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SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi. (Klas Kullander)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi. (Klas Kullander)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi. (Klas Kullander)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi. (Klas Kullander)
Visa övriga samt affilieringar
2015 (Engelska)Ingår i: Biological Psychiatry, ISSN 0006-3223, E-ISSN 1873-2402, Vol. 77, nr 6, s. 526-536Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background

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.

Methods

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

Results

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.

Conclusions

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.

Ort, förlag, år, upplaga, sidor
2015. Vol. 77, nr 6, s. 526-536
Nyckelord [en]
Acetylcholine, amphetamine, central nervous system, cocaine, noradrenaline, serotonin, synaptic transmission, transmitter
Nationell ämneskategori
Neurovetenskaper Medicinska och farmaceutiska grundvetenskaper
Forskningsämne
Neurovetenskap
Identifikatorer
URN: urn:nbn:se:uu:diva-214126DOI: 10.1016/j.biopsych.2014.07.017ISI: 000349776000006PubMedID: 25176177OAI: oai:DiVA.org:uu-214126DiVA, id: diva2:684237
Tillgänglig från: 2014-01-07 Skapad: 2014-01-07 Senast uppdaterad: 2018-01-11
Ingår i avhandling
1. Modulation of Neuronal Functions: the Role of SLC10A4
Öppna denna publikation i ny flik eller fönster >>Modulation of Neuronal Functions: the Role of SLC10A4
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Alternativ titel[en]
SLC10A4-Mediated Modulation of Neuronal Functions
Abstract [en]

Mental health of a person depends on the correct functioning of the brain. The brain and the spinal cord contain many types of cells, of which one important type are called the neurons. Neurons are special in the way they connect to each other to form large networks. The chemicals called transmitters are packed at the nerve endings into tiny packets called vesicles and when a signal arrives these vesicles fuse immediately to the attached cell surface and release their contents. The role of the synaptic vesicular transporter proteins is to ensure proper packing of transmitter molecules that can be released upon stimulation. Vesicular packing is an important process. The carrier proteins involved in packing work in coordination to determine the amount and type of transmitters to be packed. Missing a carrier protein from the vesicles might lead to improper packing and inaccurate signaliing. These signaling molecules are known for their implications in many psychiatric and neurological disorders like Alzheimer’s disease, Parkinson’s disease, Schizophrenia, and attention deficit to name just a few. 

How a vesicular transporter can affect the modulatory functions of aminergic neurons is the subject of this thesis. This thesis reports on the effects of the loss of a vesicular orphan transporter. Study I demonstrates the localization of this protein to monoaminergic and cholinergic terminals. It reports the effect of the loss of Slc10A4 on vesicular dopamine uptake, synaptic clearance of dopamine and hypersensitivity of animals to dopamine related psychostimulants. Study I also provides evidence for ATP as a possible ligand for SLC10A4 protein. Study II provides data on the clinical relevance of Slc10A4 in playing a protective role against vulnerability to epilepsy. It reports that loss of Slc10A4 renders the animals hypersensitive to cholinergic drugs. Study III provides a closer look at individual cholinergic synapses at neuromuscular junctions in mice lacking Slc10A4. The structural and electrophysiological properties of the NMJ are found compromised because of the loss of this vesicular protein. Taken together, this thesis presents a SV protein’s perspective of viewing at modulation of synaptic transmission.

Ort, förlag, år, upplaga, sidor
Uppsala: Uppsala universitet, 2014. s. 50
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 964
Nyckelord
dopamine, acetylcholine, central nervous system, neuromuscular junctions, electrophysiology, monoamine, synaptic transmission, neuromodulation
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
Neurovetenskap
Identifikatorer
urn:nbn:se:uu:diva-214162 (URN)978-91-554-8838-3 (ISBN)
Disputation
2014-02-21, B21, Biomedical Centre, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-01-28 Skapad: 2014-01-07 Senast uppdaterad: 2018-01-11
2. Neuronal Networks of Movement: Slc10a4 as a Modulator & Dmrt3 as a Gait-keeper
Öppna denna publikation i ny flik eller fönster >>Neuronal Networks of Movement: Slc10a4 as a Modulator & Dmrt3 as a Gait-keeper
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2014. s. 58
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1026
Nyckelord
Synaptic vesicle transporter, Neuromodulation, Dopamine, Central Pattern Generator, Locomotion, Gait, Horse, Mouse, Commissural Inhibitory Interneuron
Nationell ämneskategori
Neurovetenskaper
Forskningsämne
Neurovetenskap
Identifikatorer
urn:nbn:se:uu:diva-230425 (URN)978-91-554-9030-0 (ISBN)
Disputation
2014-10-24, B21, BMC, Husargatan 3, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2014-10-02 Skapad: 2014-08-25 Senast uppdaterad: 2018-01-11

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Larhammar, MartinPatra, KalicharanBlunder, MartinaEmilsson, LinaPeuckert, ChristianeArvidsson, EmmaWallén-Mackenzie, ÅsaKullander, Klas

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