Potential new target for schizophrenia drugs identified

Receptors such as the one linked to Norbin, known as mGluR5, are proteins that are embedded in the plasma membrane of a cell and respond to small molecules called ligands. As mGluR5 binds to its ligand it responds by changing its shape, which ultimately leads to the initiation of an intracellular signal. Several classes of receptors exist, the most common of which is the G-protein coupled receptor (GPCR).

"Proteins that modulate GPCR functions are becoming as important as the receptors themselves because they represent novel therapeutic targets," says Marc Flajolet, a senior research associate in Rockefeller's Laboratory of Molecular and Cellular Neuroscience headed by Paul Greengard. "About half of the drugs commercially available today target this group."

Glutamate, one of the most important neurotransmitters, acts through several GPCRs. These receptors are involved in normal processes such as development, learning and memory, as well as in various diseases.

Flajolet and first author Hong Wang searched for proteins that physically interact with mGluR5 and found several, including Norbin. The researchers paired Norbin and mGluR5 in cultured neurons and found that Norbin not only stimulated mGluR5 activity but also increased the amount of mGluR5 on the surface of the neurons.

Fajolet and Wang then looked at Norbin's effects on mGluR5 in the adult mouse brain, and found Norbin in the hippocampus, amygdala, septum and nucleus accumbens, similar to where mGluR5 is typically found.

The researchers went on to create conditional knockout mice, which are genetically engineered to shut off Norbin production after birth. These mice showed deficits in synaptic plasticity and behavior similar to those found in a rodent model of schizophrenia. For example, the Norbin knockouts were startled by a loud noise as much as normal mice, but were unable to suppress a startle response with subsequent exposure to noise.

"Our work further demonstrates the importance of GPCR regulatory proteins," says Flajolet. "We are now investigating the mechanism by which Norbin affects mGluR5 and are searching for regulatory pathways that could modify Norbin function and, indirectly, mGluR5 activity."