Sex-specific cortical, hippocampal and thalamic whole genome transcriptome data from controls and a G72 schizophrenia mouse model.

OBJECTIVES: The G72 mouse model of schizophrenia represents a well-known model that was generated to meet the main translational criteria of isomorphism, homology and predictability of schizophrenia to a maximum extent. In order to get a more detailed view of the complex etiopathogenesis of schizophrenia, whole genome transcriptome studies turn out to be indispensable. Here we carried out microarray data collection based on RNA extracted from the retrosplenial cortex, hippocampus and thalamus of G72 transgenic and wild-type control mice. Experimental animals were age-matched and importantly, both sexes were considered separately. DATA DESCRIPTION: The isolated RNA from all three brain regions was purified, quantified und quality controlled before initiation of the hybridization procedure with SurePrint G3 Mouse Gene Expression v2 8  ×  60 K microarrays. Following immunofluorescent measurement und preprocessing of image data, raw transcriptome data from G72 mice and control animals were extracted and uploaded in a public database. Our data allow insight into significant alterations in gene transcript levels in G72 mice and enable the reader/user to perform further complex analyses to identify potential age-, sex- and brain-region-specific alterations in transcription profiles and related pathways. The latter could facilitate biomarker identification and drug research and development in schizophrenia research.

Sex- and region-specific cortical and hippocampal whole genome transcriptome profiles from control and APP/PS1 Alzheimer's disease mice.

A variety of Alzheimer's disease (AD) mouse models has been established and characterized within the last decades. To get an integrative view of the sophisticated etiopathogenesis of AD, whole genome transcriptome studies turned out to be indispensable. Here we carried out microarray data collection based on RNA extracted from the retrosplenial cortex and hippocampus of age-matched, eight months old male and female APP/PS1 AD mice and control animals to perform sex- and brain region specific analysis of transcriptome profiles. The results of our studies reveal novel, detailed insight into differentially expressed signature genes and related fold changes in the individual APP/PS1 subgroups. Gene ontology and Venn analysis unmasked that intersectional, upregulated genes were predominantly involved in, e.g., activation of microglial, astrocytic and neutrophilic cells, innate immune response/immune effector response, neuroinflammation, phagosome/proteasome activation, and synaptic transmission. The number of (intersectional) downregulated genes was substantially less in the different subgroups and related GO categories included, e.g., the synaptic vesicle docking/fusion machinery, synaptic transmission, rRNA processing, ubiquitination, proteasome degradation, histone modification and cellular senescence. Importantly, this is the first study to systematically unravel sex- and brain region-specific transcriptome fingerprints/signature genes in APP/PS1 mice. The latter will be of central relevance in future preclinical and clinical AD related studies, biomarker characterization and personalized medicinal approaches.

Whole genome transcriptome data from the WT cortex and hippocampus of female and male control and APP/PS1 Alzheimer's disease mice.

A variety of Alzheimer disease (AD) mouse models has been established and characterized within the last decades. These models are generated to meet the principal criteria of AD isomorphism, homology and predictability to a maximum extent. To get an integrative view of the sophisticated etiopathogenesis of AD, whole genome transcriptome data analysis turns out to be indispensable. Here, we present a microarray-based transcriptome data collection based on RNA extracted from the retrosplenial (RS) cortex and the hippocampus of APP/PS1 AD mice and control animals. Experimental animals were age matched and importantly, both sexes were considered separately. Isolated RNA was purified, quantified und quality controlled prior to the hybridization procedure with SurePrint G3 Mouse Gene Expression v2 8 × 60K microarrays. Following immunofluorescent measurement und preprocessing/extraction of image data, raw transcriptome data were uploaded including differentially expressed gene candidates and related fold changes in APP/PS1 AD mice and controls. Our data allow further insight into alterations in gene transcript levels in APP/PS1 AD mice compared to controls and enable the reader/user to carry out complex transcriptome analysis to characterize potential age-, sex- and brain-region-specific alterations in e.g., neuroinflammatory, immunological, neurodegenerative and ion channel pathways.

Cav3 T-Type Voltage-Gated Ca2+ Channels and the Amyloidogenic Environment: Pathophysiology and Implications on Pharmacotherapy and Pharmacovigilance.

Voltage-gated Ca2+ channels (VGCCs) were reported to play a crucial role in neurotransmitter release, dendritic resonance phenomena and integration, and the regulation of gene expression. In the septohippocampal system, high- and low-voltage-activated (HVA, LVA) Ca2+ channels were shown to be involved in theta genesis, learning, and memory processes. In particular, HVA Cav2.3 R-type and LVA Cav3 T-type Ca2+ channels are expressed in the medial septum-diagonal band of Broca (MS-DBB), hippocampal interneurons, and pyramidal cells, and ablation of both channels was proven to severely modulate theta activity. Importantly, Cav3 Ca2+ channels contribute to rebound burst firing in septal interneurons. Consequently, functional impairment of T-type Ca2+ channels, e.g., in null mutant mouse models, caused tonic disinhibition of the septohippocampal pathway and subsequent enhancement of hippocampal theta activity. In addition, impairment of GABA A/B receptor transcription, trafficking, and membrane translocation was observed within the septohippocampal system. Given the recent findings that amyloid precursor protein (APP) forms complexes with GABA B receptors (GBRs), it is hypothesized that T-type Ca2+ current reduction, decrease in GABA receptors, and APP destabilization generate complex functional interdependence that can constitute a sophisticated proamyloidogenic environment, which could be of potential relevance in the etiopathogenesis of Alzheimer's disease (AD). The age-related downregulation of T-type Ca2+ channels in humans goes together with increased Aß levels that could further inhibit T-type channels and aggravate the proamyloidogenic environment. The mechanistic model presented here sheds new light on recent reports about the potential risks of T-type Ca2+ channel blockers (CCBs) in dementia, as observed upon antiepileptic drug application in the elderly.

The Janus-like Association between Proton Pump Inhibitors and Dementia.

Early pharmacoepidemiological studies suggested that Proton Pump Inhibitors (PPIs) might increase the risk of Alzheimer's Disease (AD) and non-AD related dementias. These findings were supported by preclinical studies, specifically stressing the proamyloidogenic and indirect anticholinergic effects of PPIs. However, further large-scale pharmacoepidemiological studies showed inconsistent results on the association between PPIs and dementia. Pharmacodynamically, these findings might be related to the LXR/RXR-mediated amyloid clearance effect and anti-inflammatory action of PPIs. Further aspects that influence PPI effects on AD are related to patient- specific pharmacokinetic and pharmacogenomic characteristics. In conclusion, a personalized (individualized) medicinal approach is necessary to model and predict the potential harmful or beneficial effects of PPIs in AD and non-AD-related dementias in the future.

Breeding of Cav2.3 deficient mice reveals Mendelian inheritance in contrast to complex inheritance in Cav3.2 null mutant breeding.

High voltage-activated Cav2.3 R-type Ca2+ channels and low voltage-activated Cav3.2 T-type Ca2+ channels were reported to be involved in numerous physiological and pathophysiological processes. Many of these findings are based on studies in Cav2.3 and Cav3.2 deficient mice. Recently, it has been proposed that inbreeding of Cav2.3 and Cav3.2 deficient mice exhibits significant deviation from Mendelian inheritance and might be an indication for potential prenatal lethality in these lines. In our study, we analyzed 926 offspring from Cav3.2 breedings and 1142 offspring from Cav2.3 breedings. Our results demonstrate that breeding of Cav2.3 deficient mice shows typical Mendelian inheritance and that there is no indication of prenatal lethality. In contrast, Cav3.2 breeding exhibits a complex inheritance pattern. It might be speculated that the differences in inheritance, particularly for Cav2.3 breeding, are related to other factors, such as genetic specificities of the mutant lines, compensatory mechanisms and altered sperm activity.

Spontaneous long-term and urethane induced hippocampal EEG power, activity and temperature data from mice lacking the Cav3.2 voltage-gated Ca2+ channel.

This article provides raw relative electroencephalographic (EEG) power, temperature and activity data from controls and Cav3.2 deficient mice. Radiotransmitter implantation was carried out in male experimental mice under ketamine/xylazine narcosis. Following a recovery period, radiotelemetric EEG recordings from the hippocampal CA1 region were obtained under spontaneous 24 h long-term conditions and post urethane injection. Relative EEG power values (%) for 2 s epochs were analysed for the following frequency ranges: delta 1 ( δ 1 , 0.5-4 Hz), delta 2 ( δ 2 , 1-4 Hz), theta 1 ( θ 1 , 4-8 Hz), theta 2 ( θ 2 , 4-12 Hz), alpha ( α , 8-12 Hz), sigma ( σ , 12-16 Hz), beta 1 ( ß 1 , 12-30 Hz), beta 2 ( ß 2 , 16-24 Hz), beta 3 ( ß 3 , 16-30 Hz), gamma low ( γ l o w , 30-50 Hz), gamma mid ( γ m i d , 50-70 Hz), gamma high ( γ h i g h , 70-100 Hz), gamma ripples ( γ r i p p l e s , 80-200 Hz), and gamma fast ripples ( γ f a s t r i p p l e s , 200-500 Hz). In addition, subcutaneous temperature and relative activity data were analysed for both the light and dark cycle of two long-term recordings. The same type of data was obtained post urethane injection. Detailed information is provided for the age and body weight of the experimental animals, the technical specifications of the radiofrequency transmitter, the stereotaxic coordinates for the intracerebral, deep and epidural, surface EEG electrodes, the electrode features, the filtering and sampling characteristics, the analysed EEG frequency bands and the data acquisition parameters. EEG power data, temperature and activity data are available at MENDELEY DATA (doi:10.17632/x53km5sby6.1, URL: http://dx.doi.org/10.17632/x53km5sby6.1). Raw EEG data are available at zenodo (https://zenodo.org/).

Pharmacological Neuroenhancement: Current Aspects of Categorization, Epidemiology, Pharmacology, Drug Development, Ethics, and Future Perspectives.

Recent pharmacoepidemiologic studies suggest that pharmacological neuroenhancement (pNE) and mood enhancement are globally expanding phenomena with distinctly different regional characteristics. Sociocultural and regulatory aspects, as well as health policies, play a central role in addition to medical care and prescription practices. The users mainly display self-involved motivations related to cognitive enhancement, emotional stability, and adaptivity. Natural stimulants, as well as drugs, represent substance abuse groups. The latter comprise purines, methylxanthines, phenylethylamines, modafinil, nootropics, antidepressants but also benzodiazepines, ß-adrenoceptor antagonists, and cannabis. Predominant pharmacodynamic target structures of these substances are the noradrenergic/dopaminergic and cholinergic receptor/transporter systems. Further targets comprise adenosine, serotonin, and glutamate receptors. Meta-analyses of randomized-controlled studies in healthy individuals show no or very limited verifiability of positive effects of pNE on attention, vigilance, learning, and memory. Only some members of the substance abuse groups, i.e., phenylethylamines and modafinil, display positive effects on attention and vigilance that are comparable to caffeinated drinks. However, the development of new antidementia drugs will increase the availability and the potential abuse of pNE. Social education, restrictive regulatory measures, and consistent medical prescription practices are essential to restrict the phenomenon of neuroenhancement with its social, medical, and ethical implications. This review provides a comprehensive overview of the highly dynamic field of pharmacological neuroenhancement and elaborates the dramatic challenges for the medical, sociocultural, and ethical fundaments of society.

Enhanced hippocampal type II theta activity AND altered theta architecture in mice lacking the Cav3.2 T-type voltage-gated calcium channel.

T-type Ca2+ channels are assumed to contribute to hippocampal theta oscillations. We used implantable video-EEG radiotelemetry and qPCR to unravel the role of Cav3.2 Ca2+ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Cav3.2-/- mice revealed robust increase in relative power in the theta (4-8 Hz) and theta-alpha (4-12 Hz) ranges, which was most prominent during the inactive stages of the dark cycles. Urethane injection experiments also showed enhanced type II theta activity and altered theta architecture following Cav3.2 ablation. Next, gene candidates from hippocampal transcriptome analysis of control and Cav3.2-/- mice were evaluated using qPCR. Dynein light chain Tctex-Type 1 (Dynlt1b) was significantly reduced in Cav3.2-/- mice. Furthermore, a significant reduction of GABA A receptor δ subunits and GABA B1 receptor subunits was observed in the septohippocampal GABAergic system. Our results demonstrate that ablation of Cav3.2 significantly alters type II theta activity and theta architecture. Transcriptional changes in synaptic transporter proteins and GABA receptors might be functionally linked to the electrophysiological phenotype.

Predation risk and competition affect habitat use of adult perch, Perca fluviatilis.

The aim of this study was to examine how the presence of a predator and an interspecific competitor influence the habitat use of adult perch (Perca fluviatilis; size: 15.1 ± 0.5 cm) when given the choice between two adjacent habitats. By conducting aquarium experiments, the habitat occupancy of P. fluviatilis was documented in the presence and absence of a predator (pike Esox lucius; size: 25.4 ± 2.1 cm) and a potential competitor (ruffe Gymnocephalus cernuus; size: 14.1 ± 0.3 cm) fish species. Two P. fluviatilis individuals generally shared the same habitat. In the presence of a conspecific, P. fluviatilis favoured the structurally more-complex, artificial macrophyte habitat over the less-structured rock and sand habitat, which in turn were used equally. In the predator- and competitor treatments, P. fluviatilis seemed to adapt their habitat use to the habitat occupancy of E. lucius and G. cernuus in the Macrophyte vs. Rock and, in the predator treatment, also in the Macrophyte vs. Sand habitat combination, by increasingly occupying a habitat that was used less by the predator or competitor species, respectively. This behaviour suggests that P. fluviatilis tried to avoid the other fish species by choosing a, in some cases less preferred, predator- or competitor-free habitat. This study emphasizes the importance of biological interactions illustrated by the potential of predation risk and competition to structure fish communities by influencing habitat use at small spatial scales.

Functional implications of Cav 2.3 R-type voltage-gated calcium channels in the murine auditory system - novel vistas from brainstem-evoked response audiometry.

Voltage-gated Ca2+ channels (VGCCs) are considered to play a key role in auditory perception and information processing within the murine inner ear and brainstem. In the past, Cav 1.3 L-type VGCCs gathered most attention as their ablation causes congenital deafness. However, isolated patch-clamp investigation and localization studies repetitively suggested that Cav 2.3 R-type VGCCs are also expressed in the cochlea and further components of the ascending auditory tract, pointing to a potential functional role of Cav 2.3 in hearing physiology. Thus, we performed auditory profiling of Cav 2.3+/+ controls, heterozygous Cav 2.3+/- mice and Cav 2.3 null mutants (Cav 2.3-/- ) using brainstem-evoked response audiometry. Interestingly, click-evoked auditory brainstem responses (ABRs) revealed increased hearing thresholds in Cav 2.3+/- mice from both genders, whereas no alterations were observed in Cav 2.3-/- mice. Similar observations were made for tone burst-related ABRs in both genders. However, Cav 2.3 ablation seemed to prevent mutant mice from total hearing loss particularly in the higher frequency range (36-42 kHz). Amplitude growth function analysis revealed, i.a., significant reduction in ABR wave WI and WIII amplitude in mutant animals. In addition, alterations in WI -WIV interwave interval were observed in female Cav 2.3+/- mice whereas absolute latencies remained unchanged. In summary, our results demonstrate that Cav 2.3 VGCCs are mandatory for physiological auditory information processing in the ascending auditory tract.

Data Acquisition and Analysis In Brainstem Evoked Response Audiometry In Mice.

Brainstem evoked response audiometry (BERA) is of central relevance in the clinical neurophysiology. As other evoked potential (EP) techniques, such as visually evoked potentials (VEPs) or somatosensory evoked potentials (SEPs), the auditory evoked potentials (AEPs) are triggered by the repetitive presentation of identical stimuli, the electroencephalographic (EEG) response of which is subsequently averaged resulting in distinct positive (p) and negative (n) deflections. In humans, both the amplitude and the latency of individual peaks can be used to characterize alterations in synchronization and conduction velocity in the underlying neuronal circuitries. Importantly, AEPs are also applied in basic and preclinical science to identify and characterize the auditory function in pharmacological and genetic animal models. Even more, animal models in combination with pharmacological testing are utilized to investigate for potential benefits in the treatment of sensorineural hearing loss (e.g., age- or noise-induced hearing deficits). Here we provide a detailed and integrative description of how to record auditory brainstem-evoked responses (ABRs) in mice using click and tone-burst application. A specific focus of this protocol is on pre-experimental animal housing, anesthesia, ABR recording, ABR filtering processes, automated wavelet-based amplitude growth function analysis, and latency detection.

Cav3.2 T-Type Calcium Channels Are Physiologically Mandatory for the Auditory System.

Voltage-gated Ca2+ channels (VGCCs) play key roles in auditory perception and information processing within the inner ear and brainstem. Pharmacological inhibition of low voltage-activated (LVA) T-type Ca2+ channels is related to both age- and noise induced hearing loss in experimental animals and may represent a promising approach to the treatment of auditory impairment of various etiologies. Within the LVA Ca2+ channel subgroup, Cav3.2 is the most prominently expressed T-type channel entity in the cochlea and auditory brainstem. Thus, we performed a complete gender specific click and tone burst based auditory brainstem response (ABR) analysis of Cav3.2+/- and Cav3.2-/- mice, including i.a. temporal progression in hearing loss, amplitude growth function and wave latency analysis as well as a cochlear qPCR based evaluation of other VGCCs transcripts. Our results, based on a self-programmed automated wavelet approach, demonstrate that both heterozygous and Cav3.2 null mutant mice exhibit age-dependent increases in hearing thresholds at 5 months of age. In addition, complex alterations in WI-IV amplitudes and latencies were detected that were not attributable to alterations in the expression of other VGCCs in the auditory tract. Our results clearly demonstrate the important physiological role of Cav3.2 VGCCs in the spatiotemporal organization of auditory processing in young adult mice and suggest potential pharmacological targets for interventions in the future.

Gender specific click and tone burst evoked ABR datasets from mice lacking the Cav3.2 T-type voltage-gated calcium channel.

OBJECTIVES: Voltage-gated Ca2+ channels (VGCCs) are of central relevance in regulating Ca2+ influx into living cells. The low-voltage activated (LVA) Cav3 T-type Ca2+ channels are widely distributed throughout the brain including the peripheral auditory system and ascending auditory tract. Their exact role in auditory information processing is still not fully understood. Within the LVA subgroup, Cav3.2 T-type Ca2+ channels seem to be of special importance as qPCR revealed a steady increase in Cav3.2 transcript levels over age, e.g. in the cochlea and spiral ganglion neurons (SGN). Furthermore, pharmacological studies suggested an association between Cav3.2 expression and both age-related and noise-induced hearing loss. Given the potential functional relevance of Cav3.2 VGGCs in sensorineural hearing loss, we recorded gender specific auditory evoked brainstem responses (ABRs) upon both click and tone burst presentation. Here we present auditory brainstem response (ABR) data from Cav3.2+/+, Cav3.2+/- and Cav3.2-/- mice from both genders which are of value for researchers who want to evaluate how Cav3.2 loss affects basic auditory parameters, e.g. click and tone burst based hearing thresholds, amplitude growth function and peak latencies. DATA DESCRIPTION: Information presented here includes ABR data from age-matched female and male Cav3.2+/+, Cav3.2+/- and Cav3.2-/- mice and technical aspects of the auditory recording protocol. Data were recorded using a commercially available ABR setup from Tucker Davis Technologies Inc. (TDT). Raw data files (arf.-file format) were exported as txt.-files with free access for analysis.

Gender specific click and tone burst evoked ABR datasets from mice lacking the Cav2.3 R-type voltage-gated calcium channel.

This data article provides raw auditory evoked brainstem responses (ABRs) from controls and Cav2.3 transgenics, i.e. heterozygous Cav2.3+/- and Cav2.3-/- null mutants. Gender specific ABR recordings were performed in age-matched animals under ketamine/xylazine narcosis. Data presented here include ABRs upon both click and tone burst presentation in the increasing SPL mode using a commercially available ABR setup from Tucker Davis Technologies Inc. (TDT, USA). Detailed information is provided for the sound attenuating cubicle, electrical shielding, electrode parameters, stimulus characteristics and architecture, sampling rate, filtering processes and ABR protocol application during the course of data acquisition and recording. The later are important for subsequent analysis of click and tone burst related hearing thresholds, amplitude growth function and peak latencies. Raw data are available at MENDELEY DATA, DIO: 〈DOI:10.17632/g6ygz2spzx.1〉, URL: 〈https://data.mendeley.com/datasets/g6ygz2spzx/1〉).

Automatic Detection of Highly Organized Theta Oscillations in the Murine EEG.

Theta activity is generated in the septohippocampal system and can be recorded using deep intrahippocampal electrodes and implantable electroencephalography (EEG) radiotelemetry or tether system approaches. Pharmacologically, hippocampal theta is heterogeneous (see dualistic theory) and can be differentiated into type I and type II theta. These individual EEG subtypes are related to specific cognitive and behavioral states, such as arousal, exploration, learning and memory, higher integrative functions, etc. In neurodegenerative diseases such as Alzheimer's, structural and functional alterations of the septohippocampal system can result in impaired theta activity/oscillations. A standard quantitative analysis of the hippocampal EEG includes a Fast-Fourier-Transformation (FFT)-based frequency analysis. However, this procedure does not provide details about theta activity in general and highly-organized theta oscillations in particular. In order to obtain detailed information on highly-organized theta oscillations in the hippocampus, we have developed a new analytical approach. This approach allows for time- and cost-effective quantification of the duration of highly-organized theta oscillations and their frequency characteristics.

Gender specific hippocampal whole genome transcriptome data from mice lacking the Cav2.3 R-type or Cav3.2 T-type voltage-gated calcium channel.

Voltage-gated Ca2+ channels are of central relevance in mediating numerous intracellular and transcellular processes including excitation-contraction coupling, excitation secretion-coupling, hormone and neurotransmitter release and gene expression. The Cav2.3 R-type Ca2+ channel is a high-voltage activated channel which plays a crucial role in neurotransmitter release, long-term potentiation and hormone release. Furthermore, Cav2.3 R-type channels were reported to be involved in ictogenesis, epileptogenesis, fear behavior, sleep, pre-and postsynaptic integration and rhythmicity within the hippocampus. Cav3 T-type Ca2+ channels are low-voltage activated and also widely expressed throughout the brain enabling neurons to switch between different firing patterns and to modulate burst activity. Disruption of T-type Ca2+ current has been related to sleep disorders, epilepsy, Parkinson׳s disease, depression, schizophrenia and pain. Cav3.2 ablation was further attributed to elevated anxiety and hippocampal alterations resulting in impaired long-term potentiation and memory. Given the importance of Cav2.3 and Cav3.2 voltage-gated Ca2+ channels within the CNS, particularly the hippocampus, we collected gender specific microarray transcriptome data of murine hippocampal RNA probes using the Affymetrix Exon Expression Chip Mouse Gene 1.0 ST v1. Information presented here includes transcriptome data from Cav2.3+/+, Cav2.3+/-, Cav2.3-/-, Cav3.2+/+, Cav3.2+/- and Cav3.2-/- mice from both genders, the protocol and list of primers used for genotyping animals, the hippocampal RNA isolation procedure and quality controls.

Motor Cortex Theta and Gamma Architecture in Young Adult APPswePS1dE9 Alzheimer Mice.

Alzheimer's disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study, an APPswePS1dE9 AD mouse model has been analyzed for motor cortex theta, beta and gamma frequency alterations using computerized 3D stereotaxic electrode positioning and implantable video-EEG radiotelemetry to perform long-term M1 recordings from both genders considering age, circadian rhythm and activity status of experimental animals. We previously demonstrated that APPswePS1dE9 mice exibit complex alterations in hippocampal frequency power and another recent investigation reported a global increase of alpha, beta and gamma power in APPswePS1dE9 in females of 16-17 weeks of age. In this cortical study in APPswePS1dE9 mice we did not observe any changes in theta, beta and particularly gamma power in both genders at the age of 14, 15, 18 and 19 weeks. Importantly, no activity dependence of theta, beta and gamma activity could be detected. These findings clearly point to the fact that EEG activity, particularly gamma power exhibits developmental changes and spatial distinctiveness in the APPswePS1dE9 mouse model of Alzheimer's disease.

Review: Cav2.3 R-type Voltage-Gated Ca2+ Channels - Functional Implications in Convulsive and Non-convulsive Seizure Activity.

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 Cav2.1 P/Q-type and Cav3.2 T-type Ca2+ channels relevant for absence epileptogenesis. Recent findings bring other channels entities more into focus such as the Cav2.3 R-type Ca2+ channel which exhibits an intriguing role in ictogenesis and seizure propagation. Cav2.3 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 Cav2.3 R-type Ca2+ channels and point to recent findings in the proictogenic and proneuroapoptotic role of Cav2.3 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 Cav2.3 specific modulators can be effective in the pharmacological treatment of epilepsies and other neurological disorders.

Gender-Specific Hippocampal Dysrhythmia and Aberrant Hippocampal and Cortical Excitability in the APPswePS1dE9 Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial disorder leading to progressive memory loss and eventually death. In this study an APPswePS1dE9 AD mouse model has been analyzed using implantable video-EEG radiotelemetry to perform long-term EEG recordings from the primary motor cortex M1 and the hippocampal CA1 region in both genders. Besides motor activity, EEG recordings were analyzed for electroencephalographic seizure activity and frequency characteristics using a Fast Fourier Transformation (FFT) based approach. Automatic seizure detection revealed severe electroencephalographic seizure activity in both M1 and CA1 deflection in APPswePS1dE9 mice with gender-specific characteristics. Frequency analysis of both surface and deep EEG recordings elicited complex age, gender, and activity dependent alterations in the theta and gamma range. Females displayed an antithetic decrease in theta (θ) and increase in gamma (γ) power at 18-19 weeks of age whereas related changes in males occurred earlier at 14 weeks of age. In females, theta (θ) and gamma (γ) power alterations predominated in the inactive state suggesting a reduction in atropine-sensitive type II theta in APPswePS1dE9 animals. Gender-specific central dysrhythmia and network alterations in APPswePS1dE9 point to a functional role in behavioral and cognitive deficits and might serve as early biomarkers for AD in the future.