Integrated Systems Biology Approach Identifies Novel Maternal and Placental Pathways of Preeclampsia

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Phase-amplitude coupled persistent theta and gamma oscillations in rat primary motor cortex in vitro

In vivo, theta (4-7 Hz) and gamma (30-80 Hz) neuronal network oscillations are known to coexist and display phase-amplitude coupling (PAC). However, in vitro, these oscillations have for many years been studied in isolation. Using an improved brain slice preparation technique we have, using co-application of carbachol (10 μM) and kainic acid (150 nM), elicited simultaneous theta (6.6 ± 0.1 Hz) and gamma (36.6 ± 0.4 Hz) oscillations in rodent primary motor cortex (M1). Each oscillation showed greatest power in layer V. Using a variety of time series analyses we detected significant cross-frequency coupling 74% of slice preparations. Differences were observed in the pharmacological profile of each oscillation. Thus, gamma oscillations were reduced by the GABAA receptor antagonists, gabazine (250 nM and 2 μM), and picrotoxin (50 μM) and augmented by AMPA receptor antagonism with SYM2206 (20 μM). In contrast, theta oscillatory power was increased by gabazine, picrotoxin and SYM2206. GABAB receptor blockade with CGP55845 (5 μM) increased both theta and gamma power, and similar effects were seen with diazepam, zolpidem, MK801 and a series of metabotropic glutamate receptor antagonists. Oscillatory activity at both frequencies was reduced by the gap junction blocker carbenoxolone (200 μM) and by atropine (5 μM). These data show theta and gamma oscillations in layer V of rat M1 in vitro are cross-frequency coupled, and are mechanistically distinct. The development of an in vitro model of phase-amplitude coupled oscillations will facilitate further mechanistic investigation of the generation and modulation of coupled activity in mammalian cortex

Reduced Gamma Oscillations in a Mouse Model of Intellectual Disability: A Role for Impaired Repetitive Neurotransmission?

Intellectual disability affects 2-3% of the population; mutations of the X-chromosome are a major cause of moderate to severe cases. The link between the molecular consequences of the mutation and impaired cognitive function remains unclear. Loss of function mutations of oligophrenin-1 (OPHN1) disrupt Rho-GTPase signalling. Here we demonstrate abnormal neurotransmission at CA3 synapses in hippocampal slices from Ophn1-/y mice, resulting from a substantial decrease in the readily releasable pool of vesicles. As a result, synaptic transmission fails at high frequencies required for oscillations associated with cognitive functions. Both spontaneous and KA-induced gamma oscillations were reduced in Ophn1-/y hippocampal slices. Spontaneous oscillations were rapidly rescued by inhibition of the downstream signalling pathway of oligophrenin-1. These findings suggest that the intellectual disability due to mutations of oligophrenin-1 results from a synaptopathy and consequent network malfunction, providing a plausible mechanism for the learning disabilities. Furthermore, they raise the prospect of drug treatments for affected individuals

Bimoclomol improves early electrophysiological signs of retinopathy in diabetic rats

A silent process involving both neural and vascular structures in diabetic retina persists for several years before clinically detectable retinopathy. Recordings of the electroretinogram (ERG) and visual evoked potential (VEP) provide early warning of abnormalities in the visual pathway of diabetic patients and animal models. Treatment of streptozotocin-diabetic rats for 1 or 2 months with the heat-shock protein coinducer bimoclomol, a drug ameliorating experimental neuropathy, prevented and corrected the abnormal increase in latency and reduction of amplitude of ERG and VEP waves both in acute and chronic experiments. Improvements may be explained by cytoprotective effect of bimoclomol on retinai glia and/or neurons against diabetes-related ischemic cell damages. These findings suggest that bimoclomol may have future therapeutic use in diabetic retinopathy

Spike timing of distinct types of GABAergic interneuron during hippocampal gamma oscillations in vitro.

Gamma frequency (30-100 Hz) network oscillations occur in the intact hippocampus during awake, attentive behavior. Here, we explored the underlying cellular mechanisms in an in vitro model of persistent gamma-frequency oscillations, induced by bath application of 20 microm carbachol in submerged hippocampal slices at 30 +/- 1 degrees C. Current-source density analysis of the field oscillation revealed a prominent alternating sink-source pair in the perisomatic and apical dendritic regions of CA3. To elucidate the active events generating these extracellular dipoles, we examined the firing properties of distinct neuron types. Visually guided unit recordings were obtained from individual CA3 neurons followed by intracellular labeling for anatomical identification. Pyramidal cells fired at 2.82 +/- 0.7 Hz, close to the negative peak of the oscillation (0.03 +/- 0.65 msec), and often in conjunction with a negative spike-like component of the field potential. In contrast, all phase-coupled interneurons fired after this negative peak. Perisomatic inhibitory interneurons fired at high frequency (18.1 +/- 2.7 Hz), shortly after the negative peak (1.97 +/- 0.95 msec) and were strongly phase-coupled. Dendritic inhibitory interneurons fired at lower frequency (8.4 +/- 2.4 Hz) and with less fidelity and a longer delay after the negative peak (4.3 +/- 1.1 msec), whereas interneurons with cell body in the stratum radiatum often showed no phase relationship with the field oscillation. The phase and spike time data of individual neurons, together with the current-source density analysis, support a synaptic feedback model of gamma oscillations primarily involving pyramidal cells and inhibitory cells targeting their perisomatic region

The electroretinogram and visual evoked potential of freely moving rats

The vascularised rat retina could be one of the most useful experimental objects in visual neuroscience to understand human visual physiological and pathological processes. We report here on a new method of implantation for studying the visual system of freely moving rats that provides a rat model for simultaneous recording at corneal and cortical level and is stable enough to record for months. We implanted light emitting diodes onto the skull behind the eyeball to stimulate the eye with flashes and to light adapt the retina with constant light levels. A multistrand, stainless steel, flexible fine wire electrode placed on the eyeball was used for electroretinogram recording and screw electrodes (left/right visual and parietal cortical) were used to record the visual evoked potential and the electroencephalogram. In the present report we focus on the new method of implantation for recording the corneal flash electroretinogram of normal, freely moving rats simultaneously with the visual evoked cortical potential showing examples in various visual experiments. We also introduce a program for retinogram and visual evoked potential analysis, which defines various measures (latencies, areas, amplitudes, and durations) and draw attention to the benefits of this method for those involved in visual, functional genomic, pharmacological, and human ophthalmologic research