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Patra, Kalicharan
Publications (10 of 10) Show all publications
Larhammar, M., Patra, K., Blunder, M., Emilsson, L., Peuckert, C., Arvidsson, E., . . . Kullander, K. (2015). SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis. Biological Psychiatry, 77(6), 526-536
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, p. 526-536Article in journal (Refereed) 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.

Keywords
Acetylcholine, amphetamine, central nervous system, cocaine, noradrenaline, serotonin, synaptic transmission, transmitter
National Category
Neurosciences Basic Medicine
Research subject
Neuroscience
Identifiers
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: 2018-01-11
Patra, K. (2014). Modulation of Neuronal Functions: the Role of SLC10A4. (Doctoral dissertation). Uppsala: Uppsala universitet
Open this publication in new window or tab >>Modulation of Neuronal Functions: the Role of SLC10A4
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[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.

Place, publisher, year, edition, pages
Uppsala: Uppsala universitet, 2014. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 964
Keywords
dopamine, acetylcholine, central nervous system, neuromuscular junctions, electrophysiology, monoamine, synaptic transmission, neuromodulation
National Category
Neurosciences
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-214162 (URN)978-91-554-8838-3 (ISBN)
Public defence
2014-02-21, B21, Biomedical Centre, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2014-01-28 Created: 2014-01-07 Last updated: 2018-01-11
Wootz, H., FitzSimons-Kantamneni, E., Larhammar, M., Rotterman, T. M., Enjin, A., Patra, K., . . . Alvarez, F. J. (2013). Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model. Journal of Comparative Neurology, 521(7), 1449-1469
Open this publication in new window or tab >>Alterations in the motor neuron-renshaw cell circuit in the Sod1(G93A) mouse model
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2013 (English)In: Journal of Comparative Neurology, ISSN 0021-9967, E-ISSN 1096-9861, Vol. 521, no 7, p. 1449-1469Article in journal (Refereed) Published
Abstract [en]

Motor neurons become hyperexcitable during progression of amyotrophic lateral sclerosis (ALS). This abnormal firing behavior has been explained by changes in their membrane properties, but more recently it has been suggested that changes in premotor circuits may also contribute to this abnormal activity. The specific circuits that may be altered during development of ALS have not been investigated. Here we examined the Renshaw cell recurrent circuit that exerts inhibitory feedback control on motor neuron firing. Using two markers for Renshaw cells (calbindin and cholinergic nicotinic receptor subunit alpha2 [Chrna2]), two general markers for motor neurons (NeuN and vesicular acethylcholine transporter [VAChT]), and two markers for fast motor neurons (Chondrolectin and calcitonin-related polypeptide alpha [Calca]), we analyzed the survival and connectivity of these cells during disease progression in the Sod1G93A mouse model. Most calbindin-immunoreactive (IR) Renshaw cells survive to end stage but downregulate postsynaptic Chrna2 in presymptomatic animals. In motor neurons, some markers are downregulated early (NeuN, VAChT, Chondrolectin) and others at end stage (Calca). Early downregulation of presynaptic VAChT and Chrna2 was correlated with disconnection from Renshaw cells as well as major structural abnormalities of motor axon synapses inside the spinal cord. Renshaw cell synapses on motor neurons underwent more complex changes, including transitional sprouting preferentially over remaining NeuN-IR motor neurons. We conclude that the loss of presynaptic motor axon input on Renshaw cells occurs at early stages of ALS and disconnects the recurrent inhibitory circuit, presumably resulting in diminished control of motor neuron firing.

Keywords
amyotrophic lateral sclerosis, recurrent inhibition, VAChT, synapses
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-198594 (URN)10.1002/cne.23266 (DOI)000316421900001 ()
Available from: 2013-04-23 Created: 2013-04-22 Last updated: 2017-12-06Bibliographically approved
Zelano, J., Mikulovic, S., Patra, K., Kühnemund, M., Larhammar, M., Emilsson, L., . . . Kullander, K. (2013). The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants. Experimental Neurology, 239, 73-81
Open this publication in new window or tab >>The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants
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2013 (English)In: Experimental Neurology, ISSN 0014-4886, E-ISSN 1090-2430, Vol. 239, p. 73-81Article in journal (Refereed) Published
Abstract [en]

The expanding number of disease-causing dysfunctions of synaptic proteins illustrates the importance of investigating newly discovered proteins involved in neuronal transmission. The gene Slc10A4 encodes a recently described carrier protein present in pre-synaptic terminals of cholinergic and monoaminergic neurons. The biological significance of this recently described transporter protein is currently unknown. We here investigated whether absence of the Slc10a4 protein has any impact on function of the cholinergic system. We first investigated the sensitivity of Slc10a4 null mice to cholinergic stimulus in vitro. In contrast to wild type mice, gamma oscillations occurred spontaneously in hippocampal slices from Slc10a4 null mice. Furthermore, moderate treatment of Slc10a4 null slices with the cholinergic agonist carbachol induced epileptiform activity. In vivo, 3-channel EEG measurements in freely behaving mice revealed that Slc10a4 null mice had frequent epileptiform spike-activity before treatment, and developed epileptic seizures, detected by EEG and accompanied by observable behavioral components, more rapidly after injection of the cholinergic agonist pilocarpine. Similar results were obtained on non-operated mice, as evaluated by behavioral seizures and post mortem c-Fos immunohistochemistry. Importantly, Slc10a4 null mice and wild type control mice were equally sensitive to the glutamatergic chemoconvulsant kainic acid, demonstrating that absence of Slc10a4 led to a selective cholinergic hypersensitivity. In summary, we report that absence of the recently discovered synaptic vesicle protein Slc10a4 results in increased sensitivity to cholinergic stimulation.

National Category
Medical Genetics
Research subject
Neurology
Identifiers
urn:nbn:se:uu:diva-184841 (URN)10.1016/j.expneurol.2012.09.006 (DOI)000313765000009 ()23022458 (PubMedID)
Note

Correction in: EXPERIMENTAL NEUROLOGY  Volume: 247   Pages: 750-750   DOI: 10.1016/j.expneurol.2013.01.030

Available from: 2012-11-15 Created: 2012-11-15 Last updated: 2018-01-12Bibliographically approved
Hanell, A., Clausen, F., Djupsjö, A., Vallstedt, A., Patra, K., Israelsson, C., . . . Marklund, N. (2012). Functional and Histological Outcome after Focal Traumatic Brain Injury Is Not Improved in Conditional EphA4 Knockout Mice. Journal of Neurotrauma, 29(17), 2660-2671
Open this publication in new window or tab >>Functional and Histological Outcome after Focal Traumatic Brain Injury Is Not Improved in Conditional EphA4 Knockout Mice
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2012 (English)In: Journal of Neurotrauma, ISSN 0897-7151, E-ISSN 1557-9042, Vol. 29, no 17, p. 2660-2671Article in journal (Refereed) Published
Abstract [en]

We investigated the role of the axon guidance molecule EphA4 following traumatic brain injury (TBI) in mice. Neutralization of EphA4 improved motor function and axonal regeneration following experimental spinal cord injury (SCI). We hypothesized that genetic absence of EphA4 could improve functional and histological outcome following TBI. Using qRT-PCR in wild-type (WT) mice, we evaluated the EphA4 mRNA levels following controlled cortical impact (CCI) TBI or sham injury and found it to be downregulated in the hippocampus (p < 0.05) but not the cortex ipsilateral to the injury at 24 h post-injury. Next, we evaluated the behavioral and histological outcome following CCI using WT mice and Emx1-Cre-driven conditional knockout (cKO) mice. In cKO mice, EphA4 was completely absent in the hippocampus and markedly reduced in the cortical regions from embryonic day 16, which was confirmed using Western blot analysis. EphA4 cKO mice had similar learning and memory abilities at 3 weeks post-TBI compared to WT controls, although brain-injured animals performed worse than sham-injured controls (p < 0.05). EphA4 cKO mice performed similarly to WT mice in the rotarod and cylinder tests of motor function up to 29 days post-injury. TBI increased cortical and hippocampal astrocytosis (GFAP immunohistochemistry, p < 0.05) and hippocampal sprouting (Timm stain, p < 0.05) and induced a marked loss of hemispheric tissue (p < 0.05). EphA4 cKO did not alter the histological outcome. Although our results may argue against a beneficial role for EphA4 in the recovery process following TBI, further studies including post-injury pharmacological neutralization of EphA4 are needed to define the role for EphA4 following TBI.

Keywords
axonal regeneration, behavior, traumatic brain injury
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-190345 (URN)10.1089/neu.2012.2376 (DOI)000311856400007 ()
Available from: 2013-01-09 Created: 2013-01-07 Last updated: 2018-01-11Bibliographically approved
Andersson, L. S., Larhammar, M., Memic, F., Wootz, H., Schwochow, D., Rubin, C.-J., . . . Kullander, K. (2012). Mutations in DMRT3 affect locomotion in horses and spinal circuit function in mice. Nature, 488(7413), 642-646
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, E-ISSN 1476-4687, Vol. 488, no 7413, p. 642-646Article 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
Identifiers
urn:nbn:se:uu:diva-181404 (URN)10.1038/nature11399 (DOI)000308095100053 ()
Available from: 2012-09-28 Created: 2012-09-24 Last updated: 2017-12-07Bibliographically approved
Leão, R. N., Mikulovic, S., Leão, K. E., Munguba, H., Gezelius, H., Enjin, A., . . . Kullander, K. (2012). OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons. Nature Neuroscience, 15(11), 1524-1530
Open this publication in new window or tab >>OLM interneurons differentially modulate CA3 and entorhinal inputs to hippocampal CA1 neurons
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2012 (English)In: Nature Neuroscience, ISSN 1097-6256, E-ISSN 1546-1726, Vol. 15, no 11, p. 1524-1530Article in journal (Refereed) Published
Abstract [en]

The vast diversity of GABAergic interneurons is believed to endow hippocampal microcircuits with the required flexibility for memory encoding and retrieval. However, dissection of the functional roles of defined interneuron types has been hampered by the lack of cell-specific tools. We identified a precise molecular marker for a population of hippocampal GABAergic interneurons known as oriens lacunosum-moleculare (OLM) cells. By combining transgenic mice and optogenetic tools, we found that OLM cells are important for gating the information flow in CA1, facilitating the transmission of intrahippocampal information (from CA3) while reducing the influence of extrahippocampal inputs (from the entorhinal cortex). Furthermore, we found that OLM cells were interconnected by gap junctions, received direct cholinergic inputs from subcortical afferents and accounted for the effect of nicotine on synaptic plasticity of the Schaffer collateral pathway. Our results suggest that acetylcholine acting through OLM cells can control the mnemonic processes executed by the hippocampus.

National Category
Basic Medicine
Identifiers
urn:nbn:se:uu:diva-184961 (URN)10.1038/nn.3235 (DOI)000310424900012 ()
Available from: 2012-11-15 Created: 2012-11-15 Last updated: 2018-01-12Bibliographically approved
Motallebipour, M., Ameur, A., Bysani, M. R., Patra, K., Wallerman, O., Mangion, J., . . . Wadelius, C. (2009). Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq. Genome Biology, 10(11), R129
Open this publication in new window or tab >>Differential binding and co-binding pattern of FOXA1 and FOXA3 and their relation to H3K4me3 in HepG2 cells revealed by ChIP-seq
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2009 (English)In: Genome Biology, ISSN 1465-6906, E-ISSN 1474-760X, Vol. 10, no 11, p. R129-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: The forkhead box/winged helix family members FOXA1, FOXA2, and FOXA3 are of high importance in development and specification of the hepatic linage and the continued expression of liver-specific genes. RESULTS: Here, we present a genome-wide location analysis of FOXA1 and FOXA3 binding sites in HepG2 cells through chromatin immunoprecipitation with detection by sequencing (ChIP-seq) studies and compare these with our previous results on FOXA2. We found that these factors often bind close to each other in different combinations and consecutive immunoprecipitation of chromatin for one and then a second factor (ChIP-reChIP) shows that this occurs in the same cell and on the same DNA molecule, suggestive of molecular interactions. Using co-immunoprecipitation, we further show that FOXA2 interacts with both FOXA1 and FOXA3 in vivo, while FOXA1 and FOXA3 do not appear to interact. Additionally, we detected diverse patterns of trimethylation of lysine 4 on histone H3 (H3K4me3) at transcriptional start sites and directionality of this modification at FOXA binding sites. Using the sequence reads at polymorphic positions, we were able to predict allele specific binding for FOXA1, FOXA3, and H3K4me3. Finally, several SNPs associated with diseases and quantitative traits were located in the enriched regions. CONCLUSIONS: We find that ChIP-seq can be used not only to create gene regulatory maps but also to predict molecular interactions and to inform on the mechanisms for common quantitative variation.

National Category
Medical and Health Sciences Biological Sciences
Identifiers
urn:nbn:se:uu:diva-119751 (URN)10.1186/gb-2009-10-11-r129 (DOI)000273344600016 ()19919681 (PubMedID)
Note

De två (2) första författarna delar förstaförfattarskapet.

Available from: 2010-03-01 Created: 2010-03-01 Last updated: 2017-12-12Bibliographically approved
Wallerman, O., Motallebipour, M., Enroth, S., Patra, K., Bysani, M. S., Komorowski, J. & Wadelius, C. (2009). Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing. Nucleic Acids Research, 37(22), 7498-7508
Open this publication in new window or tab >>Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing
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2009 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 22, p. 7498-7508Article in journal (Refereed) Published
Abstract [en]

Gene expression is regulated by combinations of transcription factors, which can be mapped to regulatory elements on a genome-wide scale using ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here, we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. Distal elements with USF2 signal was frequently bound also by HNF4a and FOXA2. GABP peaks were found at transcription start sites, whereas 94% of FOXA2 and 90% of HNF4a peaks were located at other positions. We developed a method to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An interaction between HNF4a and GABP was seen at TSS, with one-third of the HNF4a positive promoters being bound also by GABP, and this interaction was verified by co-immunoprecipitations.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-198454 (URN)10.1093/nar/gkp823 (DOI)19822575 (PubMedID)
Note

De två första författarna delar förstaförfattarskapet.

Available from: 2013-04-21 Created: 2013-04-15 Last updated: 2017-12-06Bibliographically approved
Wallerman, O., Motallebipour, M., Enroth, S., Patra, K., Bysani, M. R., Komorowski, J. & Wadelius, C. (2009). Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing. Nucleic Acids Research, 37(22), 7498-7508
Open this publication in new window or tab >>Molecular interactions between HNF4a, FOXA2 and GABP identified at regulatory DNA elements through ChIP-sequencing
Show others...
2009 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 22, p. 7498-7508Article in journal (Refereed) Published
Abstract [en]

Gene expression is regulated by combinations of transcription factors, which can be mapped to regulatory elements on a genome-wide scale using ChIP experiments. In a previous ChIP-chip study of USF1 and USF2 we found evidence also of binding of GABP, FOXA2 and HNF4a within the enriched regions. Here, we have applied ChIP-seq for these transcription factors and identified 3064 peaks of enrichment for GABP, 7266 for FOXA2 and 18783 for HNF4a. Distal elements with USF2 signal was frequently bound also by HNF4a and FOXA2. GABP peaks were found at transcription start sites, whereas 94% of FOXA2 and 90% of HNF4a peaks were located at other positions. We developed a method to accurately define TFBS within peaks, and found the predicted sites to have an elevated conservation level compared to peak centers; however the majority of bindings were not evolutionary conserved. An interaction between HNF4a and GABP was seen at TSS, with one-third of the HNF4a positive promoters being bound also by GABP, and this interaction was verified by co-immunoprecipitations.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-121011 (URN)10.1093/nar/gkp823 (DOI)000272935000022 ()19822575 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2017-12-12Bibliographically approved
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