In the adult cerebral cortex, the neurotransmitter GABA is strongly inhibitory, as it profoundly decreases neuronal excitability and suppresses the network propensity for synchronous activity. When fast, GABA A receptor (GABA A R)-mediated neurotransmission is blocked in the mature cortex, neuronal firing is synchronized via recurrent excitatory (glutamatergic) synaptic connections, generating population discharges manifested extracellularly as spontaneous paroxysmal field potentials (sPFPs). This epileptogenic effect of GABA A R antagonists has rarely been observed in the neonatal cortex, and indeed, GABA in the neonate has been proposed to have an excitatory, rather than inhibitory, action. In contrast, we show here that when fast GABAergic neurotransmission was blocked in slices of neonatal mouse and rat hippocampus and neocortex, sPFPs occurred in nearly half the slices from postnatal day 4 (P4) to P7 neocortex and in most slices from P2 to P7 hippocampus. In Mg 2ϩ -free solution, GABA A R antagonists elicited sPFPs in nearly all slices of P2 and older neocortex and P0 and older hippocampus. Mg 2ϩ -free solution alone induced spontaneous events in the majority of P2 and older slices from both regions; addition of GABA A R antagonists caused a dramatic increase in the mean amplitude, but not frequency, of these events in the hippocampus and in their mean frequency, but not amplitude, in the neocortex. In the hippocampus, GABA A R agonists suppressed amplitudes, but not frequency, of sPFPs, whereas glutamate antagonists suppressed frequency but not amplitudes. We conclude that neonatal rodent cerebral cortex possesses glutamatergic circuits capable of generating synchronous network activity and that, as in the adult, tonic GABA A R-mediated inhibition prevents this activity from becoming paroxysmal. Key words: paroxysmal field potentials; GABA A receptors; NMDA receptors; AMPA receptors; synaptic development; rodent; neocortex; hippocampus; CA3; synaptic inhibitionThe cerebral cortical mantle, which includes the hippocampus and the neocortex, is an intricate network of neurons communicating via chemical and electrical synapses and using glutamate and GABA as the major neurotransmitters. In the adult cortex, excitation is mediated mostly by glutamate receptors of the NMDA or AMPA subtypes, whereas GABA, acting via fast (GABA A ) and slow (GABA B ) receptors, is strongly inhibitory, as it profoundly decreases the excitability of individual neurons and suppresses the propensity of the network to generate synchronous discharges (Connors et al., 1988). Indeed, when GABA A receptors (GABA A Rs) in the mature hippocampus or neocortex are blocked, positive feedback mediated by recurrent excitatory (glutamatergic) circuits triggers a chain reaction of neuronal firing, culminating in epileptiform events (Wong et al., 1986;Traub and Miles, 1991). These events have an all-or-none character and consist of synaptically induced discharges of action potentials, which occur nearly simultaneously in all neurons within a given l...

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Under both pathological and experimental conditions, area CA3 of the adult or juvenile hippocampus generates periodic population discharges known as interictal bursts. Whereas the ionic and synaptic basis of individual bursts has been comprehensively studied experimentally and computationally, the pacemaker mechanisms underlying interictal rhythmicity remain conjectural. We showed previously that rhythmic population discharges resembling interictal bursts can be induced in hippocampal slices from first postnatal week mice, in Mg2+-free solution with GABA(A) receptor-mediated inhibition blocked. Here we show that these neonatal bursts occurred with high temporal precision and that their frequency and regularity were greatly reduced by the bradycardic agent ZD-7288 when applied at concentrations and durations that selectively block the hyperpolarization-activated, cationic current I(h). Augmenting I(h) by elevating intracellular cAMP dramatically increased burst frequency in a protein kinase A-independent manner. Burst amplitudes were strongly correlated with the preceding, but not the following, interburst intervals. The experimentally observed distribution of interburst intervals was modeled by assuming that a burst was triggered whenever the instantaneous rate of spontaneous EPSPs (sEPSPs) exceeded a threshold and that the mean sEPSP rate was minimal immediately after a burst and then relaxed exponentially to a steady-state level. The effect of blocking I(h) in any given slice could be modeled by decreasing only the steady-state sEPSP rate, suggesting that the instantaneous rate of sEPSPs is governed by the level of I(h) activation and raising the novel possibility that interburst intervals reflected the slow activation kinetics of I(h) in the neonatal CA3.

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