Alzheimer's disease is associated with an increased risk of unprovoked seizures. However, the underlying mechanisms of seizure induction remain elusive. Here, we performed video-EEG recordings in mice carrying mutant humanAPPsweandPS1dE9genes (APdE9mice) and their wild-type littermates to determine the prevalence of unprovoked seizures. In two recording episodes at the onset of amyloid β (Aβ) pathogenesis (3 and 4.5 months of age), at least one unprovoked seizure was detected in 65% ofAPdE9mice, of which 46% had multiple seizures and 38% had a generalized seizure. None of the wild-type mice had seizures. In a subset ofAPdE9mice, seizure phenotype was associated with a loss of calbindin-D28k immunoreactivity in dentate granular cells and ectopic expression of neuropeptide Y in mossy fibers. InAPdE9mice, persistently decreased resting membrane potential in neocortical layer 2/3 pyramidal cells and dentate granule cells underpinned increased network excitability as identified by patch-clamp electrophysiology. At stimulus strengths evoking single-component EPSPs in wild-type littermates,APdE9mice exhibited decreased action potential threshold and burst firing of pyramidal cells. Bath application (1 h) of Aβ1–42 or Aβ25–35 (proto-)fibrils but not oligomers induced significant membrane depolarization of pyramidal cells and increased the activity of excitatory cell populations as measured by extracellular field recordings in the juvenile rodent brain, confirming the pathogenic significance of bath-applied Aβ (proto-)fibrils. Overall, these data identify fibrillar Aβ as a pathogenic entity powerfully altering neuronal membrane properties such that hyperexcitability of pyramidal cells culminates in epileptiform activity.

GABA depolarizes immature cortical neurons. However, whether GABA excites immature neocortical neurons and drives network oscillations as in other brain structures remains controversial. Excitatory actions of GABA depend on three fundamental parameters: the resting membrane potential ( E_m), reversal potential of GABA ( E_GABA), and threshold of action potential generation ( V_thr). We have shown recently that conventional invasive recording techniques provide an erroneous estimation of these parameters in immature neurons. In this study, we used noninvasive single N-methyl-d-aspartate and GABA channel recordings in rodent brain slices to measure both E_mand E_GABAin the same neuron. We show that GABA strongly depolarizes pyramidal neurons and interneurons in both deep and superficial layers of the immature neocortex (P2–P10). However, GABA generates action potentials in layer 5/6 (L5/6) but not L2/3 pyramidal cells, since L5/6 pyramidal cells have more depolarized resting potentials and more hyperpolarized V_thr. The excitatory GABA transiently drives oscillations generated by L5/6 pyramidal cells and interneurons during development (P5–P12). The NKCC1 co-transporter antagonist bumetanide strongly reduces [Cl⁻]_i,GABA-induced depolarization, and network oscillations, confirming the importance of GABA signaling. Thus a strong GABA excitatory drive coupled with high intrinsic excitability of L5/6 pyramidal neurons and interneurons provide a powerful mechanism of synapse-driven oscillatory activity in the rodent neocortex in vitro. In the companion paper, we show that the excitatory GABA drives layer-specific seizures in the immature neocortex.

In pyramidal cells, induction of long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic transmission by coincidence of presynaptic and postsynaptic activity is considered relevant to learning processes in vivo. Here we show that temporally correlated spiking activity of a pyramidal cell and an inhibiting interneuron may cause LTD or LTP of unitary IPSPs. Polarity of change in synaptic efficacy depends on timing between Ca²⁺ influx induced by a backpropagating train of action potentials (APs) in pyramidal cell dendrites (10 APs, 50 Hz) and subsequent activation of inhibitory synapses. LTD of IPSPs was induced by synaptic activation in the vicinity of the AP train (400 msec relative to the beginning of the AP train). Solely AP trains induced neither LTP nor LTD. Both LTP and LTD were prevented by 5 mm BAPTA loaded into pyramidal cells. LTD was prevented by 5 mmEGTA, whereas EGTA failed to affect LTP. Synaptic plasticity was not dependent on activation of GABA_B receptors. It was also not affected by the antagonists of vesicular exocytosis, botulinum toxin D, and GDP-β-S.