Voltage-gated calcium-channels are key molecular regulators of calcium-dependent signaling processes in electrically excitable cells. The members of the L-type calcium-channel family (LTCCs, Cav1.1-Cav1.4 pore-forming α1-subunits) are sensitive to organic calcium-channel blockers (e.g. dihydropyridines) clinically used to treat hypertension (1). In the brain only the Cav1.2 and Cav1.3 isoforms are expressed, both located postsynaptically at dendrites and the cell soma. This allows them to control neuronal excitability and to couple neuronal activity to gene transcription. Through their distinct biophysical properties Cav1.2 and Cav1.3 contribute in different ways to various forms of learning, memory, emotional and drug-taking behaviors (1, for review). No CNS side effects have been reported during antihypertensive therapy with brain-permeable LTCC blockers. However, recent evidence from human genetics strongly suggests an important role of LTCC gain-of-function for neuropsychiatric diseases (1). Timothy syndrome is a rare disease in which the mutation-induced increase in Cav1.2 channel function (CACNA1C gene) causes not only long QT syndrome and other organ abnormalities but also autism in surviving patients (1). Large-scale genome-wide association studies revealed a strong association between intronic SNPs in the CACNA1C gene and susceptibility for various psychiatric disorders, including bipolar disease, schizophrenia and major depression. For one of these SNPs (rs1006737) increased Cav1.2 activity in fibroblast-derived induced neurons has been reported (2). More recently, we (3) and others (4) discovered somatic mutations in the pore-forming α1-subunit of Cav1.3 (CACNA1D) which induce a strong increase in Cav1.3 channel function and cause excess aldosterone production in aldosterone producing adenomas. When present germline, two of these de novo mutations cause a severe congenital syndrome with primary aldosteronism, but also with neurodevelopmental deficits and seizures at early age (PASNA, 4). Moreover, we have recently found that two very similar de novo mutations (G407R, A749G) identified in two patients with autism and intellectual disability also cause a strong gain-of-channel function (5). Together these data strongly suggest that altered channel gating of Cav1.2 and Cav1.3 channels can lead to neuropsychiatric disease. To directly address this question we have generated mice expressing Cav1.3 α1 subunits with a hemagglutinine antibody (HA-) tag inserted in the C-terminal tail (Cav1.3HA/HA). This HA-tag disrupts a C-terminal modulatory domain which, as shown in heterologous expression systems (1), moderates channel function in long (but not short) splice variants of the channel which comprise about 50% of the Cav1.3 channels in the brain (1). Using these mice we demonstrate that, while the long splice variant is still expressed at unchanged levels in the brain of homzygous mutants, disruption of its C-terminal modulatory domain also alters Cav1.3 channel gating in their native cellular environment. Behavioral analysis revealed an increased anxiety-like behavior in Cav1.3HA/HA mice. These data in mice further support the hypothesis that Cav1.3 dysregulation can lead to CNS dysfunction. Based on the finding that enhanced LTCC activity contributes to neuropsychiatric disease risk, already existing or novel (e.g. Cav1.3-selective) LTCC blockers should be considered as potential therapeutics in individuals with increased genetic risk.