The coactivation of prefrontal and hippocampal networks in oscillatory rhythms is critical for precise information flow in mnemonic and executive tasks, yet the mechanisms governing its development are still unknown. Here, we demonstrate that already in neonatal rats, patterns of discontinuous oscillatory activity precisely entrain the firing of prefrontal neurons and have distinct spatial and temporal organization over cingulate and prelimbic cortices. Moreover, we show that hippocampal theta bursts drive the generation of neonatal prefrontal oscillations by phase-locking the neuronal firing via axonal pathways. Consequently, functional impairment of the hippocampus reduces the prefrontal activity. With ongoing maturation continuous theta-gamma oscillations emerge and mutually entrain the prejuvenile prefrontal-hippocampal networks. Thus, theta-modulated communication within developing prefrontal-hippocampal networks may be relevant for circuitry refinement and maturation of functional units underlying information storage at adulthood.

We compared the dynamics of hippocampal and prefrontal interactions in rats as they used spatial contexts to guide the retrieval of object memories. Upon context entry, functional connectivity analysis indicated a flow of contextual information from the hippocampus to prefrontal cortex. Conversely, upon the onset of object sampling, the direction of information flow reversed, consistent with prefrontal control over the retrieval of context-appropriate hippocampal memory representations.

Precise information flow during mnemonic and executive tasks requires the coactivation of adult prefrontal and hippocampal networks in oscillatory rhythms. This interplay emerges early in life, most likely as an anticipatory template of later cognitive performance. At neonatal age, hippocampal theta bursts drive the generation of prefrontal theta-gamma oscillations. In the absence of direct reciprocal interactions, the question arises of which feedback mechanisms control the early entrainment of prefrontal-hippocampal networks. Here, we demonstrate that prefrontal-hippocampal activity couples with discontinuous theta oscillations and neuronal firing in both lateral entorhinal cortex and ventral midline thalamic nuclei of neonatal rats. However, these two brain areas have different contributions to the neonatal long-range communication. The entorhinal cortex mainly modulates the hippocampal activity via direct axonal projections. In contrast, thalamic theta bursts are controlled by the prefrontal cortex via mutual projections and contribute to hippocampal activity. Thus, the neonatal prefrontal cortex modulates the level of hippocampal activation by directed interactions with the ventral midline thalamus. Similar to the adult task-related communication, theta-band activity ensures the feedback control of long-range coupling in the developing brain.

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In humans, genetic variants of DLGAP1-4 have been linked with neuropsychiatric conditions, including autism spectrum disorder (ASD). While these findings implicate the encoded postsynaptic proteins, SAPAP1-4, in the etiology of neuropsychiatric conditions, underlying neurobiological mechanisms are unknown. To assess the contribution of SAPAP4 to these disorders, we characterized SAPAP4-deficient mice. Our study reveals that the loss of SAPAP4 triggers profound behavioural abnormalities, including cognitive deficits combined with impaired vocal communication and social interaction, phenotypes reminiscent of ASD in humans. These behavioural alterations of SAPAP4-deficient mice are associated with dramatic changes in synapse morphology, function and plasticity, indicating that SAPAP4 is critical for the development of functional neuronal networks and that mutations in the corresponding human gene, DLGAP4, may cause deficits in social and cognitive functioning relevant to ASD-like neurodevelopmental disorders.

Due to improved survival rates and outcome of human infants experiencing a hypoxic-ischemic episode, cognitive dysfunctions have become prominent. They might result from abnormal communication within prefrontal-hippocampal networks, as synchrony and directed interactions between the prefrontal cortex and hippocampus account for mnemonic and executive performance. Here, we elucidate the structural and functional impact of hypoxic-ischemic events on developing prefrontal-hippocampal networks in an immature rat model of injury. The magnitude of infarction, cell loss and astrogliosis revealed that an early hypoxic-ischemic episode had either a severe or a mild/moderate outcome. Without affecting the gross morphology, hypoxia-ischemia with mild/moderate outcome diminished prefrontal neuronal firing and gamma network entrainment. This dysfunction resulted from decreased coupling synchrony within prefrontal-hippocampal networks and disruption of hippocampal theta drive. Thus, early hypoxia-ischemia may alter the functional maturation of neuronal networks involved in cognitive processing by disturbing the communication between the neonatal prefrontal cortex and hippocampus.