Summary:  Purpose: Recently the Ca_v2.3 (E/R‐type) voltage‐gated calcium channel (VGCC) has turned out to be not only a potential target for different antiepileptic drugs (e.g., lamotrigine, topiramate) but also a crucial component in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and epileptiform activity in CA1 neurons. The aim of our study was to perform an electroencephalographic analysis, seizure‐susceptibility testing, and histomorphologic characterization of Ca_v2.3^−/− mice to unravel the functional relevance of Ca_v2.3 in ictogenesis. Methods: Generalized and brain‐specific Ca_v2.3 knockout animals were analyzed for spontaneous epileptiform discharges by using both electrocorticographic and deep intracerebral recordings. In addition, convulsive seizure activity was induced by systemic administration of either 4‐aminopyridine (4‐AP; 10 mg/kg, i.p.) or pentylenetetrazol (PTZ; 80 mg/kg, s.c.) to reveal possible alterations in seizure susceptibility. Besides histomorphologic analysis, expression studies of other voltage‐gated Ca²⁺ channels in Ca_v2.3^−/− brains were carried out by using semiquantitative reverse transcription–polymerase chain reaction (RT‐PCR). Results: Both electrocorticographic and deep intrahippocampal recordings exhibited no spontaneous epileptiform discharges indicative of convulsive or nonconvulsive seizure activity during long‐term observation. Gross histology and expression levels of other voltage‐gated Ca²⁺ channels remained unchanged in various brain regions. Surprisingly, PTZ‐induced seizure susceptibility was dramatically reduced in Ca_v2.3‐deficient mice, whereas 4‐AP sensitivity remained unchanged. Conclusions: Ca_v2.3 ablation results in seizure resistance, strongly supporting recent findings in CA1 neurons that Ca_v2.3 triggers epileptiform activity in specialized neurons via plateau potentials and afterdepolarizations. We provide novel insight into the functional involvement of Ca_v2.3 in ictogenesis and seizure susceptibility on the whole‐animal level.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling.

Voltage-gated calcium channels are key components in the etiology and pathogenesis of epilepsies. Former studies mainly focused on P/Q-type Ca_v2.1 and T-type Ca_v3.2 Ca²⁺ channels involved in absence epileptogenesis, but recent findings also point to an intriguing role of the Ca_v2.3 E/R-type Ca²⁺ channel in ictogenesis and seizure propagation. Based on the observation that Ca_v2.3 is thought to induce plateau potentials in CA1 pyramidal cells, which can trigger epileptiform activity, our recent investigation revealed reduced PTZ-seizure susceptibility and altered seizure architecture in Ca_v2.3^−/− mice compared with controls. In the present study we tested hippocampal seizure susceptibility in Ca_v2.3-deficient mice using surface and deep intrahippocampal telemetric EEG recordings as well as phenotypic seizure video analysis. Administration of kainic acid (30 mg/kg ip) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Ca_v2.3^−/− mice compared with controls, whereas no difference in hippocampal EEG seizure activity between both genotypes could be detected at this suprathreshold dosage. The same tendency was observed for NMDA seizure susceptibility (150 mg/kg ip) approaching the level of significance. In addition, histochemical analysis within the hippocampus revealed that excitotoxic effects after kainic acid administration are absent in Ca_v2.3^−/− mice, whereas Ca_v2.3^+/+ animals exhibited clear and typical signs of excitotoxic cell death. These findings clearly indicate that the Ca_v2.3 voltage-gated calcium channel plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration after excitotoxic events.

EEG radiotelemetry plays an important role in the neurological characterization of transgenic mouse models of neuropsychiatric and neurodegenerative diseases as well as epilepsies providing valuable insights into underlying pathophysiological mechanisms and thereby facilitating the development of new translational approaches. We elaborate on the major advantages of nonrestraining EEG radiotelemetry in contrast to restraining procedures such as tethered systems or jacket systems containing recorders. Whereas a main disadvantage of the latter is their unphysiological, restraining character, telemetric EEG recording overcomes these disadvantages. It allows precise and highly sensitive measurement under various physiological and pathophysiological conditions. Here we present a detailed description of a straightforward successful, quick, and efficient technique for intraperitoneal as well as subcutaneous pouch implantation of a standard radiofrequency transmitter in mice and rats. We further present computerized 3D-stereotaxic placement of both epidural and deep intracerebral electrodes. Preoperative preparation of mice and rats, suitable anaesthesia, and postoperative treatment and pain management are described in detail. A special focus is on fields of application, technical and experimental pitfalls, and technical connections of commercially available radiotelemetry systems with other electrophysiological setups.

Background: Researchers have gained substantial insight into mechanisms of synaptic transmission, hyperexcitability, excitotoxicity and neurodegeneration within the last decades. Voltage-gated Ca²⁺channels are of central relevance in these processes. In particular, they are key elements in the etiopathogenesis of numerous seizure types and epilepsies. Earlier studies predominantly targeted on Ca_v2.1 P/Q-type and Ca_v3.2 T-type Ca²⁺channels relevant for absence epileptogenesis. Recent findings bring other channels entities more into focus such as the Ca_v2.3 R-type Ca²⁺channel which exhibits an intriguing role in ictogenesis and seizure propagation. Ca_v2.3 R-type voltage gated Ca²⁺channels (VGCC) emerged to be important factors in the pathogenesis of absence epilepsy, human juvenile myoclonic epilepsy (JME), and cellular epileptiform activity,e.g. in CA1 neurons. They also serve as potential target for various antiepileptic drugs, such as lamotrigine and topiramate.Objective: This review provides a summary of structure, function and pharmacology of VGCCs and their fundamental role in cellular Ca²⁺homeostasis. We elaborate the unique modulatory properties of Ca_v2.3 R-type Ca²⁺channels and point to recent findings in the proictogenic and proneuroapoptotic role of Ca_v2.3 R-type VGCCs in generalized convulsive tonic–clonic and complex-partial hippocampal seizures and its role in non-convulsive absence like seizure activity.Conclusion: Development of novel Ca_v2.3 specific modulators can be effective in the pharmacological treatment of epilepsies and other neurological disorders.