In the adult brain temporal entrainment of prelimbic-hippocampal networks that takes place during specific behavioral epochs has been described as the main mechanism CT99021 manufacturer underlying the transfer and storage of information, thus underlying the mnemonic and executive abilities of animals and humans (Siapas and Wilson, 1998, Sirota et al., 2008 and Hyman et al., 2010). For example, the coupling between the PL and Hipp as well as the portion of phase-locked prefrontal neurons increases during anxiety-like behavior and during working or spatial memory tasks (Adhikari et al., 2010, Hyman et al., 2010 and Moran et al., 2010). Functional basis of this behaviorally relevant coupling are the direct

monosynaptic projections timing the prefrontal and hippocampal firing (Siapas et al., 2005)

as well as the PFC organization find more in hypercolumns that are globally “pushed” by the hippocampal input during the task (Hasselmo, 2005 and Hyman et al., 2005). During development the strong prefrontal-hippocampal communication is not related to an overt behavioral task, but takes place during sleep. We propose that the oscillatory drive from the Hipp facilitates not only the morphological and functional development of the PFC but enables also the refinement of the behaviorally relevant communication scaffold between the two areas. Neonatal prelimbic neurons receive via synaptic projections theta-phase

modulated inputs from the Hipp and start to tune their firing. As long as the functional hypercolumns amplifying the hippocampal signal in the PFC are not fully refined, a very low number of prefrontal neurons seems to be clocked by the Hipp and may act as a sort of “hub” that organizes the local networks (Bonifazi et al., 2009). This hippocampus-timed gamma entrainment of local networks may shape and plastically modify the prelimbic connectivity. The PFC reaches its functional maturation during adolescence by undergoing an intense reorganization and pruning of connectivity under the influence of various neurotransmitters. At this developmental stage the PFC and Hipp are still synchronized and theta entrained, but their network and cell-to-cell interactions are not unidirectional anymore. The temporary loss of precision within juvenile prefrontal-hippocampal communication Bay 11-7085 may represent one of the mechanisms contributing to impulsive and uncontrolled behavior during adolescence (Casey et al., 2008). Because the early theta drive from the Hipp seems to be mandatory for the refinement of functional organization within the PFC and for precise prefrontal-hippocampal interactions, this developmental period corresponding to the second and third trimester of gestation in humans (Clancy et al., 2001) may be considered as critical period for the maturation of mnemonic and executive abilities.