Ulrik Gether Group – University of Copenhagen

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Neuropharmacology > Research > Ulrik Gether Group

The overall purpose of our research is to achieve insight into molecular, cellular and genetic processes responsible for synaptic signal transmission and how these processes can be modulated by drugs.

Research

The biogenic amines, including dopamine, norepinephrine and serotonin, are some of the most important chemical messengers in the central nervous system, regulating a myriad of different functions, such as mood, sleep, sexual drive, locomotion, cognition, reward mechanisms and neuroendocrine processes. Upon release from the presynaptic nerve terminal the biogenic amines exert their effects by activating distinct post- and presynaptic receptors, which almost exclusively belong to the large superfamily of G protein coupled 7TM receptors. The effects exerted by the biogenic amines are rapidly terminated by presynaptic transport proteins that mediate reuptake of the biogenic amines from the synaptic cleft into the presynaptic nerve terminal. The transport proteins, which belongs to the large family of neurotransmitter:sodium symporters (NSS) (or the solute carrier [SLC] 6 family), tightly control the availability of the biogenic amines in the synaptic cleft and thereby synaptic transmission mediated by these transmitters. While more than twenty five different genes encoding biogenic amine receptors are known, only three distinct transporter proteins for the biogenic amines have been identified, the dopamine transporter (DAT), the norepinephrine transporter (NET), and the serotonin transporter (SERT).

The biogenic amine receptors and transporters are not only playing a key role in neuronal signaling but are also major targets for the action of several widely used drugs, such as antidepressants and antipsychotics. Furthermore, direct inhibition of biogenic amine uptake mediated by the transporters represents the principal mechanism underlying the rewarding and addictive properties of cocaine, amphetamine, ecstasy and related psychostimulants.

The importance of the biogenic amine transporters have recently been further substantiated by observations linking genetic variations in the genes encoding the transporters to neurological and neuropsychiatric disorders. Specifically, missense mutations in the DAT have been linked to parkinsonism both in children and adults as well as DAT missense mutations appear to be a risk factor in neuropsychiatric diseases.

We have build up a strong expertise in studying the molecular, cellular and in vivo function of biogenic amine transporters and receptors. Currently, our main focus is on the dopamine system and on diseases characterized by dysfunctional dopamine homeostasis such as Parkinson’s disease, ADHD, schizophrenia and addiction.

It is the overall goals of our group i) to understand the molecular and cellular processes controlling activity and availability of biogenic amine transporters and receptors in the synapse; ii) to determine how these processes can be altered in diseased states and how they can be modulated by drugs; iii) to gain insight into how genetic variation in the genes encoding biogenic amine transporters and receptors can contribute to diseases characterized by altered biogenic amine homeostasis; and iiii) to use genetic mouse models together with synthetic biology tools, including chemogenetics and optogenetics, to develop models for these diseases and decipher the underlying disease biology.

Our work involves a broad range of methodologies ranging from classical pharmacological assays, cloning techniques and biochemical assays to advanced imaging techniques and use of genetic mouse models. Most recently, we have implemented the use of superresolution microscopy in our studies including PALM (photo-activated localization microscopy) and STORM (stochastic optical reconstruction microscopy). Moreover, we now employ both optogenetic and chemogenetic tools in our in vivo work. While optogenetics enables the use of light to control neuronal activity, chemogenetics enables pharmacological control of neurons by use of reengineered G protein coupled receptors (so called DREADDs) together with synthetic ligands.