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Neuronal Networks of Movement: Slc10a4 as a Modulator & Dmrt3 as a Gait-keeper
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics. (Kullander)
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nerve cells are organized into complex networks that comprise the building blocks of our nervous system. Neurons communicate by transmitting messenger molecules released from synaptic vesicles. Alterations in neuronal circuitry and synaptic signaling contribute to a wide range of neurological conditions, often with consequences for movement. Intrinsic neuronal networks in the spinal cord serve to coordinate vital rhythmic motor functions. In spite of extensive efforts to address the organization of these neural circuits, much remains to be revealed regarding the identity and function of specific interneuron cell types and how neuromodulation tune network activity. In this thesis, two novel genes initially identified as markers for spinal neuronal populations were investigated: Slc10a4 and Dmrt3.

The orphan transporter SLC10A4 was found to be expressed on synaptic vesicles of the cholinergic system, including motor neurons, as well as in the monoaminergic system, including dopaminergic, serotonergic and noradrenergic nuclei. Thus, it constitutes a novel molecular denominator shared by these classic neuromodulatory systems. SLC10A4 was found to influence vesicular transport of dopamine and affect neuronal release and reuptake efficiency in the striatum. Mice lacking Slc10a4 displayed impaired monoamine homeostasis and were hypersensitive to the drugs amphetamine and tranylcypromine. These findings demonstrate that SLC10A4 is capable of modulating the modulatory systems of the brain with potential clinical relevance for neurological and mental disorders.

The transcription factor encoded by Dmrt3 was found to be expressed in a population of inhibitory commissural interneurons originating from the dorsal interneuron 6 (dI6) domain in the spinal cord. In parallel, a genome-wide association study revealed that a non-sense mutation in horse DMRT3 is permissive for the ability to perform pace among other alternate gaits. Further analysis of Dmrt3 null mutant mice showed that Dmrt3 has a central role for spinal neuronal network development with consequences for locomotor behavior. The dI6 class has been suggested to take part in motor circuits but remains one of the least studied classes due to lack of molecular markers. To further investigate the Dmrt3-derived neurons, and the dI6 population in general, a Dmrt3Cre mouse line was generated which allowed for characterization on the molecular, cellular and  behavioral level. It was found that Dmrt3 neurons synapse onto motor neurons, receive extensive synaptic inputs from various neuronal sources and are rhythmically active during fictive locomotion. Furthermore, silencing of Dmrt3 neurons in Dmrt3Cre;Viaatlx/lx mice led to impaired motor coordination and alterations in gait, together demonstrating the importance of this neuronal population in the control of movement.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 58 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1026
Keyword [en]
Synaptic vesicle transporter, Neuromodulation, Dopamine, Central Pattern Generator, Locomotion, Gait, Horse, Mouse, Commissural Inhibitory Interneuron
National Category
Research subject
URN: urn:nbn:se:uu:diva-230425ISBN: 978-91-554-9030-0OAI: oai:DiVA.org:uu-230425DiVA: diva2:745033
Public defence
2014-10-24, B21, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2014-10-02 Created: 2014-08-25 Last updated: 2015-01-23
List of papers
1. SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
Open this publication in new window or tab >>SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
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2015 (English)In: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, no 6, 526-536 p.Article in journal (Refereed) Published
Abstract [en]


The neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.


We used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.


We show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice overexpressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine.


Our results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.

Acetylcholine, amphetamine, central nervous system, cocaine, noradrenaline, serotonin, synaptic transmission, transmitter
National Category
Neurosciences Basic Medicine
Research subject
urn:nbn:se:uu:diva-214126 (URN)10.1016/j.biopsych.2014.07.017 (DOI)000349776000006 ()25176177 (PubMedID)
Available from: 2014-01-07 Created: 2014-01-07 Last updated: 2016-04-24
2. Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
Open this publication in new window or tab >>Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice
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2012 (English)In: Nature, ISSN 0028-0836, Vol. 488, no 7413, 642-646 p.Article in journal (Refereed) Published
Abstract [en]

Locomotion in mammals relies on a central pattern-generating circuitry of spinal interneurons established during development that coordinates limb movement(1). These networks produce left-right alternation of limbs as well as coordinated activation of flexor and extensor muscles(2). Here we show that a premature stop codon in the DMRT3 gene has a major effect on the pattern of locomotion in horses. The mutation is permissive for the ability to perform alternate gaits and has a favourable effect on harness racing performance. Examination of wild-type and Dmrt3-null mice demonstrates that Dmrt3 is expressed in the dI6 subdivision of spinal cord neurons, takes part in neuronal specification within this subdivision, and is critical for the normal development of a coordinated locomotor network controlling limb movements. Our discovery positions Dmrt3 in a pivotal role for configuring the spinal circuits controlling stride in vertebrates. The DMRT3 mutation has had a major effect on the diversification of the domestic horse, as the altered gait characteristics of a number of breeds apparently require this mutation.

National Category
Biological Sciences
urn:nbn:se:uu:diva-181404 (URN)10.1038/nature11399 (DOI)000308095100053 ()
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2015-01-23Bibliographically approved
3. Dmrt3 derived neurons are “Gait-keepers” in spinal locomotor circuitry
Open this publication in new window or tab >>Dmrt3 derived neurons are “Gait-keepers” in spinal locomotor circuitry
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(English)Manuscript (preprint) (Other academic)
National Category
Research subject
urn:nbn:se:uu:diva-230429 (URN)
Neuronal Networks of Movement
Available from: 2014-08-25 Created: 2014-08-25 Last updated: 2015-01-23

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