Neurons in the human cortex generally process their information by means of electrical signals and thus enable the electrical recording of their activity, the electroencephalogram (EEG). Due to their unique orientation with their long apical dendrites perpendicular to the cortical surface, large cortical pyramidal neurons in deep cortical layers play a major role in the generation of the EEG. Specific and non-specific thalamic nuclei, as well as distant cortical areas, terminate on these apical dendrites and form myriads of excitatory and inhibitory afferents. The release of excitatory and inhibitory neurotransmitters by these fibers activates specific postsynaptic receptors and generates excitatory and inhibitory postsynaptic potentials, respectively. By electrotonic spread of postsynaptic potentials along the apical dendrites and equivalent capacitive currents, they become electrical dipoles. Positive or negative deflections are generated by both excitatory and inhibitory afferents, depending on the location of these synapses on the apical dendrites. Negative (upward) deflections are due to superficial excitatory or deep inhibitory inputs, whereas positive (downward) deflections represent deep excitatory or superficial inhibitory inputs.

Purpose: γ-Aminobutyric acid (GABA)ergic transmission plays an important role in the initiation of epileptic activity and the generation of ictal discharges. The functional alterations in the epileptiform hippocampus critically depend on GABAergic mechanisms and cation-chloride cotransporters. Methods: To understand the cellular basis of specific functional alterations in the epileptic hippocampus, we studied physiologic characteristics and pharmacologically isolated evoked GABA_A receptor–mediated inhibitory postsynaptic currents (IPSCs) recorded from principal neurons in hippocampal slices from status epilepticus (SE) and control rats using whole-cell and gramicidin perforated patch-clamp recordings. Key Findings: Whereas the resting membrane potential and input resistance were not significantly different between control and epileptic tissue, the reversal potential (E_GABA) of IPSCs was significantly shifted to more positive values in SE rats with regard to the resting membrane potential. Pharmacologic experiments and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) showed that the observed changes in the epileptic tissue were due to a decreased ratio of the main Cl⁻ extrusion transporter (K⁺-Cl⁻ cotransporter, KCC2) to the main Cl⁻ uptake transporter (Na⁺-K⁺-2Cl⁻ cotransporter, NKCC1). Significance: Our results suggest that alterations of cation-chloride cotransporter functions, comprising a higher NKCC1 action, contribute to hyperexcitability within the hippocampus following SE.

The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed.

Synaptic plasticity is thought to be a key mechanism of information storage in the CNS. Different forms of synaptic long-term potentiation have been shown to be impaired in neurological disorders. Here, we show that metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), but not NMDA receptor-dependent LTD at Schaffer collateral–CA1 synapses, is profoundly impaired after status epilepticus. Brief application of the group I mGluR agonist (R,S)-3,5-dihydroxyphenylglycine (100 μm; 5 min) induced mGluR LTD in control, but not in pilocarpine-treated rats. Experiments in the presence of selective inhibitors of either mGluR5 [2-methyl-6-(phenylethynyl)-pyridine] or mGluR1 [7-(hydroxyimino)cyclopropachromen-carboxylate ethyl ester and (S)-(+)-α-amino-4-carboxy-2-methylbenzeneacetic acid] demonstrate that loss of mGluR LTD is most likely attributable to a loss of mGluR5 function. Quantitative real-time reverse transcription PCR revealed a specific downregulation of mGluR5 mRNA, but not of mGluR1 mRNA in the CA1 region. Furthermore, we detected a strong reduction in mGluR5 protein expression by immunofluorescence and quantitative immunoblotting. Additionally, the scaffolding protein Homer that mediates coupling of mGluR5 to downstream signaling cascades was downregulated. Thus, we conclude that the reduction of mGluR LTD after pilocarpine-induced status epilepticus is the result of the subtype-specific downregulation of mGluR5 and associated downstream signaling components.

Purpose: Limbic encephalitis associated with autoantibodies against N-methyl D-aspartate receptors (NMDARs) often presents with memory impairment. NMDARs are key targets for memory acquisition and retrieval, and have been mechanistically linked to its underlying process, synaptic plasticity. Clinically, memory deficits are largely compatible with a pre-dominantly hippocampus-dependent phenotype, which, in rodents, is principally involved in spatial memory. Previous studies confirmed the impaired spatial memory in the rat model of anti-NMDAR encephalitis. Here, we hypothesized that non-spatial memory functions, such as object recognition might also be affected in this model. Methods: We performed stereotactic intrahippocampal bolus injection of human cerebrospinal fluid (CSF) from anti-NMDAR encephalitis and control patients into the hippocampus of the anesthetized rat. After recovery for 1–8 days, hippocampal slices were prepared from these animals and NMDAR-dependent long-term potentiation was assessed at the Schaffer collateral-CA1 synapse. In addition, we performed behavioral analyses using the open field and novel object recognition tasks. Results: NMDAR-dependent long-term potentiation in the hippocampal CA1 area was significantly suppressed, indicating successful NMDAR dysfunction in this subfield. Spontaneous locomotor activity as well as anxiety-related behavior in the open field did not differ between NMDAR-CSF-treated and control animals. In the novel object recognition task, there were no differences in the motivation to approach objects. In contrast, we observed a significantly preferred exploration of the novel object only in control, but not in NMDAR-CSF-treated rats. Conclusion: These results indicate that NMDAR dysfunction obtained by intrahippocampal stereotactic injection does not alter locomotor or anxiety-related behavior. In addition, approach to an object or exploratory behavior in general are not affected either, but intact initial NMDAR-dependent processes might be involved in novel object recognition.