Developmental trajectories of brain rhythm dynamics in healthy adolescent rats: oscillatory network reconfigurations at the vulnerable age of schizophrenia prodrome

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The primary aim of the proposed research is to study the developmental trajectory of oscillatory synchronization in neural networks of normal healthy rats during adolescence, as its alterations in human may contribute to the pathology of psychiatric diseases, including schizophrenia (SZ). In fact, sudden manifestation of SZ is preceded by a prodromal period but the underlying mechanisms leading to accumulation of neuronal network abnormalities through development which eventually lead to prodromal signs in late-adolescence and then to the fully manifested disorder after crossing into adulthood are not well-known. Oscillatory synchronization of neural activity is an essential mechanism of network function and abnormal oscillations, well established in SZ, may underlie downstream phenotypic deficits characteristic for SZ. Neural oscillations are directly related to parvalbumin-expressing (PV+) GABA interneurons. Regular neuronal oscillations appear when GABAergic synapses switch from excitatory in early neonates to inhibitory at later stages which is then followed by development of a functional oscillator hierarchy which normally operates across multiple spatial and temporal scales. The major input controlling PV+ cell activity, specifically targeting NMDA receptors expressing the NR2A (GluN2A) subunit, develops weeks after birth, well after the switch in GABA transmission. We hypothesize that maturation of oscillatory cortical networks is a protracted process occurring over the length of adolescence and into early adulthood during which the different components of the oscillatory hierarchy and patterns of their coordination may follow different trajectories to arrive to the pattern of well-coordinated local and inter-regional coupling, found in adults. Thus, we propose longitudinal investigations through the peri-adolescent period of normal rats, males and females to define how the oscillatory hierarchy develops, including local and inter-regional rhythmic coupling, focusing on hippocampus (HC) and prefrontal cortex (PFC) networks and their rhythmic coordination (Aim 1). We have preliminary data indicating that PFC- delta, HC-theta, and gamma oscillations may follow distinct developmental trajectories during adolescence with notable sex differences. To gain a mechanistic insight into development of oscillatory circuits, we also propose (Aim 2) to examine the role of PV+ interneurons in slow and fast oscillations at different stages of neurodevelopment by manipulating their NMDAR input. Specifically, we will explore the potential effect of the NMDA-NR2 switch, known to take place in postnatal development, on the maturation of oscillatory networks. We hypothesize that the developmental increase of the NR2A:NR2B ratio, relatively protracted in associative brain regions, strongly affects the development of gamma oscillations and its low frequency modulation. Identifying the principles of normal neurodevelopment of oscillatory neural networks in peri-adolescence, and collecting vital information of reconfigurations in cortical microcircuitry at a vulnerable age of SZ prodrome, may help establishing a basis for future translational studies.