Main Content

Animal Models

The complex and heterogeneous architecture of neuropsychiatric disorders is a challenging factor in uncovering the exact biological mechanisms underlying the behavior. The immense contribution of genetic factors and lack of reliable biomarkers make it necessary to test animal models of neuropsychiatric disorders for a deeper understanding of the disease pathogenesis. Developing models that meet the validity criteria plays a crucial role to advance our understanding, thus behavioral phenotyping of these models is a key component of the current translational approach.

Psychiatric Diseases and genetic Models

  • Autism Spectrum Disorder | SHANK

    Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders characterized by persistent deficits in social communication and interaction across multiple contexts, and restricted, repetitive patterns of behavior; frequently comorbid with intellectual disability. The exact neurobiological causes of ASD remain largely undiscovered. However, several studies highlight immense contribution of genetic factors to disease etiology. Particularly, the SHANK family of postsynaptic proteins has emerged as promising candidates, considering that mutations in SHANK genes have repeatedly been reported in individuals with ASD. SHANK proteins are the master scaffolding proteins of the postsynaptic density, and are strongly involved in various synaptic functions, connecting neurotransmitter receptors and other membrane proteins with downstream signaling cascade and actin cytoskeleton.  

    The diagnostic criteria for ASD are still purely behaviorally defined and an in-depth genetic screening is a challenging factor due to heterogeneity of the disorder. Here, animal models for ASD provide excellent translational tools to discover disease pathogenesis underlying behavioral and neurobiological abnormalities. In order to study the contribution of SHANK genes to ASD several Shank mouse models for ASD were generated. In our research we aim to investigate ASD-like behavioral phenotypes and cognitive functions of Shank mouse models. Applying behavioral tests with high relevance to diagnostic symptoms of ASD, such as by analyzing their social behavior and ultrasonic communication, we aim to establish a translational link across species.

     

    Literature:

    Sungur A.Ö., Schwarting R.K.W., Wöhr M. (2016). Early communication deficits in the Shank1 knockout mouse model for autism spectrum disorder: Developmental aspects and effects of social context. Autism Research 9:696–709.

  • Fear and Anxiety | SERT

    Anxiety per se serves as a functional reaction to threatening situations and ensures survival. Anxiety disorders, in contrast, are defined by excessive, exaggerated reactions in the absence of a real threat. These reactions range from diffuse and unspecific panic attacks to phobic responses to objects or situations.

    Several neurotransmitter systems are discussed to play a crucial part in the pathophysiology of anxiety. Due to the anxiolytic properties of substances working through the serotonergic system, serotonin (5-hydroxytryptamine, 5-HT) itself is considered a key modulator in anxious behavior.

    5-HT is an important modulatory neurotransmitter. While the 5-HT system is complex and includes several 5-HT receptors, a key component of the system is the 5-HT transporter (5-HTT also known as SERT), since it controls the amount of 5-HT available in the synaptic cleft.

    Alterations in the gene coding for SERT have been associated with higher vulnerabilities to neuropsychiatric disorders, such as depression and anxiety. Furthermore, impairments in learning behavior, such as extinction, have been reported. 

    To model altered 5-HT transmission resulting from changes in the availability of SERT, animals are genetically modified. In rodents for example, it is possible to completely abolish the expression of SERT in the brain. In these animals the gene for SERT is knocked out – referred to as SERT knockout rats and mice. SERT knockout rats are known to mirror behavioral phenotypes found in humans with altered SERT expression, for example higher levels of anxiety. This gives us the unique opportunity to study behavioral and neurological differences resulting from altered 5-HT transmission in a controlled environment.

  • Affective Disorders | CACNA1C

    Affective disorders are a specific form of psychiatric disorder characterised by a wide array of disruptive symptoms ranging from severe sadness to mania – episodes of great excitement or euphoria, delusions and over activity. Several widely known affective disorders include, major depressive disorder (MDD) and bipolar disorder (BPD) but also anxiety disorder. Causes are not fully understood although imbalances in neurotransmitters are believed to play a major role. Recent developments in affective research has suggested that both environmental and genetic factors may play a key role in the risk of developing affective disorders. For example, a well-known risk gene in humans known as CACNA1C, has recently been implicated in both MDD and BDP. CACNA1C is a gene that provides instructions for making L-type voltage gated calcium (Ca2+) channels. These channels play a key role in regulating a cells ability to generate and transmit electrical signals. Mutations in these channels, for example, have been linked to the Autism-like disorder known as Timothy Syndrome. Specific channels produced by the CACNA1C gene, known as Cav1.2 channels, are found in the heart but also in the brain and play a major role in modulating neuronal excitability, synaptic plasticity and gene expression. Due to recent advancements in transgenic animal models we have a transgenic Cacna1c rat line in which the heterozygous rats have a global reduction of approximately 50% in Cav1.2 channels throughout the brain and body. With this model we aim to explore the role of this gene and its interaction with differing environmental factors, from early life to late adulthood in areas such as learning and memory, and social behavior and ultrasonic communication, with respect to the development and risk for developing affective disorders.