| 1. |
- Egea, Joaquim, et al.
(författare)
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Regulation of EphA 4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function
- 2005
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Ingår i: Neuron. - : Elsevier BV. - 0896-6273 .- 1097-4199. ; 47:4, s. 515-528
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Tidskriftsartikel (refereegranskat)abstract
- Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4(EE)), whose kinase is constitutively activated in the absence of ephrinB ligands, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4(EE), including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation of ephexin1. These results suggest that signaling of Eph RTKs follows a multistep process of induced kinase activity and higher-order clustering different from RTKs responding to soluble ligands.
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| 2. |
- Haring, Martin, et al.
(författare)
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Neuronal atlas of the dorsal horn defines its architecture and links sensory input to transcriptional cell types
- 2018
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Ingår i: Nature Neuroscience. - : NATURE PUBLISHING GROUP. - 1097-6256 .- 1546-1726. ; 21:6, s. 869-880
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Tidskriftsartikel (refereegranskat)abstract
- The dorsal horn of the spinal cord is critical to processing distinct modalities of noxious and innocuous sensation, but little is known of the neuronal subtypes involved, hampering efforts to deduce principles governing somatic sensation. Here we used single-cell RNA sequencing to classify sensory neurons in the mouse dorsal horn. We identified 15 inhibitory and 15 excitatory molecular subtypes of neurons, equaling the complexity in cerebral cortex. Validating our classification scheme in vivo and matching cell types to anatomy of the dorsal horn by spatial transcriptomics reveals laminar enrichment for each of the cell types. Neuron types, when combined, define a multilayered organization with like neurons layered together. Employing our scheme, we find that heat and cold stimuli activate discrete sets of both excitatory and inhibitory neuron types. This work provides a systematic and comprehensive molecular classification of spinal cord sensory neurons, enabling functional interrogation of sensory processing.
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| 3. |
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| 4. |
- Kullander, Klas, et al.
(författare)
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Role of EphA4 and EphrinB3 in local neuronal circuits that control walking
- 2003
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 299:5614, s. 1889-1892
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Tidskriftsartikel (refereegranskat)abstract
- Local circuits in the spinal cord that generate locomotion are termed central pattern generators (CPGs). These provide coordinated bilateral control over the normal limb alternation that underlies walking. The molecules that organize the mammalian CPG are unknown. Isolated spinal cords from mice lacking either the EphA4 receptor or its ligand ephrinB3 have lost left-right limb alternation and instead exhibit synchrony. We identified EphA4-positive neurons as an excitatory component of the locomotor CPG. Our study shows that dramatic locomotor changes can occur as a consequence of local genetic rewiring and identifies genes required for the development of normal locomotor behavior.
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| 5. |
- Leão, Richardson N., et al.
(författare)
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Medial septal dysfunction by A beta-induced KCNQ channel-block in glutamatergic neurons
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:9, s. 2046-2061
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid beta (A beta) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying A beta toxicity, however, are poorly understood. Here we show that A beta 25-35 and A beta 1-40 acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons A beta increases firing frequency and blocks the A-and the M-current (I-A and I-M, respectively). While the I-A block is similar in other MS neuron classes, the block of I-M is specific to glutamatergic neurons. I-M block and a simulated A beta block mimic the A beta-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. A beta increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that A beta-induced dysfunction of glutamatergic neurons via I-M decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.
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| 6. |
- Leão, Richardson N, et al.
(författare)
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Medial septal dysfunction by Aβ-induced KCNQ channel-block in glutamatergic neurons.
- 2012
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580 .- 1558-1497. ; 33:9, s. 2046-61
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Tidskriftsartikel (refereegranskat)abstract
- Amyloid β (Aβ) peptides play a central role in the pathophysiology of Alzheimer's disease (AD). The cellular mechanisms underlying Aβ toxicity, however, are poorly understood. Here we show that Aβ(25-35) and Aβ(1-40) acutely and differentially affect the characteristics of 3 classes of medial septum (MS) neurons in mice. In glutamatergic neurons Aβ increases firing frequency and blocks the A- and the M-current (I(A) and I(M), respectively). While the I(A) block is similar in other MS neuron classes, the block of I(M) is specific to glutamatergic neurons. I(M) block and a simulated Aβ block mimic the Aβ-induced increase in spontaneous firing in glutamatergic neurons. Calcium imaging shows that under control conditions glutamatergic neurons rarely fire while nonglutamatergic neurons fire coherently at theta frequencies. Aβ increases the firing rate of glutamatergic neurons while nonglutamatergic neurons lose theta firing coherence. Our results demonstrate that Aβ-induced dysfunction of glutamatergic neurons via I(M) decrease diminishes MS rhythmicity, which may negatively affect hippocampal rhythmogenesis and underlie the memory loss observed in Alzheimer's disease.
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| 7. |
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| 8. |
- Zhang, Ming-Dong, et al.
(författare)
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Neuronal calcium-binding proteins 1/2 localize to dorsal root ganglia and excitatory spinal neurons and are regulated by nerve injury
- 2014
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 111:12, s. E1149-E1158
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal calcium (Ca2+)-binding proteins 1 and 2 (NECAB1/2) are members of the phylogenetically conserved EF-hand Ca2+-binding protein superfamily. To date, NECABs have been explored only to a limited extent and, so far, not at all at the spinal level. Here, we describe the distribution, phenotype, and nerve injury-induced regulation of NECAB1/NECAB2 in mouse dorsal root ganglia (DRGs) and spinal cord. In DRGs, NECAB1/2 are expressed in around 70% of mainly small-and medium-sized neurons. Many colocalize with calcitonin gene-related peptide and isolectin B4, and thus represent nociceptors. NECAB1/2 neurons are much more abundant in DRGs than the Ca2+-binding proteins (parvalbumin, calbindin, calretinin, and secretagogin) studied to date. In the spinal cord, the NECAB1/2 distribution is mainly complementary. NECAB1 labels interneurons and a plexus of processes in superficial layers of the dorsal horn, commissural neurons in the intermediate area, and motor neurons in the ventral horn. Using CLARITY, a novel, bilaterally connected neuronal system with dendrites that embrace the dorsal columns like palisades is observed. NECAB2 is present in cell bodies and presynaptic boutons across the spinal cord. In the dorsal horn, most NECAB1/2 neurons are glutamatergic. Both NECAB1/2 are transported into dorsal roots and peripheral nerves. Peripheral nerve injury reduces NECAB2, but not NECAB1, expression in DRG neurons. Our study identifies NECAB1/2 as abundant Ca2+-binding proteins in pain-related DRG neurons and a variety of spinal systems, providing molecular markers for known and unknown neuron populations of mechanosensory and pain circuits in the spinal cord.
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