Loss of Inhibitory Interneurons in the Dorsal Spinal Cord and Elevated Itch in Bhlhb5 Mutant Mice

Ross, Sarah E.; Mardinly, Alan R.; McCord, Alejandra E.; Zurawski, Jonathan; Cohen, Sonia; Jung, Cynthia C.; Hu, Linda; Mok, Stéphanie; Shah, Alap; Savner, Erin M.; Tolias, Christos M.; Corfas, Roman; Chen, Suzhen; Inquimbert, Perrine; Xu, Yi; McInnes, Roderick R.; Rice, Frank L.; Corfas, Gabriel; Ma, Qiufu; Woolf, Clifford J.; Greenberg, Michael E.

doi:10.1016/j.neuron.2010.02.025

Cited by 380 publications

(381 citation statements)

References 49 publications

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“…Thus, the output of projection neurons is influenced by local excitatory and inhibitory neurons (Todd, 2010;Larsson and Broman, 2011). The balance between excitation and inhibition is crucial for maintaining normal sensory function (Basbaum et al, 2009;Costigan et al, 2009;Ross et al, 2010;Takazawa and MacDermott, 2010). Among the two distinct sets of transmitter and peptide receptors, deletion of Npy1r results in a pronounced mechanical hypersensitivity, suggesting that Npy1r plays an important role in the control of transmission of sensory information (Naveilhan et al, 2001;Shi et al, 2006).…”

Section: Potential Role Of Selector Genes In Controlling Expression Omentioning

confidence: 99%

Tlx1/3 and Ptf1a Control the Expression of Distinct Sets of Transmitter and Peptide Receptor Genes in the Developing Dorsal Spinal Cord

Guo

Zhao²,

Huang³

et al. 2012

Journal of Neuroscience

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Establishing the pattern of expression of transmitters and peptides as well as their receptors in different neuronal types is crucial for understanding the circuitry in various regions of the brain. Previous studies have demonstrated that the transmitter and peptide phenotypes in mouse dorsal spinal cord neurons are determined by the transcription factors Tlx1/3 and Ptf1a. Here we show that these transcription factors also determine the expression of two distinct sets of transmitter and peptide receptor genes in this region. We have screened the expression of 78 receptor genes in the spinal dorsal horn by in situ hybridization. We found that receptor genes Gabra1, Gabra5, Gabrb2, Gria3, Grin3a, Grin3b, Galr1, and Npy1r were preferentially expressed in Tlx3-expressing glutamatergic neurons and their derivatives, and deletion of Tlx1 and Tlx3 resulted in the loss of expression of these receptor genes. Furthermore, we obtained genetic evidence that Tlx3 uses distinct pathways to control the expression of receptor genes. We also found that receptor genes Grm3, Grm4, Grm5, Grik1, Grik2, Grik3, and Sstr2 were mainly expressed in Pax2-expressing GABAergic neurons in the spinal dorsal horn, and their expression in this region was abolished or markedly reduced in Ptf1a and Pax2 deletion mutant mice. Together, our studies indicate that Tlx1/3 and Ptf1a, the key transcription factors for fate determination of glutamatergic and GABAergic neurons in the dorsal spinal cord, are also responsible for controlling the expression of two distinct sets of transmitter and peptide receptor genes.

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Section: Potential Role Of Selector Genes In Controlling Expression Omentioning

confidence: 99%

Tlx1/3 and Ptf1a Control the Expression of Distinct Sets of Transmitter and Peptide Receptor Genes in the Developing Dorsal Spinal Cord

Guo

Zhao²,

Huang³

et al. 2012

Journal of Neuroscience

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“…A set of transcription factors, including Gsx1/2, Tlx1/3, Ptf1a, and Lbx1, has been found to specify the glutamatergic versus GABAergic cell fates in the dorsal horn (Gross et al, 2002;Müller et al, 2002;Cheng et al, 2004Cheng et al, , 2005Glasgow et al, 2005;Mizuguchi et al, 2006). Furthermore, some additional transcription factors control the specification and the migration of subsets of dorsal horn neurons, and are required for the generation of normal pain and itch sensation (Chen et al, 2001;Ding et al, 2004;Holstege et al, 2008;Rottkamp et al, 2008;Rebelo et al, 2010;Ross et al, 2010). How neurons in laminae III/IV of the dorsal horn are specified during development remains largely unknown.…”

Section: Transcriptional Control Of Development Of Dorsal Horn Neuronsmentioning

confidence: 99%

c-Maf Is Required for the Development of Dorsal Horn Laminae III/IV Neurons and Mechanoreceptive DRG Axon Projections

Hu¹,

Huang²,

Li³

et al. 2012

J. Neurosci.

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“…6B lists several of these genes, which are implicated in nociception, depression, and antidepressant drug actions. For example, the transcription factors Bhlhe22 and Npas4 have been implicated in nociceptive and depressive behaviors respectively (58,59). Importantly, the direction of gene expression change in the SNI-DMI-treated Rgs9KO mice is the same as in the naive Rgs9KO mice, suggesting that the basal gene expression profile upon knockout of Rgs9 facilitates DMI actions.…”

Section: Resultsmentioning

confidence: 99%

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

Mitsi

Terzi

Purushothaman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The striatal protein Regulator of G-protein signaling 9-2 (RGS9-2) plays a key modulatory role in opioid, monoamine, and other G-protein-coupled receptor responses. Here, we use the murine spared-nerve injury model of neuropathic pain to investigate the mechanism by which RGS9-2 in the nucleus accumbens (NAc), a brain region involved in mood, reward, and motivation, modulates the actions of tricyclic antidepressants (TCAs). Prevention of RGS9-2 action in the NAc increases the efficacy of the TCA desipramine and dramatically accelerates its onset of action. By controlling the activation of effector molecules by G protein α and βγ subunits, RGS9-2 affects several protein interactions, phosphoprotein levels, and the function of the epigenetic modifier histone deacetylase 5, which are important for TCA responsiveness. Furthermore, information from RNA-sequencing analysis reveals that RGS9-2 in the NAc affects the expression of many genes known to be involved in nociception, analgesia, and antidepressant drug actions. Our findings provide novel information on NAc-specific cellular mechanisms that mediate the actions of TCAs in neuropathic pain states.desipramine | duloxetine | HDAC5 | spared nerve injury | gene expression R egulator of G-protein signaling 9-2 (RGS9-2) is an intracellular modulator of G-protein-coupled receptor (GPCR) function, which is expressed in medium spiny neurons and cholinergic interneurons of the striatum (1, 2). RGS9-2 influences the magnitude and time course of GPCR signaling by promoting GTPase activity of the Gα subunit and by preventing activation of Gα effectors (3). This modulation can also influence the duration of interactions between the Gβγ subunits and their effector molecules. In addition to Gα subunits, RGS9-2 interacts with several scaffolds and signal transduction proteins that affect its function, expression, and cellular localization. Interactions with the Gβ5 subunit and the adaptor protein R7BP determine the stability and cellular localization of RGS9-2, respectively (3, 4). Several recent studies have provided information on the regulation and function of RGS9-2 complexes in the striatum and how these complexes affect pharmacologic responses (2, 5, 6). In particular, RGS9-2 has been shown to modulate the actions of various psychotropic, antiparkinsonian, neuroleptic, and opiate analgesic drugs (1, 7). The nucleus accumbens (NAc) is a striatal brain region that is a major site of antidepressant drug action (8). Recent studies provided information on signal transduction events triggered by tricyclic antidepressants (TCAs) in NAc neurons and identified several second messengers, transcription factors, and epigenetic molecules involved in their therapeutic actions (9-11). TCAs, such as desipramine (DMI) and nortriptyline (NTL), and selective serotonin/norepinephrine reuptake inhibitors (SNRIs) have also been used to treat neuropathic pain, a complex chronic disorder that is highly comorbid with anxiety and depression (12, 13) and is characterized by thermal hyperalgesia, mech...

show abstract

Loss of Inhibitory Interneurons in the Dorsal Spinal Cord and Elevated Itch in Bhlhb5 Mutant Mice

Cited by 380 publications

References 49 publications

Tlx1/3 and Ptf1a Control the Expression of Distinct Sets of Transmitter and Peptide Receptor Genes in the Developing Dorsal Spinal Cord

Tlx1/3 and Ptf1a Control the Expression of Distinct Sets of Transmitter and Peptide Receptor Genes in the Developing Dorsal Spinal Cord

c-Maf Is Required for the Development of Dorsal Horn Laminae III/IV Neurons and Mechanoreceptive DRG Axon Projections

RGS9-2–controlled adaptations in the striatum determine the onset of action and efficacy of antidepressants in neuropathic pain states

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