Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity

Holmes, Fiona E.; Mahoney, Sally; King, Von R.; Bacon, Andrea; Kerr, Niall C. H.; Pachnis, Vassilis; Curtis, Rory; Priestley, John V.; Wynick, David

doi:10.1073/pnas.210221897

Cited by 193 publications

(189 citation statements)

References 47 publications

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“…To explain the above disparities, we hypothesized that the chronic absence of galanin throughout sensory neuron development may cause the loss of a subset of neurons that is important for injury-related pain behavior. Consistent with this, we have demonstrated previously a 13% reduction in the total number of neurons in the adult DRG of galanin mutant animals (37). These deficits were associated with a 2.8-fold increase in the number of apoptotic cells at postnatal day 3 (37).…”

Section: Figsupporting

confidence: 86%

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Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Holmes

Bacon

Pope

et al. 2003

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

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The neuropeptide galanin is expressed in the dorsal root ganglia (DRG) and spinal cord and is thought to be involved in the modulation of pain processing. However, its mechanisms of action are complex and poorly understood, as both facilitatory and inhibitory effects have been described. To understand further the role played by galanin in nociception, we have generated two transgenic lines that overexpress galanin in specific populations of primary afferent DRG neurons in either an inducible or constitutive manner. In the first line, a previously defined enhancer region from the galanin locus was used to target galanin to the DRG (Gal-OE). Transgene expression recapitulates the spatial endogenous galanin distribution pattern in DRG neurons and markedly overexpresses the peptide in the DRG after nerve injury but not in the uninjured state. In the second line, an enhancer region of the c-Ret gene was used to constitutively and ectopically target galanin overexpression to the DRG (Ret-OE). The expression of this second transgene does not alter significantly after nerve injury. Here, we report that intact Ret-OE, but not Gal-OE, animals have significantly elevated mechanical and thermal thresholds. After nerve damage, using a spared nerve-injury model, mechanical allodynia is attenuated markedly in both the Gal-OE and Ret-OE mice compared with WT controls. These results support an inhibitory role for galanin in the modulation of nociception both in intact animals and in neuropathic pain states.T he neuropeptide galanin is widely distributed within the somatosensory system, where it has been implicated in the modulation of nociception (reviewed in refs. 1-3). In the adult dorsal root ganglia (DRG), galanin is expressed at relatively low levels in Ͻ5% of neurons that are predominantly small-diameter C fiber type (4). Expression of the peptide also is detected in the primary afferent terminals of the dorsal spinal cord and in subsets of dorsal horn interneurons (5). Galanin mRNA and peptide levels markedly increase in the DRG after axotomy and in several neuropathic pain models of sciatic nerve injury (4, 6-9). After axotomy, galanin is expressed in Ϸ40-50% of all DRG neurons (4, 10). In the dorsal horn, axotomy-induced galanin immunoreactivity increases in the afferent terminals, with a concurrent enhancement of synaptic release of the peptide (11).The role of galanin in pain signaling is complex (reviewed in refs. 2, 12, and 13). Electrophysiological and behavioral studies in the intact, uninjured peripheral nervous system have demonstrated both facilitatory (14-21) and inhibitory (22, 23) effects of exogenously applied galanin on nociception, sometimes in a modality-specific manner (14,16,20,21), tending toward inhibition at higher doses.A number of groups have used rodent models of neuropathic pain to study the role of galanin in the modulation of chronic pain behavior. The oldest and least understood pain model involves the scoring of autotomy behavior (self-mutilation of the denervated limb) after sciatic nerve a...

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Section: Figsupporting

confidence: 86%

“…To study further the role played by galanin in the adaptive response of the nervous system to injury, we previously generated and characterized mice carrying a targeted deletion of the galanin gene (16,37,38). Uninjured galanin mutant animals have decreased thermal and mechanical thresholds, supporting the proposed inhibitory role for galanin in nociception.…”

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confidence: 98%

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Holmes

Bacon

Pope

et al. 2003

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

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“…Galanin-binding sites have been mapped (7,8), and three receptor subtypes, GalR1 (9-11), GalR2 (12)(13)(14)49), and GalR3 (15), have been cloned. There is evidence for involvement of galanin in multiple neuronal functions (16,17), as also revealed in recent studies on transgenic mice (18)(19)(20).…”

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confidence: 54%

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

Kokaia

Holmberg

Nanobashvili

et al. 2001

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

103

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The neuropeptide galanin has been shown to suppress epileptic seizures. In cortical and hippocampal areas, galanin is normally mainly expressed in noradrenergic afferents. We have generated a mouse overexpressing galanin in neurons under the plateletderived growth factor B promoter. RIA and HPLC analysis revealed up to 8-fold higher levels of galanin in transgenic as compared with wild-type mice. Ectopic galanin overexpression was detected especially in dentate granule cells and hippocampal and cortical pyramidal neurons. Galanin-overexpressing mice showed retardation of seizure generalization during hippocampal kindling, a model for human complex partial epilepsy. The high levels of galanin in mossy fibers found in the transgenic mice were further increased after seizures. Frequency facilitation of field excitatory postsynaptic potentials, a form of short-term synaptic plasticity assessed in hippocampal slices, was reduced in mossy fiber-CA3 cell synapses of galanin-overexpressing mice, indicating suppressed glutamate release. This effect was reversed by application of the putative galanin receptor antagonist M35. These data provide evidence that ectopically overexpressed galanin can be released and dampen the development of epilepsy by means of receptor-mediated action, at least partly by reducing glutamate release from mossy fibers.G alanin, a 29-aa neuropeptide (1), is widely distributed throughout the rat brain (2, 3) and coexists with classic transmitters in several systems (4), with particularly high levels in noradrenergic locus coeruleus neurons (5, 6). Galanin-binding sites have been mapped (7,8), and three receptor subtypes, GalR1 (9-11), 49), and GalR3 (15), have been cloned. There is evidence for involvement of galanin in multiple neuronal functions (16,17), as also revealed in recent studies on transgenic mice (18)(19)(20).Many studies support an important role of neuropeptides in seizure activity (21)(22)(23). This role is true also for galanin. Thus, intrahippocampal injection of galanin during status epilepticus (SE) in rats has powerful anticonvulsant effects (24). In accordance with these data, mice overexpressing the galanin gene under the dopamine-␤-hydroxylase promoter, presumably in noradrenergic fibers, show increased resistance to SE and kainate-and pentylenetetrazol-evoked seizures (25). Conversely, administration of galanin antagonists, such as M35 (26), and targeted disruption of the galanin gene increase seizure susceptibility in these models (24,25). Taken together, available data indicate that galanin released from noradrenergic fibers (3, 5, 27) can suppress epileptic seizures. Although the underlying mechanisms are not known, it has been shown that galanin can inhibit glutamate release by means of activation of presynaptic ATP-dependent K ϩ channels (28).We speculated that galanin release from neurons not normally containing this neuropeptide, e.g., in the epileptic focus, might be necessary to optimize the seizure-suppressant action of galanin. To explore the functional conseque...

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“…All efforts were made to minimize the number of animals used and to reduce their discomfort. The GALTG and GALKO mice were developed and characterized as previously described (Holmes et al, 2000;Mazarati et al, 2000;Steiner et al, 2001;Wynick et al, 1998).…”

Section: Experimental Procedures Animalsmentioning

confidence: 99%

Distribution and regulation of galanin receptor 1 messenger RNA in the forebrain of wild type and galanin-transgenic mice

et al. 2003

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Abstract-To learn more about molecular alterations in the brain that occur as a consequence of either the chronic excess or absence of peptide neurotransmitters, we examined the impact of genetically manipulating the neuropeptide galanin on the expression of one of its cognate receptors, galanin receptor 1. First, we examined the distribution of galanin receptor 1 messenger RNA in the mouse forebrain, and found it to be abundantly expressed in many brain regions, including in numerous hypothalamic and other forebrain regions associated with neuroendocrine function. The distribution of galanin receptor 1 messenger RNA in the mouse was similar to previous reports in the rat, with additional expression noted in the caudate putamen and in several midbrain regions. Next, using quantitative in situ hybridization, we measured cellular levels of galanin receptor 1 messenger RNA in the brains of mice that either overexpress galanin (galanin transgenic) or lack a functional galanin gene (galanin knockout). We report that relative to wild-type controls, the expression of galanin receptor 1 messenger RNA was increased in discrete areas of the brain in galanin-transgenic mice, but that depletion of galanin/noradrenergic innervation to the hypothalamus with the neurotoxin 6-hydroxydopamine did not alter levels of galanin receptor 1 messenger RNA. We also report that levels of galanin receptor 1 messenger RNA were not different between galanin-knockout and wild-type mice. These results suggest that compensatory adjustments in the expression of cognate receptors represent one mechanism by which the developing nervous system attempts to maintain homeostasis in response to overexpression of a peptidergic transmitter. However, the lack of significant changes in galanin receptor 1 messenger RNA in galanin-knockout mice suggests that developmentally programmed levels of receptor expression are maintained even in the complete absence of ligand.

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Targeted disruption of the galanin gene reduces the number of sensory neurons and their regenerative capacity

Cited by 193 publications

References 47 publications

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Transgenic overexpression of galanin in the dorsal root ganglia modulates pain-related behavior

Suppressed kindling epileptogenesis in mice with ectopic overexpression of galanin

Distribution and regulation of galanin receptor 1 messenger RNA in the forebrain of wild type and galanin-transgenic mice

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