One of the most sophisticated features of our species is an elaborate nervous system. In order to function properly nerve cells must maintain an electrochemical gradient in concert with multifarious signaling pathways. This is carried out by a number of ion-handling systems including ion channels, such as calcium channels. Especially when located in the brain they do not only influence the electrochemical properties of the cell but also affect neurotransmitter release, configure different calcium-dependent pathways and shape neuronal firing. The slightest aberration in such a well-established system can have immense consequences for the organism as a whole. Recent findings in genome wide association studies suggest a link between mutations in such calcium channels and different neurological and neuropsychiatric diseases including autism spectrum disorder (ASD). ASD is a complex illness characterized by a multitude of different symptoms with behavioral and communicational problems being the most characteristic. One specific variation that came into focus through whole-exome sequencing studies was a de novo missense mutation in the CACNA1D gene which encodes an L-type calcium channel classified as Cav1.3. As of now six different mutations in individuals experiencing neurodevelopmental/neurological symptoms are identified. Electrophysiological testing in vitro demonstrated altered biophysical properties that were induced by these mutations. For the purpose of further elucidating the actual physiological impact of the mentioned mutations we introduced one of the high-risk mutations (A749G) into C57BL/6N mice, which we refer to as the CavAG mouse- line. To investigate if the mutation affects neurodevelopment with changes in brain structure and volume as observed in Cav1.3 knockout mice and other autism models, I analyzed the neuroanatomy of these mice in this thesis. To visualize overall brain structures Nissl staining of 40 m coronal brain sections cut on a cryostat was performed. Striatal volumes and cell numbers of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA) were determined by staining for tyrosine hydroxylase (TH) on serial vibratome-cut 40 m thick coronal sections. For the visualization of cerebellar Purkinje cells, the neurons were stained against Calbindin on 40 m thick sagittal serial sections.
We found no change in the overall gross neuroanatomy, and neither significant differences in the volume nor total cell number of selected, potentially disease- associated regions. This finding is agreement with the absence of gross neuroanatomical lesions in the MRI of the affected patient. In a next step other target brain areas will be studied as well as changes in neuronal morphology, such as dendritic arborization, spine number and morphology.