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