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

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

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 Aβ 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

Spontaneous long-term and urethane induced hippocampal EEG power, activity and temperature data from mice lacking the Ca(v)3.2 voltage-gated Ca2+ channel

This article provides raw relative electroencephalographic (EEG) power, temperature and activity data from controls and Ca-v 3.2 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 (81 , 0.5-4 Hz), delta 2 (82 , 1-4 Hz), theta 1 (01 , 4-8 Hz), theta 2 (02 , 4-12 Hz), alpha (alpha, 8-12 Hz), sigma (sigma, 12- 16 Hz), beta 1 (beta 1 , 12-30 Hz), beta 2 (beta 2 , 16-24 Hz), beta 3 (beta 3 , 16-30 Hz), gamma low (gamma(low) , 30-50 Hz), gamma mid (gamma(mid) , 50-70 Hz), gamma high (gamma(high) , 70-100 Hz), gamma rip-ples (yripples, 80-200 Hz), and gamma fast ripples (y(fast) ripples, 20 0-50 0 Hz). In addition, subcutaneous temperature and rel-ative 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 experimen-tal animals, the technical specifications of the radiofrequency transmitter, the stereotaxic coordinates for the intracerebral, deep and epidural, surface EEG electrodes, the electrode fea-tures, the filtering and sampling characteristics, the analysed EEG frequency bands and the data acquisition parameters. EEG power data, temperature and activity data are avail-able 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/ ). (C) 2021 The Authors. Published by Elsevier Inc

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, β-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 Ca(v)3.2 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 Ca(v)3.2 Ca2+ channels in hippocampal theta genesis. Frequency analysis of spontaneous long-term recordings in controls and Ca(v)3.2(-/-) 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 Ca(v)3.2 ablation. Next, gene candidates from hippocampal transcriptome analysis of control and Ca(v)3.2(-/-) mice were evaluated using qPCR. Dynein light chain Tctex-Type 1 (Dynlt1b) was significantly reduced in Ca(v)3.2(-/-) mice. Furthermore, a significant reduction of GABA A receptor delta subunits and GABA B1 receptor subunits was observed in the septohippocampal GABAergic system. Our results demonstrate that ablation of Ca(v)3.2 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

GO analysis of DEGs (FC < -1.2, p < 0.05).

Bar graphs of enriched terms across the input gene list were obtained from the Metascape gene list analysis report for (A) the RS cortex of female APP/PS1 AD vs. WT mice, (B) the hippocampus of female APP/PS1 AD vs. WT mice, (C) the RS cortex of male APP/PS1 AD vs. WT mice and (D) the hippocampus of male APP/PS1 AD vs. WT mice. The individual categories are provided together with their related -Log(10)P values in a descending fashion. Note that no GO analysis results could be obtained in the RS cortex of female APP/PS1 AD mice vs. WT controls. Overall, GO analysis for downregulated gene candidates revealed a limited number of categories compared to upregulated gene candidates (see also Fig 2).</p

Comparative qPCR analysis of selected DEGs from the RS cortex of female and male APP/PS1 AD.

Transcript levels (CNRQ) for Siglech (A, B), Ptpn6 (C, D), Laptm5 (E, F), Plek (G, H), Arpp21 (I, J), Shisa9 (K, L) were obtained from eight APP/PS1 AD mice (four ♂, four ♀) and eight WT control animals (three ♂, five ♀). Results are depicted using scatter plots including mean ± SEM. RNA was taken from the same animals analyzed in the transcriptome approach. Control mice are shown in black, APP/PS1 animals are highlighted in light blue.</p

S1 File -

S1 Fig: Genotyping of APP/PS1 AD mice and WT control animals. S2 Fig: 3D image of the murine brain including the RS cortex and hippocampus (BROIs) used for transcriptome analysis in our study. S3 Fig: PCA of transcriptomes from the RS cortex and hippocampus of WT controls and APP/PS1 AD mice of both sexes. S4 Fig: Hierarchical clustering of transcriptome data from the RS cortex and hippocampus of WT control and APP/PS1 AD mice of both sexes. S5 Fig: Bar diagrams of the top 30 candidates of DEGs with highest significant FCs (FC > 1.5 and FC S6 Fig: Pathway analysis of intersectional and signature gene sets in APP/PS1 subgroups. S7 Fig: Comparative qPCR analysis of selected gene transcript levels from the hippocampus of female and male APP/PS1 AD with 5XFAD mice. S1 Table: PCR reaction set-up using PCR Mastermix and genomic DNA. S2 Table: Materials used for one-color microarray-based gene expression data collection. S3 Table: Software used for one-color microarray-based gene expression data collection. S4 Table: Details on genes, forward and reverse primer sequences and annealing temperatures relevant for qPCR experimentation. S5 Table: Characteristics of DEGs in the RS cortex of female APP/PS1 AD mice. S6 Table: Characteristics of DEGs in the hippocampus of female APP/PS1 AD mice. S7 Table: Characteristics of DEGs in the RS cortex of male APP/PS1 AD mice. S8 Table: Characteristics of DEGs in the hippocampus of male APP/PS1 AD mice. S9 Table: Venn analysis of DEGs in the RS cortex and hippocampus of female APP/PS1 AD mice. S10 Table: Venn analysis of DEGs genes in the RS cortex and hippocampus of male APP/PS1 AD mice. S11 Table: Venn analysis of DEGs in the RS cortex of male and female APP/PS1 AD mice. S12 Table: Venn analysis of DEGs in the hippocampus of male and female APP/PS1 AD mice. S13 Table: Differentially regulated l(i)ncRNAs in APP/PS1 AD vs. WT mice. S14 Table: qPCR-based FC analysis of selected genes in the hippocampus of APP/PS1 AD vs. WT control mice. S15 Table: Design of transcriptome studies carried out in APP/PS1 AD mice. S16 Table: Functional implications of DEGs in AD. (ZIP)</p