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A3 - Interaction between network, intracellular, and gene expression dynamics via VG Ca2+ channels

Principal investigator(s):

Abteilung Molekularbiologie
Zentralinstitut fŁr Seelische Gesundheit
68159 Mannheim


Projects within the BCCN:

The main objectives of this project were the generation of the conditional knockout Cav1.2 and Cav1.3 mice in pyramidal cells for behavioral, electrophysiological and computational analysis. L-type voltage-gated calcium channels (LVGCCs) regulate intracellular Ca≤+ concentrations and play an important role in synaptic plasticity and learning and memory. SNP in genes encoding CaV1.3 (CACNA1D) and CaV1.2 (CACNA1C) pore forming α1 subunits have been associated with defects in memory formation and several forms of mental illnesses like bipolar disorder, depression, Parkinsonís disease and schizophrenia (Berger and Bartsch, 2014). To further investigate the role of CaV1.3, we generated genetically modified mice with a FLEX conditional allele of this subunit. While homozygous ubiquitous knockout mice are embryonically lethal, heterozygous mutant mice show phenotypes that might interfere with behavioral analysis (deafness, heart insufficiency). For this reason, we generated conditional knockout mice with deletion of CaV1.3 specifically in the brain (nestin-cre) or in selected neuronal populations such as serotonergic and dopaminergic neurons. We have also generated NestinCre/CaV1.2 and NestinCre/Cav1.3 mutant mice and tested them for in-vivo and in vitro neurogenesis (our group), electrophysiological and computational implications (B5/ B6) and learning and memory (P. Gass & B. Vollmayr, C8). For NestinCre/Cav1.3 mice, we could demonstrate that the mice are not deaf and that the brain-specific Cav1.3 deletion yielded an anxiolytic and antidepressive effect in the respective mice. Concerning age-related effects of a Cav1.3 deletion, NesCre/Cav1.3 mice were investigated in an animal model for Parkinsonís disease in collaboration with Klaus Unsicker (Freiburg) and Oliver von Bohlen und Halbach (Greifswald). In further collaborations, we investigated the regulation of CaV1.3 (Marschallinger et. al. 2015) and the role of LVGCCs in hearing (Satheesh et al. 2012) and alcohol dependence (Uhrig et al. 2017)
LVGCCs are expressed in neuronal stem cells and were postulated to trigger neuronal differentiation in vitro. We have therefore assayed the effect of ablation of CaV1.2 and CaV1.3 in Type 1 neuronal cells in vivo. We analyzed adult neurogenesis in mice with conditional CaV1.2 or CaV1.3 ablation using the above mentioned nestin-cre and GLAST-cre driver line. In both knockouts, the ablation of CaV1.2 or CaV1.3 leads to significant defect in adult neurogenesis (Marschallinger et al. 2015). Detailed analysis of different stages of neurogenesis revealed that the affected stage is most likely not the differentiation of Type 1 cells into neurons, but rather the asymmetrical division of Type 1 cells. Interestingly, Electroconvulsive Therapy (ECT) like treatment of mice with both knockouts can ameliorate this defect and restore normal neurogenesis in both mutants (Volkening et.al 2017).
The conditional mouse mutants generated in our laboratory are available and distributed to other labs for further research.

Participating groups:

Key publications:

Uhrig S, Vandael D, Marcantoni A, Dedic N, Bilbao A, Vogt MA, Hirth N, Broccoli L, Bernardi RE, Schonig K, Gass P, Bartsch D, Spanagel R, Deussing JM, Sommer WH, Carbone E, Hansson AC (2017) Differential Roles for L-Type Calcium Channel Subtypes in Alcohol Dependence Neuropsychopharmacology .
Volkening B, Schonig K, Kronenberg G, Bartsch D, Weber T (2017) Deletion of psychiatric risk gene Cacna1c impairs hippocampal neurogenesis in cell-autonomous fashion Glia .
Marschallinger J, Sah A, Schmuckermair C, Unger M, Rotheneichner P, Kharitonova M, Waclawiczek A, Gerner P, Jaksch-Bogensperger H, Berger S, Striessnig J, Singewald N, Couillard-Despres S, Aigner L (2015) The L-type calcium channel Cav1.3 is required for proper hippocampal neurogenesis and cognitive functions Cell Calcium .
Scharinger A, Eckrich S, Vandael DH, Schonig K, Koschak A, Hecker D, Kaur G, Lee A, Sah A, Bartsch D, Benedetti B, Lieb A, Schick B, Singewald N, Sinnegger-Brauns MJ, Carbone E, Engel J, Striessnig J (2015) Cell-type-specific tuning of Cav1.3 Ca(2+)-channels by a C-terminal automodulatory domain Front Cell Neurosci 9:309 .
Berger SM, Bartsch D (2014) The role of L-type voltage-gated calcium channels Cav1.2 and Cav1.3 in normal and pathological brain function Cell and tissue research 357:463-476 .
Satheesh SV, Kunert K, Ruttiger L, Zuccotti A, Schonig K, Friauf E, Knipper M, Bartsch D, Nothwang HG (2012) Retrocochlear function of the peripheral deafness gene Cacna1d Hum Mol Genet .