It is now recognized that many mental disorders can only be understood as an interaction between brain development and susceptibility to risk factors. While the characterization of the latter has increased in recent years, less is known on how risk factors alter the normal trajectory of maturation in brain circuits, especially during adolescence when the onset of many psychiatric disorders occurs including schizophrenia. Thus, our long-term goal is to identify neurodevelopmental processes underlying the adolescent vulnerability for the onset of psychiatric disorders where the prefrontal cortex (PFC) is compromised, focusing on the impact of external risk factors on the functional maturation of GABAergic inhibitory circuits therein. One such risk factor is the use of cannabis during adolescence, which has been causally linked to increased risk of developing schizophrenia and PFC-dependent cognitive symptoms later in life. The objective of this application is to identify how adolescent exposure to cannabinoids alters the normative development of the PFC GABAergic transmission and determine how these changes could elicit long-lasting impairments in PFC function. Given that GABAergic interneurons in the PFC are undergoing vast developmental changes during adolescence, the central hypothesis of this proposal is that the adolescent PFC GABAergic system is highly vulnerable to the effects of exogenous cannabinoids through a CB1R-dependent mechanism, and that this untimely exposure leads to an impaired and disinhibited PFC network function that endures to adulthood. This hypothesis will be tested through the following Specific Aims: (1) identify the cellular mechanisms underlying the enduring disruption of PFC GABAergic function resulting from repeated cannabinoid exposure during adolescence; (2) determine the impact of repeated cannabinoid exposure on the maturation of PFC network synchrony; (3) determine whether repeated cannabinoid exposure during adolescence results in enduring PFC-dependent behavioral deficits in adulthood. The proposed plan is innovative in our opinion because it will identify for the first time the cellular mechanisms underlying the age-dependent susceptibility of PFC GABAergic circuits to cannabinoid exposure, with special emphasis on parvalbumin/fast-spiking interneurons as the target of exogenous cannabinoids through a CB1R-dependent presynaptic inhibition of interneuronal activity. All in all, the proposed research is significant because it wll uncover for the first time key neurodevelopmental mechanisms that contribute to the age-dependent, long-lasting detrimental effects of cannabinoid use during adolescence. This knowledge is expected to have a positive impact in prevention and intervention strategies for those afflicted by cognitive impairments caused by early cannabis consumption, and importantly, it will guide the public policy regarding the regulation of cannabis use in adolescent and adults.
The proposed research is highly relevant to public health because it will uncover fundamental mechanisms by which untimely exposure to cannabinoids during adolescence alters the functional maturation of the prefrontal cortex to produce enduring prefrontal deficits in adulthood. This goal is directly aligned with the NIMH agenda by establishing a developmental framework in which mental disorders can be understood, specifically those arising during the adolescent to adult transition. This knowledge is expected to fully serve NIH mission by devising the proper timing of intervention strategies to prevent or ameliorate the onset of mental disorders.
|Mizrahi, Romina; Watts, Jeremy J; Tseng, Kuei Y (2017) Mechanisms contributing to cognitive deficits in cannabis users. Neuropharmacology 124:84-88|
|Caballero, Adriana; Tseng, Kuei Y (2016) GABAergic Function as a Limiting Factor for Prefrontal Maturation during Adolescence. Trends Neurosci 39:441-448|
|Caballero, Adriana; Granberg, Rachel; Tseng, Kuei Y (2016) Mechanisms contributing to prefrontal cortex maturation during adolescence. Neurosci Biobehav Rev 70:4-12|