Investigating drug mechanisms in psychiatric disease: an interview with Dr. Jardemark and Dr. Sinclair, Karolinska Institutet
Here we meet Dr. Kent Jardemark, Associate Professor, and Dr. Jon Sinclair, Researcher, at the Karolinska Institutet, Stockholm. Their lab is part of the Division of Pharmacology – one of the top ranked pharmacology departments in the world – and their research is focused on the drug mechanisms related to psychiatric diseases, including schizophrenia and major depression.
In this interview, Dr. Jardemark and Dr. Sinclair discuss their work, and how Cellectricon’s Dynaflow® Resolve automated perfusion system is frequently utilized to aid this research.
What is the current area of research within your group?
We are mainly focusing on the actions of drugs on cognitive symptoms in psychiatric diseases such as schizophrenia, bipolar disorder and major depression. In our research, we want to use an applied approach to problem solving (e.g. to find a better pharmacologically-based treatment to the disease) rather than just looking at basic physiological functions related to the brain.
To do this, we are using existing, clinically-tested drugs with known functioning pharmacological properties in patients. Although these drugs have been around for decades and have proven therapeutic value in patients, there is still much unknown about how they act on the cellular level and on neuronal networks. Deducing the specific ways these drugs modulate neuronal networks related to specific symptoms, for example cognitive symptoms, will enable us to better understand the mechanisms of these drugs and hopefully propose new strategies to design more efficient drugs with less side-effects.
We are also involved in two collaborations with other groups that focus on pain in rheumatoid arthritis and cardiac disease. In these collaborations we mainly assist with our expertise in running electrophysiological recordings.
Isn’t that a rather broad scope of research?
It may seem to be. However, when you look at what is effective in terms of pharmacology and also which genes ‘pop-up’ in genetic studies, these psychiatric diseases seem to be more or less connected with regards to the cellular mechanisms that are involved.
From another point of view, the brain area that we are mostly interested in, the prefrontal cortex, is also thought to be key for the cognitive function working memory. What you can see is that in patients with these diseases (e.g. schizophrenia and major depression), there is a clear disturbance of working memory.
Finally, with our collaboration work, we try to avoid narrowing our field down too far so that we can partner with different groups and take forward the good ideas that are generated by other high quality research. Another aspect is to generate funding and one part is that it is challenging and fun to work with new research areas.
What techniques are you using in your lab?
We mainly use electrophysiology techniques and we have the capability for doing everything, from in vivo recordings to single channel analyses. We also have access to behaviour models, microdialyses and imaging.
Why are you using the Dynaflow Resolve system?
For us it’s one of the most easy to use and robust perfusion systems available for single cell whole cell patch-clamp. We pretty much use it as an all-purpose perfusion system. You almost never have trouble with unstable flows, you have reliable solution exchange times and, since it’s made of glass, it’s easy to clean and there is minimal risk for cross contamination compared to plastic tubing systems.
The drawback is that it’s does not work if you are interested in cell-to-cell connectivity, but we prefer to do that kind of studies in brain slices anyway and then you are stuck with slow bath perfusion.
Can you exemplify for which applications you use Dynaflow Resolve – how you use the system in your research and the rationale behind it?
We are working with acutely isolated prefrontal cortical pyramidal neurons, to try to understand the postsynaptic effects of drugs such as clozapine and ketamine. In comparison, most of the experiments in slices show mainly presynaptic activity. In isolated neurons we are measuring the effect of the drugs on NMDA- and AMPA-induced currents. These drugs do not directly open and close the ion channels and the Dynaflow Resolve chip enables us to apply rather complex series of drug applications. It also enables us to test different combinations of applications to the same cell. This is of great value, since it is quite hard to get many cells from each preparation and therefore we want to maximize the amount of information we can get from each cell.
The ability to exactly program and optimize the channel times is also of great help to create very standardized experimental protocols. This is especially important as these cells have a variety of receptors and can behave differently from one another (compared to cloned receptors in cell lines where you only get what you put in and thereby you do not get new information apart from the interaction between the receptor and your molecule). This obviously gives a need for very accurate experimental protocols which we get when using the Dynaflow system.
For the pain project our starting point was quite different. Here we were actually approached by another research group after they heard us talk about the Dynaflow system. They are working with a novel target for pain activation where they use an expensive human-derived antibody which they want to apply to DRG neurons. Their basic need was to have the lowest substance consumption possible, and here the Dynaflow chip fitted as hand in glove. The patch-clamp experiments themselves are fairly standard, applying substances in different concentrations and applying one dose of capsaicin to confirm that the cell is the right sort. We also see a clear benefit from using the Dynaflow system in that it enables us to get very stable recordings and that it increases the throughput when looking at cells surviving many compound applications.
Lastly, we run recordings on acutely isolated cardiac myocytes. Here, we measure l-type calcium channels and we are working from mice that have been on different diets.
Thank you for providing an insight into your research. Do you have any additional comments?
We are hoping that more pharmacology research will use more complex and disease-related model systems rather than using cloned receptors in cell lines, which so far has generated a lot of good chemistry but not really any good drugs. We are also hoping that technology companies such as Cellectricon continue to develop tools such as the Dynaflow system to increase the throughput in more complex model systems such as acutely isolated cells and slices.
Kent Jardemark, PI and Associate Professor of Pharmacology at Karolinska Institutet
Since 1992, Dr. Jardemark has expertise in electrophysiological techniques and pharmacological research. He has had industrial collaborations with established pharmaceutical companies (e.g. AstraZeneca, Merck, A/S Lundbeck, Pfizer etc) in pharmacological projects. He has also collaborated with Cellectricon AB and Pronexus Analytical AB, in developing novel technology which will be used in preclinical research with the purpose of investigating the mechanisms of drugs (e.g. antipsychotic and antidepressant drugs) on various neurotransmitter systems in the central nervous system.
Jon Sinclair, researcher at Karolinska Institutet
Since 2001, Dr Sinclair has expertise in developing tools and assays for Ion Channel research and imaging, He is one of the inventors and developers to the Dynflow system for ion channel screening and has more than 10 years’ experience from working with customer driven assay development first as VP of R&D at Cellectricon AB and then as Group leader for Ion channels at Inovacia AB, both companies focusing on delivering results for the pharma industry he has been responsible for several large customer financed projects for screening of membrane proteins working with amongst others Astra Zeneca, Merck etc, and several academic institutions around the world.