Dr. Kathryn Partin

For the millions of people who suffer from them, the mental illnesses of depression and schizophrenia are destructive and disabling diseases with limited treatment options that frustrate patients and doctors alike. But in the laboratory of Dr. Kathryn Partin, testing is underway on a family of compounds that may one day provide another option for treatment of these debilitating conditions.

“Cognition-enhancing drugs, like those used to treat dementia and cognitive declines due to aging or diseases such as Alzheimer’s, seem to have therapeutic application in the treatment of mental illnesses including depression and schizophrenia,” said Dr. Partin, who is a Professor in the Department of Biomedical Sciences and Director of Colorado State University’s Molecular, Cellular, and Integrative Neurosciences Program. “This is an enormous population of people with stubbornly hard-to-treat mental illnesses so it’s very exciting to be part of a research program that could provide them with new hope for the future.”

Dr. Partin and her team are investigating compounds that enhance communication between nerve cells by forcing the channels of communication to stay open a little bit longer. In particular, they are looking at compounds that impact the function of glutamate receptors, a primary mediator at neuronal synapses that plays a critical role in cognition. Their most recent paper was published in May in Molecular Pharmacology on two new compounds that regulate a specific type of glutamate receptor.

Glutamate is one of the 20 amino acids used to assemble proteins in the human body and is particularly abundant in the nervous system where it functions as a neurotransmitter. Glutamate receptors are located primarily on the membranes of neuronal cells where they serve an important role in neural communication, memory formation, learning, and regulation.

“When we have an experience, the presynaptic and postsynaptic cells in our brain communicate,” said Dr. Partin. “The first cell will release glutamate and the second cell will have a glutamate receptor to receive the glutamate. What happens with some of the mental health diseases is that this communication is cut off. There may not be enough receptors, or they aren’t healthy, or the responders may be broken. What we want to do is force the glutamate faucet to open a little wider and stay open a little longer to help bond the presynaptic and postsynaptic cells together to encode a memory.

“For reasons we don’t yet understand, this improvement in cognition potential seems to help improve the symptoms of chronic mental illnesses such as depression and schizophrenia. It might be because these compounds help improve memory tone, a similar idea to muscle tone, and give the brain a bigger tool kit from which to function in a healthier way.”

Dr. Partin’s work focuses on the AMPA glutamate receptor family, named after the agonist that binds to it with a high degree of specificity. An agonist is a compound, in this case AMPA, that binds to a receptor of a cell and triggers a response. Glutamate receptors, and in particular the AMPA receptor family, are unique among ligand-gated ion channels in that they desensitize very rapidly, allowing the channel to close despite the fact that glutamate is still bound to its receptor.

“Part of what we are looking at is how effective specific compounds are at blocking or slowing down desensitization,” said Dr. Partin, whose research is funded by the National Institutes of Health. “We partner with drug companies to match compounds to specific receptor types, and then drug companies can take that information and further investigate the best drug candidates -- compounds that achieve the desired therapeutic effects and can be made ‘druggable’ – and eventually bring new therapeutics to the market.”

Dr. Partin receives select compounds from the libraries of several different pharmaceutical companies to look specifically at activity of those compounds, called ampakines, on AMPA receptors. Ampakines have a high degree of specificity to glutamate AMPA receptors with which they strongly interact. They are known to enhance attention span and aid in learning and memory. There currently are ampakines in clinical trials, particularly being developed as anti-drowsiness medications (for use, for example, by airline pilots on long flights), as well as for treatment of narcolepsy and regulation of sleep. In Dr. Partin’s laboratory, her team conducts a number of assays from molecular activity to physiological activity to assess basic mechanisms and uncover compounds with therapeutic potential.

“When we find a molecule that does something fun, I’m dancing around the laboratory because I know each time we make a discovery it has the potential to change lives,” said Dr. Partin. “I do pre-clinical work, and then you have Phase 1, 2, and 3 clinical trials. It takes 10 years to get a new drug to market, but if we don’t start here those new drugs may not be available when I need them, or someone else needs them. We can’t let those people down, so we have to keep trying. You never know when the next life-changing drug will happen.”