Canadian team aims to refine 'crude' antipsychotic therapies

Novel peptides fire up healthy neurons — and much clinical interest

By David McLay

The Canadian team, led by Dr Yu Tian Wang, PhD, aims to develop what he describes as a "new generation of therapeutics that can repair brain abnormalities associated with psychiatric disorders, and will have few side effects." Dr Wang is at the University of British Columbia but the group also includes collaborating scientists from the University of Western Ontario and McGill University.

Before they can develop these novel therapies, the researchers are first seeking to understand the intracellular interactions involved in synaptic transmissions between healthy neurons, and how this process changes in diseased neurons. Then, the group will develop compounds that are meant to "disrupt abnormal interactions, but leave normal interactions intact." Their trepans will be small peptides.

MOLDING PLASTICITY
The team's first target is glutamate receptors, which have been linked to synaptic plasticity — a leading model of how the brain learns and remembers. Synaptic plasticity refers to the variability of the strength of a signal transmitted through a synapse — the specialized junction through which cells signal to one another. People with addictions have fewer synapses with active glutamate receptors. The removal of receptors from a cell's surface is regulated by a pathway activated only in affected neurons.

The first peptide Dr Wang created specifically blocks removal of the receptor in affected neurons. After successful in vitro studies, the researchers tested the peptide in an animal model. Their soon to be published results show that administering the peptide to rats blocked the animals from developing new memories associated with addiction in a narcotic self-administration assay.

Besides showing efficacy in treating addiction, this study demonstrated that the drug can be delivered safely in animals, a necessary step towards clinical application. While the results from the rat model apply to the formation of a new addiction, the ultimate goal is to treat established addictions.

INHIBITING AUTISM
Another approach taken in the project is to fine-tune the overall level of excitation in a neuron by adjusting the ratio of excitatory-to-inhibitory presynaptic contacts. The interaction of two proteins, neuroligin and PSD95, determines this ratio during synapse formation. In the September 21, 2004 issue of the Proceedings of the National Academy of Sciences, Dr Alaa El-Husseini, PhD, a member of the Canadian team, describes how altering the levels of neuroligin and PSD95 in cultured neurons changes the ratio of excitatory-to-inhibitory synaptic input.

Dr El-Husseini predicts strategies such as this may be particularly useful in diseases with abnormal synapse formation. And he's looking at autism first. Recent reports have linked autism to deletions in the neuroligin 4 gene, located on the X chromosome. According to Dr El-Husseini's research, a lack of neuroligin would result in an increase in overall excitation. He postulates this increase might play a role in the learning difficulties associated with autism. By adjusting the ratio of excitatory to inhibitory signals perhaps the basal excitation of affected neurons in autistic people could be lowered and synaptic plasticity improved.

If continuing studies are successful, the peptides developed in this project will be a significant advance in antipsychotic therapy. Current drugs target extracellular receptors and block whole signal pathways. They also target indiscriminately, affecting both sick and healthy neurons. In contrast, these peptides work only in affected cells. "We are trying to specifically target abnormal function without targeting normal function," explains Dr Wang. "The advantage over current drug therapy should be fewer side effects." With research still in pre-clinical stages, Dr Wang estimates that the first of these new drugs will be available in five to 10 years.