Late-adolescent onset of prefrontal endocannabinoid control of hippocampal and amygdalar inputs and its impact on trace-fear conditioning behavior.

Prefrontal cortex (PFC) maturation during adolescence is characterized by structural and functional changes, which involve the remodeling of GABA and glutamatergic synapses, as well as changes in the endocannabinoid system. Yet, the way PFC endocannabinoid signaling interacts with local GABA and glutamatergic function to impact its processing of afferent transmission during the adolescent transition to adulthood remains unknown. Here we combined PFC local field potential recordings with local manipulations of 2-AG and anandamide levels to assess how PFC endocannabinoid signaling is recruited to modulate ventral hippocampal and basolateral amygdalar inputs in vivo in adolescent and adult male rats. We found that the PFC endocannabinoid signaling does not fully emerge until late-adolescence/young adulthood. Once present, both 2-AG and anandamide can be recruited in the PFC to limit the impact of hippocampal drive through a CB1R-mediated mechanism whereas basolateral amygdalar inputs are only inhibited by 2-AG. Similarly, the behavioral effects of increasing 2-AG and anandamide in the PFC do not emerge until late-adolescence/young adulthood. Using a trace fear conditioning paradigm, we found that elevating PFC 2-AG levels preferentially reduced freezing behavior during acquisition without affecting its extinction. In contrast, increasing anandamide levels in the PFC selectively disrupted the extinction of trace fear memory without affecting its acquisition. Collectively, these results indicate a protracted recruitment of PFC endocannabinoid signaling, which becomes online in late adolescence/young adulthood as revealed by its impact on hippocampal and amygdalar-evoked local field potential responses and trace fear memory behavior.