Alterations of cortical and hippocampal EEG activity in MeCP2-deficient mice.

Rett syndrome is a pediatric neurological condition caused by mutations of the gene encoding the transcriptional regulator MECP2. In this study, we examined cortical and hippocampal electroencephalographic (EEG) activity in male and female MeCP2-deficient mice at symptomatic stages during different behavioral states. During acute sleep, MeCP2-deficient mice displayed normal delta-like activity in cortex and sharp-wave activity in hippocampus. However, when the mice were awake but immobile, abnormal spontaneous, rhythmic EEG discharges of 6-9 Hz were readily detected in the somatosensory cortex. During exploratory activity, MeCP2-deficient mice displayed clear theta rhythm activity in hippocampus, but its peak frequency was significantly attenuated compared to wild type. Collectively, these findings indicate that a deficiency in MeCP2 function in mice leads to alterations in EEG activity with similarities to what has been observed clinically in Rett syndrome patients.

Regulating hippocampal hyperexcitability through GABAB Receptors.

Abstract Disturbances of GABAergic inhibition are a major cause of epileptic seizures. GABA exerts its actions via ionotropic GABAA receptors and metabotropic G protein-coupled GABAB receptors. Malfunction of GABAA inhibition has long been recognized in seizure genesis but the role of GABAB receptors in controlling seizure activity is still not well understood. Here, we examined the anticonvulsive, or inhibitory effects, of GABAB receptors in a mouse model of hippocampal kindling as well as mouse hippocampal slices through the use of GS 39783, a positive allosteric GABAB receptor modulator, and CGP 55845, a selective GABAB receptor antagonist. When administered via intraperitoneal injections in kindled mice, GS 39783 (5 mg/kg) did not attenuate hippocampal EEG discharges, but did reduce aberrant hippocampal spikes, whereas CGP 55845 (10 mg/kg) prolonged hippocampal discharges and increased spike incidences. When examined in hippocampal slices, neither GS 39783 at 5 µmol/L nor the GABAB receptor agonist baclofen at 0.1 µmol/L alone significantly altered repetitive excitatory field potentials, but GS 39783 and baclofen together reversibly abolished these field potentials. In contrast, CGP 55845 at 1 µmol/L facilitated induction and incidence of these field potentials. In addition, CGP 55845 attenuated the paired pulse depression of CA3 population spikes and increased the frequency of EPSCs in individual CA3 pyramidal neurons. Collectively, these data suggest that GABABB receptors regulate hippocampal hyperexcitability by inhibiting CA3 glutamatergic synapses. We postulate that positive allosteric modulation of GABAB receptors may be effective in reducing seizure-related hyperexcitability.

Selective reduction of excitatory hippocampal sharp waves by docosahexaenoic acid and its methyl ester analog ex-vivo.

Excitatory sharp waves (SPWs) originating from the hippocampus are considered to model the interictal "spikes" that occur in people with temporal lobe epilepsy. Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid that has been reported to reduce neuronal excitability in vitro. The effect of DHA on hippocampal SPWs, however, is not known. Our goal was to determine whether DHA suppresses SPWs in thick mouse hippocampal slices, and to compare its effects with those of oleic acid (OA, control) and the standard anticonvulsant carbamazepine (CBZ). Also tested, were DHA's structural PUFA analogs n-3 docosapentaenoic acid (n-3 DPA), n-6 docosapentaenoic acid (n-6 DPA) and DHA-methyl ester (DHA-Me). The possible involvement of GABAergic activity was also examined using GABA receptor blockers. Extracellular recordings from CA1 and CA3 regions in hippocampal slices revealed that DHA reduced the incidence of SPWs. CBZ also reduced the incidence of SPWs and was 5 time more potent than DHA. DHA's effects on SPWs was abolished in the presence of GABA-receptor blockers, suggesting involvement of the GABA system in reducing excitatory SPWs. (14)C-DHA application to the slices confirmed the incorporation of DHA into membrane phospholipids. N-3 DPA and n-6 DPA, however, which also incorporate into phospholipids, had no effect on SPWs, while DHA-Me, a DHA analog that does not incorporate into membrane phospholipids, was effective at reducing them. We conclude that DHA, but not its n-3 and n-6 analogs, reduces network excitability of the recurrent CA3 circuitry in the mouse hippocampus. This reduction may be mediated by DHA in its unesterified form, and is likely related to a modulatory effect of DHA on GABAergic activity.

Predicting synchronous and asynchronous network groupings of hippocampal interneurons coupled with dendritic gap junctions.

Direct electrical communication between central nervous system (CNS) neurons including those in the hippocampus is well-established. This form of communication is mediated by gap junctions and it is known that this coupling is important for brain rhythms such as gamma (20-80 Hz) which occur during active behavioural states. It is also known that gap junctions are present at several locations along the dendrites of hippocampal interneurons including parvalbumin-positive basket cell types. Weakly coupled oscillator theory, which uses phase response curves (PRCs), has been used to understand and predict the dynamics of electrically coupled networks. Here we use compartmental models of hippocampal basket cells with different levels of basal and apical spike attenuation together with the theory to show that network output can be broken down into three groupings: synchronous, asynchronous and antiphase-like patterns. Moreover, quantified PRCs can be used as a rule of thumb to determine the occurrence of a particular grouping under weak coupling conditions, which in turn implies that spike delays are critical factors in determining network output. In moving beyond weak coupling to encompass the full physiological regime of coupling strengths with network simulations, we note that it is important to be able to differentiate between these different groupings as it affects how the network responds with modulation. Specifically, an asynchronous grouping provides more dynamic richness as a larger range of phase-locked states can be expressed with strength changes. From a functional viewpoint it may be that modulation of electrically coupled networks are key to controlling cell assemblies that contribute to information coding brain substrates.

An improved screw-free method for electrode implantation and intracranial electroencephalographic recordings in mice.

We recently developed a glue-based method for the implantation of intracranial electrodes in mice. Our approach is to secure a preconstructed electrode array using a cyanoacrylate-based glue (similar to Krazy Glue). This method is applicable to both young and aging mice and is suitable for long-term electroencephalographic recordings. In the present experiment, we explored whether the glue-based method is capable of securing individual electrodes in addition to securing the electrode array. C57 black mice aged 25-35 days or 13-19 months were operated on under isoflurane anesthesia. Monopolar or bipolar electrodes were inserted independently in the ipsilateral hippocampal CA3 and entorhinal cortical areas, and they were fixed onto the skull using the glue together with dental acrylic, but without anchoring screws. We found that the implanted electrodes were stable and allowed repeat intracranial recordings and electrical stimulation in freely moving mice.