Mechanisms contributing to prefrontal cortex maturation during adolescence

Abstract

Adolescence is defined as a transitional period between childhood and adulthood characterized by changes in social interaction and acquisition of mature cognitive abilities. These changes have been associated with the maturation of brain regions involved in the control of motivation, emotion, and cognition. Among these regions, the protracted development of the human prefrontal cortex during adolescence has been proposed to underlie the maturation of cognitive functions and the regulation of affective responses. Studies in animal models allow us to test the causal contribution of specific neural processes in the development of the prefrontal cortex and the acquisition of adult behavior. This review summarizes the cellular and synaptic mechanisms occurring in the rodent prefrontal cortex during adolescence as a model for understanding the changes underlying human prefrontal development.

Keywords: Adolescence; Cannabinoid; Dopamine; GABA; Glutamate; Interneurons; Prefrontal cortex.

Figure 1. Postnatal development of dopamine and glutamatergic transmission in the PFC

(A) D1 receptor modulation of NMDA transmission in deep-layer pyramidal neurons increases after P45 to reach steady state, adult level by around P60 (Tseng and O’Donnell 2005; Flores-Barrera et al., 2014). A similar pattern of dopamine (DA) innervation was observed in the PFC. Dopaminergic fibers can be found in deep layers soon after birth, yet the density of DA innervation in the prelimbic cortex continues to increase until P60 (Kalsbeek et al, 1988). Similarly, DA modulation of GABAergic activity in the PFC undergoes developmental regulation such that D1 and D2 receptor-mediated facilitation of interneuronal excitability becomes markedly enhanced after P50 (Tseng and O’Donnell 2007). (B) GluN2B-NMDA receptor transmission begins to emerge in the apical dendrite of layer V pyramidal neurons in the PFC around P45 (Flores-Barrera et al., 2014). This developmental change is required to strengthening PFC processing of ventral hippocampal inputs (Flores-Barrera et al., 2014) and to enable the increased D1 receptor modulation of NMDA-mediated responses described in A. (C) PFC processing of ventral hippocampal drive is also developmentally regulated as revealed by the mechanisms contributing to the induction of prefrontal LTP and LTD following high-frequency stimulation of the ventral hippocampus (Caballero et al., 2014; Flores-Barrera et al., 2014). While prefrontal LTP is dependent on local GluN2B-NMDA transmission, D1 receptor (D1R) activation and protein-kinase A (PKA) signaling, prefrontal LTD relies on the recruitment of local GABAergic interneurons and GABA-A receptor (GABA_AR)-mediated transmission.

Figure 2. Periadolescent changes in GABAergic function are associated with shifts in dominance of GABAergic populations in the PFC

(A) Early adolescent rats exhibit lower levels of PV expression in the PFC when compared to adults, a developmental hallmark that is associated with diminished glutamatergic transmission onto PV-positive, fast-spiking interneurons (PV/FSI). On the other hand, the expression of CR in the PFC is higher during early adolescence and lower in adulthood. However, the levels of glutamatergic transmission onto CR-positive, non-fast spiking interneurons (CR/NFS) remain unchanged throughout adolescence. (B) In the adult PFC, the frequency of glutamatergic synaptic activity onto PV/FSI increases significantly in tandem with a marked upregulation of PV expression. No developmental changes are observed in glutamatergic transmission onto CR/NFS, yet there is a robust decrease of CR expression in adults. The identity of such glutamatergic inputs remains to be defined.