Friday, August 24, 2007

Molecular Psychiatry: Schizophrenia Mouse Model

Here's another interesting knockout mouse model for schizophrenia. This was in the July 31 issue of Molecular Psychiatry, "Phospholipase C-1 knockout mice exhibit endophenotypes modeling schizophrenia which are rescued by environmental enrichment and clozapine administration," by McOmish et al., in Australia.

"Phospholipase C-1 (PLC-1) is a rate-limiting enzyme implicated in postnatal-cortical development and neuronal plasticity. PLC-1 transduces intracellular signals from specific muscarinic, glutamate and serotonin receptors, all of which have been implicated in the pathogenesis of schizophrenia. Here, we present data to show that PLC-1 knockout mice display locomotor hyperactivity, sensorimotor gating deficits as well as cognitive impairment. These changes in behavior are regarded as endophenotypes homologous to schizophrenia-like symptoms in rodents. Importantly, the locomotor hyperactivity and sensorimotor gating deficits in PLC-1 knockout mice are subject to beneficial modulation by environmental enrichment. Furthermore, clozapine but not haloperidol (atypical and typical antipsychotics, respectively) rescues the sensorimotor gating deficit in these animals, suggesting selective predictive validity. We also demonstrate a relationship between the beneficial effects of environmental enrichment and levels of M1/M4 muscarinic acetylcholine receptor binding in the neocortex and hippocampus. Thus we have demonstrated a novel mouse model, displaying disruption of multiple postsynaptic signals implicated in the pathogenesis of schizophrenia, a relevant behavioral phenotype and associated gene–environment interactions."
PLC-1 is one of those proteins involved in processing the signal after the receptor is activated. Think of the ignition in your car. If the key is the neurotransmitter, like serotonin (or medication, like Prozac) and the lock (or keyhole) is the receptor, then PLC-1 is one of the wires that connects the lock on the steering column to the starter, which gets the engine going. We are all so used to thinking that what is important is the action at the receptor, but it is easy to forget that there is this whole other layer of machinery that gets engaged once the receptor is activated.

These so-called second messenger systems use a cascade of Rube Goldberg connectors to make things happen. Just like a genetic error can cause a receptor to malfunction, so can errors in this second messenger cascade.

This particular enzyme is involved in the growth and connectivity of brain cells. The researchers show that mice who are engineered to not produce PLC-ß-1 develop cognitive problems which have similarities to those seen in humans with schizophrenia. Changes in the environment can minimize these problems, suggesting that this animal model could be used to test other treatments -- including medications that work very differently from what is out there now -- for potential use in this neurodevelopmental illness.