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.

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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The cholinergic drive enhances input processing in attentional and mnemonic context by interacting with the activity of prefrontalhippocampal networks. During development, acetylcholine modulates neuronal proliferation, differentiation, and synaptic plasticity, yet its contribution to the maturation of cognitive processing resulting from early entrainment of neuronal networks in oscillatory rhythms remains widely unknown. Here we show that cholinergic projections growing into the rat prefrontal cortex (PFC) toward the end of the first postnatal week boost the generation of nested gamma oscillations superimposed on discontinuous spindle bursts by acting on functional muscarinic but not nicotinic receptors. Although electrical stimulation of cholinergic nuclei increased the occurrence of nested gamma spindle bursts by 41%, diminishment of the cholinergic input by either blockade of the receptors or chronic immunotoxic lesion had the opposite effect. This activation of locally generated gamma episodes by direct cholinergic projections to the PFC was accompanied by indirect modulation of underlying spindle bursts via cholinergic control of hippocampal theta activity. With ongoing maturation and switch of network activity from discontinuous bursts to continuous theta-gamma rhythms, accumulating cholinergic projections acting on both muscarinic and nicotinic receptors mediated the transition from high-amplitude slow to low-amplitude fast rhythms in the PFC. By exerting multiple actions on the oscillatory entrainment of developing prefrontal-hippocampal networks, the cholinergic input may refine them for later gating processing in executive and mnemonic tasks.

Group II metabotropic glutamate receptors (mGluRs) play an important role in the regulation of hippocampal synaptic plasticity in vivo: long-term potentiation (LTP) is inhibited and long-term depression (LTD) is enhanced by activation of these receptors. The contribution, in vivo, of the individual group II mGluR subtypes has not been characterized. We analysed the involvement of the subtype mGluR3 in LTD and LTP. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Neither the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), nor the antagonist beta-NAAG, given intracerebrally, affected basal synaptic transmission. beta-NAAG significantly inhibited LTD expression. NAAG exhibited transient inhibitory effects on the intermediate phase of LTD. Whereas NAAG altered paired-pulse responses, beta-NAAG had no effect, suggesting that antagonism of mGluR3 prevents LTD via a postsynaptic mechanism, whereas agonist activation of mGluR3 modulates LTD at a presynaptic locus. NAAG impaired the expression of LTP, whereas beta-NAAG had no effect. NAAG effects on LTP were blocked by EGLU, a selective group II mGluR antagonist. Our data suggest an essential role for mGluR3 in LTD, and a modulatory role for mGluR3 in LTP, with effects being mediated by distinct pre- and post-synaptic loci.

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Durch Acylierung von (I) zu den Ketonen (II) und weitere Umsetzung mit den 1,2‐Diaminen (III) erhält man die Pyrazolodiazepine (IV).