Hippocampal hyperexcitability in fetal alcohol spectrum disorder: Pathological sharp waves and excitatory/inhibitory synaptic imbalance.

Prenatal alcohol exposure (PAE) can lead to long-lasting neurological alterations that may predispose individuals to seizures and neurobehavioral dysfunction. To date, there exists limited information regarding the underlying pathophysiological mechanisms. The hippocampal CA3 region generates excitatory population activity, called sharp waves (SPWs), that provide an ideal model to study perturbations in neuronal excitability at the network and cellular levels. In the present study, we utilized a mouse model of PAE and used dual extracellular and whole-cell patch-clamp recordings from CA3 hippocampal pyramidal cells to evaluate the effect of 1st trimester-equivalent ethanol exposure (10% v/v) on SPW activity and excitatory/inhibitory balance. We observed that PAE significantly altered in vitro SPW waveforms, with an increased duration and amplitude, when compared to controls. In addition, PAE slices exhibited reduced pharmacological inhibition by the GABA-A receptor antagonist bicuculline (BMI) on SPW activity, and increased population spike paired-pulse ratios, all indicative of network disinhibition within the PAE hippocampus. Evaluation of PAE CA3 pyramidal cell activity associated with SPWs, revealed increased action potential cell firing, which was accompanied by an imbalance of excitatory/inhibitory synaptic drive, shifted in favor of excitation. Moreover, we observed intrinsic changes in CA3 pyramidal activity in PAE animals, including increased burst firing and instantaneous firing rate. This is the first study to provide evidence for hippocampal dysfunction in the ability to maintain network homeostasis and underlying cellular hyperexcitability in a model of PAE. These circuit and cellular level alterations may contribute to the increased propensity for seizures and neurobehavioral dysfunction observed in patients with a history of PAE.

320-channel active probe for high-resolution neuromonitoring and responsive neurostimulation.

We present a 320-channel active probe for high-spatial-resolution neuromonitoring and responsive neurostimulation. The probe comprises an integrated circuit (IC) cell array bonded to the back side of a pitch-matched microelectrode array. The IC enables up to 256-site neural recording and 64-site neural stimulation at the spatial resolution of 400 µ m and 200 µ m, respectively. It is suitable for direct integration with electrode arrays with the shank pitch of integer multiples of 200 µm. In the presented configuration, the IC is bonded with a 8 × 8 400 µ m-pitch Utah electrode array (UEA) and up to additional 192 recording channels are used for peripheral neuromonitoring. The 0.35 µ m CMOS circuit array has a total die size of 3.5 mm × 3.65 mm. Each stimulator channel employs a current memory for simultaneous multi-site neurostimulation, outputs 20 µA-250 µA square or arbitrary waveform current, occupies 0.02 mm (2), and dissipates 2.76 µ W quiescent power. Each fully differential recording channel has two stages of amplification and filtering and an 8-bit single-slope ADC, occupies 0.035 mm (2) , and consumes 51.9 µ W. The neural probe has been experimentally validated in epileptic seizure propagation studies in a mouse hippocampal slice in vitro and in responsive neurostimulation for seizure suppression in an acute epilepsy rat model in vivo .

Propofol enhances the field excitatory postsynaptic potentials in CA1 hippocampal slices of young and aged mice.

BACKGROUND: Increasing age was shown to decrease the requirements for propfol. However, the mechanisms of ageing-induced potentiation of anesthetic actions have not been clearly explored. The aim of this study is to compare the effects of propofol on the field excitatory postsynaptic potentials (fEPSPs) in hippocampal slices of young and aging mice. METHODS: Brain slices were prepared from C57BL6 male young (2 months) and aging (>12 months) mice. The dendritic field excitatory postsynaptic potential was recorded from the CA1 stratum radiatum using patch clamp electrophysiological methods. A bipolar concentric stimulating electrode was placed along the Schaffer collateral for othodromic stimulation. The effects of clinically-relevant concentrations of propofol were studied in the young and ageing mouse tissues. RESULTS: Propofol application increased the orthodromically evoked fEPSP produced in slices taken from young and older animals. A striking feature in the I/O relationship was the decreased enhancement of the fEPSPs by propofol in slices from older mice. A clinically relevant concentration of propofol, 10 µmol/L, showed more significant enhancement in amplitude and area under the curve (AUC) of fEPSP in young compared to tissues from older mice (amplitude: young (24.9 ± 3.4)%, old (4.6 ± 1.6)%; AUC young (30.6 ± 5.4)%, old (2.1 ± 1.7)%). There was no statistically significant difference between the paired-pulse facilitation (PPF) ratios calculated for the responses obtained in tissues from young mice. In slices from older mice, in the presence of 10 µmol/L propofol, PPF was decreased and returned to baseline after washout (baseline 1.21 ± 0.01, propofol: 1.16 ± 0.01). Bicuculline (15 µmol/L) blocked the enhancement of propofol on fEPSP in tissues from young and old mice. CONCLUSION: The fEPSP of slices from aging mice demonstrates diminished sensitivity to the enhancing actions of propofol.

Transition to seizure: ictal discharge is preceded by exhausted presynaptic GABA release in the hippocampal CA3 region.

How the brain transitions into a seizure is poorly understood. Recurrent seizure-like events (SLEs) in low-Mg2+/ high-K+ perfusate were measured in the CA3 region of the intact mouse hippocampus. The SLE was divided into a "preictal phase," which abruptly turns into a higher frequency "ictal" phase. Blockade of GABA(A) receptors shortened the preictal phase, abolished interictal bursts, and attenuated the slow preictal depolarization, with no effect on the ictal duration, whereas SLEs were blocked by glutamate receptor blockade. In CA3 pyramidal cells and stratum oriens non-fast-spiking and fast-spiking interneurons, recurrent GABAergic IPSCs predominated interictally and during the early preictal phase, synchronous with extracellularly measured recurrent field potentials (FPs). These IPSCs then decreased to zero or reversed polarity by the onset of the higher-frequency ictus. However, postsynaptic muscimol-evoked GABA(A) responses remained intact. Simultaneously, EPSCs synchronous with the FPs markedly increased to a maximum at the ictal onset. The reversal potential of the compound postsynaptic currents (combined simultaneous EPSCs and IPSCs) became markedly depolarized during the preictal phase, whereas the muscimol-evoked GABA(A) reversal potential remained unchanged. During the late preictal phase, interneuronal excitability was high, but IPSCs, evoked by local stimulation, or osmotically by hypertonic sucrose application, were diminished, disappearing at the ictal onset. We conclude that the interictal and early preictal states are dominated by GABAergic activity, with the onset of the ictus heralded by exhaustion of presynaptic release of GABA, and unopposed increased glutamatergic responses.