Mice with Reduced NMDA Receptor Expression Display Behaviors Related to Schizophrenia

Mohn, A.R. et al. (1999). Cell 98: 427-436.

Now, here's an interesting paper!  We might finally have a good animal model for schizophrenia...whew!  It's hard enough developing animal models for non-psychiatric diseases, but psychiatric diseases have been much more difficult to model in animals (especially mice) since it's so difficult to "diagnose them".  Luckily, some psychiatric diseases, like schizophrenia, have some markers you can use to find similarities between mice with "schizophrenia" and human patients.  These are used in this paper to "diagnose" these genetically manipulated mice with this debilitating illness.

First, what do I mean by "genetically manipulated"?  Well, you may (or may not) have heard of knock out mice.  These are mice that are genetically engineered to lack a specific gene (you can check out my drug addiction website where I cover this in more detail).  So, mice lacking a specific receptor called the NMDA receptor (actually, this receptor is made of several proteins, and mice have been made lacking each of these proteins...what I am referring to here are mice that lack the critical protein of the receptor, the NR1 subunit) have been made, but unfortunately die very early.  This, of course, makes it difficult to discern the effects on mouse behavior.  Thus, in this paper, the authors produce mice that express 5-10% of the normal levels of the NR1 subunit.  This is enough to allow the mice to live through adulthood, but not enough for them to act normally.

What they found was that mice with this genetic deficit displayed behaviors similar to what is seen in human patients diagnosed with schizophrenia.  For example, these mice display social isolation from other mice as well as increased movement and hyperactivity.  Importantly, drugs used to treat schizophrenics (called anti-psychotics or neuroleptics) help reduce these behaviors in this mice, again suggesting that these mice may be good animal models for this disease.

Schizophrenia is a psychiatric illness characterized by both positive and negative symptoms.  The way I usually keep them straight is like this: positive symptoms are those that are gained as a result of the disease and negative symptoms are those are lost as a result of the disease.  So, positive symptoms might include delusions, hallucinations, and paranoia, and negative symptoms might include flattened affect, social withdrawl, and cognitive impairments.

What causes schizophrenia?  Now, that's an easy one...just kidding!  Seriously, scientists still aren't completely sure.  There are a couple of different hypotheses out there, but they seem mostly to revolve around the neurotransmitter dopamine (a neurotransmitter is a chemical released by one neuron that binds to a receptor on another neuron to transfer information).  The drugs that are used to treat schizophrenia block the dopamine receptors in the brain, suggesting that schizophrenia is caused by excess dopamine.  This is supported by the notion that drugs that increase dopamine in the brain (like cocaine or amphetamine) lead to schizophrenia-like symptoms.  Does this fit in with the animal model described above?  Not exactly.

NMDA receptors (the receptors in the above paper) are not receptors for dopamine, but rather another neurotransmitter called glutamate.  However, glutamate can regulate dopamine function in the brain, which may be why the mice exhibited the schizophrenia-like behaviors.  This was supported by the finding that the anti-psychotics used could somewhat alleviate the abnormal behaviors in these animals.  Keep in mind, the brain is a complicated system: there are many neurotransmitter systems, many of which interact and regulate one another.  Thus, it is possible that disturbances in one system can cause disturbances in another system leading to a particular disease. 

Well, that's about it for this article...we'll see how this animal model for schizophrenia pans out and what new advances it leads to!  I hope you check back again soon!  Thanks!