Friday, April 16, 2010

Mad Mice

The mighty mouse has become an invaluable tool in biomedical research, due to the fact that its genome can readily be manipulated, using genetic engineering techniques in embryonic stem cells.  These techniques were first developed to “knock out” or delete any gene in the mouse genome and this approach is so established now that off-the-shelf knockouts for most genes in the genome are already available from several centres.  Genetic technologies have become increasingly sophisticated, giving researchers the ability to remove a gene’s function in just some cells in an animal or just at specific stages of development and also to engineer larger sections of chromosomes so that deletions or duplications that affect multiple genes can be modeled in the mouse. 

These genetic approaches have been used extremely successfully to model a vast number of human medical conditions in the mouse, following a simple pathway from the discovery of mutations associated with the disorder in humans to the generation and analysis of mice with mutations in those same genes.  Such mice can be investigated to elucidate the functions of the encoded proteins, the pathogenic consequences and mechanisms of the mutations and ultimately to inspire and to test novel therapeutics.

When it comes to psychiatric disorders however, the development and fruitful analysis of genetic animal models has lagged considerably behind other areas of medicine.  There are several reasons for this – first, we had not, until recently, identified many mutations in humans which result in a psychiatric disorder.  Indeed, the field has for decades been misdirected by the theory that psychiatric disorders are not caused by single mutations at all, but rather by toxic combinations of genetic variants that are common in the population; such combinations would obviously be almost impossible to model in an animal.  Fortunately, this theory can now be rejected on empirical and theoretical grounds and a welcome return in psychiatry to established principles of genetics is underway.  This paradigm shift is being driven in large part by the identification of quite a large number of single mutations in many different genes or chromosomal regions, which do indeed cause psychiatric disorders.  (For more on this see our recent review, below).  

We can thus be confident that single mutations in mice can be genetically valid models for psychiatric disorders and we also now have a list of candidate mutations to generate and investigate.  But what are we modeling? 

If we want to understand how a mutation in gene A or gene B can result in schizophrenia in a human, is there any point looking at the effects of mutations in those genes in a mouse?  Can a mouse ever be said to be schizophrenic? Well, it is obviously not possible to directly model the psychology of these disorders in mice, because mice do not have human minds, they have mouse minds (or no minds, depending on one’s philosophical point of view).  We thus cannot expect to model the human-specific expression of these disorders, which may include thought disorders, delusions, paranoia, and other high-level effects.  However, we can most certainly hope to model the underlying nervous system dysfunction in a mouse. 

This approach is powerfully illustrated by a recent paper from Maria Karayiorgou and colleagues.  She and her colleagues have been investigating for many years a condition known as Velo-Cardio Facial Syndrome.  This is caused by deletion of a small region of chromosome 22 (at position 22q11), which removes about thirty genes.  It is characterised by a variety of clinical effects, including characteristic facial morphology, cleft palate and heart defects.  It is also associated with a 30-fold increased risk of psychosis.  To try and better understand how removal of one copy of this set of genes can lead to psychosis, Karayiorgou and colleagues have generated a mutant mouse where this same set of thirty genes has been deleted.  Over several years they have been able to demonstrate a variety of neurodevelopmental defects in these mutant mice along with a spectrum of concomitant behavioural alterations.  They have also been able to narrow down which genes in the region are most important.  Their latest paper takes these analyses one step further – by investigating the effects on the functions of neural networks in the mouse brain.  It is at this level that the parallels with humans are likely to be most direct and most informative. 

They show that mice with this deletion have altered communication between two brain areas known to be central to many of the defects of schizophrenia in humans – the hippocampus and prefrontal cortex.  During a task requiring working memory (which is known to be disrupted in schizophrenia patients), these two brain areas usually maintain a communication channel with each other by phase-locking oscillations in neural activity.  (Such oscillations, or brain rhythms, are seen in all areas of the brain and occur at multiple different frequencies.  When one brain area sends a signal, it is most readily received by other areas whose oscillations are timed in synchrony with it – this is because the ongoing oscillations represent peaks and troughs of membrane depolarization which affects how responsive the cells are to incoming signals).  In the 22q11-model mutant mice, the synchronization of these oscillations across the two brain regions was disrupted and the magnitude of this effect in each animal correlated with the decrement in performance on the working memory task. 

These studies represent the discovery pathway that can be followed for the growing number of other candidate genes for psychiatric disorders: find a mutation in humans, generate a corresponding mutation in mice and analyse them in an integrative fashion across developmental, anatomical, neurophysiological and behavioural levels.  These approaches should elucidate the disease-causing effects of each mutation and allow comparison across mutations to see how their effects converge.  By allowing the tools of modern genetics and neuroscience to be applied to the problem, mutant mice should ultimately suggest new ways to intervene and aid the rational design and development of new therapeutics.

Mitchell, K., & Porteous, D. (2010). Rethinking the genetic architecture of schizophrenia Psychological Medicine DOI: 10.1017/S003329171000070X

Sigurdsson T, Stark KL, Karayiorgou M, Gogos JA, & Gordon JA (2010). Impaired hippocampal-prefrontal synchrony in a genetic mouse model of schizophrenia. Nature, 464 (7289), 763-7 PMID: 20360742