive to the negative impact of cannabis through a ventral hippocampal -mediated mechanism. Thus, the rationale for undertaking this research is that if PFC GABA maturation is compromised by adolescent THC exposure, the normal facilitation of PFC inhibitory control will be arrested, which in turn could lead to an enduring state of PFC disinhibition resulting in behavioral deficits in adulthood. We will fill this gap in knowledge through the pursuit of 3 Specific Aims. We will use a recently developed combustion/smoking chamber to deliver THC at 3 non-overlapping adolescent windows to establish the precise period during which changes in PFC GABA function (Aim 1) and PFC-sensitive behaviors (Aim 2) are susceptible to repeated THC exposure. Currently available input-specific DREADD manipulations will be used in Aim 3 to establish whether the enduring PFC GABA deficit elicited by THC is causally linked to disruption of ventral hippocampal-to-PFC transmission.