Electrophysiological evidence for a hyperpolarizing, galanin (1-15)-selective receptor on hippocampal CA3 pyramidal neurons

Xu, Zhi‐Qing David; Ma, Xiaosong; Soomets, Ursel; Langel, Ülo; Hökfelt, Tomas

doi:10.1073/pnas.96.25.14583

Cited by 34 publications

(19 citation statements)

References 58 publications

(80 reference statements)

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“…Quantitative autoradiographic 125 I-GAL-binding studies showed a strong cortical binding in the human brain (39,41), in sharp contrast with the rat brain, which lacks 125 I-GAL binding in dorsal cortical and hippocampal areas (37,38). However, 125 I-GAL(1-15ol) binds to these regions (92), and GAL(1-15) hyperpolarizes hippocampal C3 neurons (93). Investigation of these findings is continuing (SI Discussion, Dorsolateral Prefrontal Cortex) (94).…”

Section: Discussionmentioning

confidence: 99%

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

Barde

Rüegg

Prud’homme

et al. 2016

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

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Major depressive disorder (MDD) is a substantial burden to patients, families, and society, but many patients cannot be treated adequately. Rodent experiments suggest that the neuropeptide galanin (GAL) and its three G protein-coupled receptors, GAL 1-3 , are involved in mood regulation. To explore the translational potential of these results, we assessed the transcript levels (by quantitative PCR), DNA methylation status (by bisulfite pyrosequencing), and GAL peptide by RIA of the GAL system in postmortem brains from depressed persons who had committed suicide and controls. Transcripts for all four members were detected and showed marked regional variations, GAL and galanin receptor 1 (GALR1) being most abundant. Striking increases in GAL and GALR3 mRNA levels, especially in the noradrenergic locus coeruleus and the dorsal raphe nucleus, in parallel with decreased DNA methylation, were found in both male and female suicide subjects as compared with controls. In contrast, GAL and GALR3 transcript levels were decreased, GALR1 was increased, and DNA methylation was increased in the dorsolateral prefrontal cortex of male suicide subjects, however, there were no changes in the anterior cingulate cortex. Thus, GAL and its receptor GALR3 are differentially methylated and expressed in brains of MDD subjects in a region-and sex-specific manner. Such an epigenetic modification in GALR3, a hyperpolarizing receptor, might contribute to the dysregulation of noradrenergic and serotonergic neurons implicated in the pathogenesis of MDD. Thus, one may speculate that a GAL 3 antagonist could have antidepressant properties by disinhibiting the firing of these neurons, resulting in increased release of noradrenaline and serotonin in forebrain areas involved in mood regulation.epigenetics | human postmortem brain | neuropeptides | stress | transmitter coexistence

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Section: Discussionmentioning

confidence: 99%

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

Barde

Rüegg

Prud’homme

et al. 2016

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

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“…Many of these inhibitory effects are mediated by the GAL-R1 receptor subtype, which couples to Gi/o type G-proteins, reducing cAMP formation, closing voltage-sensitive calcium channels, and opening ATP-sensitive potassium channels (Branchek et al 2000;Waters and Krause 2000). Galanin has been shown to inhibit forskolin-stimulated adenylate cyclase activity in hippocampus and cortex (Waters and Krause 2000;Xu et al 1999), and to inhibit the stimulation of cAMP induced by norepinephrine in rat cerebral cortex (Branchek et al 1998(Branchek et al , 2000. Thus, in the present experiment, it is possible that release of endogenous galanin during stress may have inhibited output of the BST, consistent with the suggestion that the BST may inhibit neuroendocrine and behavioral reactivity to stress.…”

Section: Discussionmentioning

confidence: 99%

Modulatory Effects of Galanin in the Lateral Bed Nucleus of the Stria Terminalis on Behavioral and Neuroendocrine Responses to Acute Stress

Khoshbouei

Cecchi

Morilak

2002

Neuropsychopharmacology

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The neuropeptide galanin has been identified as a possible neurotransmitter/neuromodulator within the central nervous system. In the present study, a potential role for galanin in the lateral bed nucleus of the stria terminalis (BSTL) in modulating behavioral and neuroendocrine responses to an acute stress was investigated. In the first experiment, acute immobilization stress induced anxietylike behavioral responses in ratsSince its discovery (Tatemoto et al. 1983), the peptide neurotransmitter galanin has been implicated in numerous autonomic and physiologic regulatory processes, including feeding (Crawley 1999), cardiovascular control (Shih et al. 1996), learning and memory (McDonald et al. 1998), and the response to stress (Holmes et al. 1995; Khoshbouei et al. 2000;Sweerts et al. 1999Sweerts et al. , 2000. Furthermore, it has been hypothesized that galanin may also be involved in disease states such as depression (Seutin et al. 1989), feeding disorders (Crawley et al. 1990(Crawley et al. , 1993, and Alzheimer's disease (Bartfai et al. 1992;Mufson et al. 1993Mufson et al. , 1998Mufson et al. , 2000.Limbic forebrain structures important for the expression of fear and anxiety, such as the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BST), show a rich expression of galanin and galanin receptors (Bartfai et al. 1992; Gustafson et al. 1996; Melander et al. 1986a,b). Within the BST, there is extensive overlap between galanin-immunoreactive terminals and galanin receptors (Gray and Magnuson 1987b; . 1993b, 1997). The BST is a component of the "extended amygdala", which plays a critical role in the integration of autonomic and behavioral responses to stress (Davis and Shi 1999; Davis et al. 1997a; Herman and Cullinan 1997). The lateral BST (BSTL) in particular has been implicated in modulation of behavioral-affective responses (Cecchi et al. 2001; Davis and Shi 1999). Lesions of the BST blocked the enhancement of acoustic startle induced by i.c.v. infusion of CRH (Davis et al. 1997b). Similarly, blockade of glutamate receptors in BSTL antagonized the unconditioned potentiation of startle induced by exposure to bright light (reviewed by (Davis and Shi 1999)).In addition to playing a potential role in modulating the behavioral response to stress, the BSTL also exerts an extrahypothalamic modulatory influence on stressinduced hypothalamic-pituitary-adrenal (HPA) activation (Cecchi et al. 2001; Herman and Cullinan 1997; Herman et al. 1996). While some investigators have suggested that the BST has an inhibitory influence on HPA activation (Herman and Cullinan 1997), others have suggested a facilitatory role. A small cluster of CRF-immunoreactive neurons in ventrolateral BST project to mid-parvocellular PVN (Moga and Saper 1994). Lesions of BST attenuated the increase in plasma ACTH and corticosterone induced by reintroduction of rats into a context in which they had previously been exposed to foot shock (Gray et al. 1993), and specific lesioning of anterolateral BST cause a decrease ...

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“…In addition to GALR1 and 5-HT1A receptor heterodimers (97), an involvement of the galanin (1-15) fragment in mood regulation via GALR1 and GALR2 heterocomplexes in the dorsal HPC and DR has been reported (98). Interestingly, galanin (1-15) causes a dose-dependent hyperpolarization of hippocampal CA3 neurons (99), and, after iodination, it binds to, among other things, the dorsal HPC as shown in autoradiographic studies (100).…”

Section: Discussionmentioning

confidence: 99%

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

Wang

Barde

et al. 2016

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

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The neuropeptide galanin coexists in rat brain with serotonin in the dorsal raphe nucleus and with noradrenaline in the locus coeruleus (LC), and it has been suggested to be involved in depression. We studied rats exposed to chronic mild stress (CMS), a rodent model of depression. As expected, these rats showed several endophenotypes relevant to depression-like behavior compared with controls. All these endophenotypes were normalized after administration of a selective serotonin reuptake inhibitor. The transcripts for galanin and two of its receptors, galanin receptor 1 (GALR1) and GALR2, were analyzed with quantitative real-time PCR using laser capture microdissection in the following brain regions: the hippocampal formation, LC, and ventral periaqueductal gray (vPAG). Only Galr1 mRNA levels were significantly increased, and only in the latter region. After knocking down Galr1 in the vPAG with an siRNA technique, all parameters of the depressive behavioral phenotype were similar to controls. Thus, the depression-like behavior in rats exposed to CMS is likely related to an elevated expression of Galr1 in the vPAG, suggesting that a GALR1 antagonist could have antidepressant effects.dorsal raphe | neuropeptide | siRNA | stress | transmitter coexistence T he indoleamine hypothesis of depression was formulated some five decades ago (1, 2), in parallel with the catecholamine hypothesis (3, 4), and has been supported by the success of selective serotonin reuptake inhibitors (SSRIs) for treatment of major depression (MD) (5). However, in a considerable number of cases, SSRIs are associated with side effects or lack of efficacy. For example, after treatment with SSRIs, only one-third of patients obtain full remission of symptoms (6). Therefore, there is an ongoing search for new medications targeting mood disorders, such as MD and anxiety. Here, neuropeptides and their receptors, the most diverse family of neurotransmitters in the brain (7), have been extensively explored (5,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), including galanin and its three receptors.Galanin is a 29-aa (30-aa in humans) neuropeptide (18) with a wide distribution in the rat brain (19,20), where it is coexpressed with noradrenaline/norepinephrine (NA) in locus coeruleus (LC) neurons and with 5-hydroxytryptamine (5-HT) in dorsal raphe nucleus (DR) neurons (21-25). There are three galanin receptors, GALR1-GALR3, which all belong to the family of seven transmembrane-spanning, G protein-coupled receptors (26-29). They are found in many areas of the rat brain, as first shown with autoradiographic ligand-binding methodology (30, 31), and later with in situ hybridization (ISH)/quantitative real-time PCR (qPCR) (32-36). The galanin system has been associated with numerous physiological and pathophysiological functions (29), including depression-and anxiety-like behaviors.There is early evidence from studies on the rat that central administration of galanin influences mood-related behavior in a region-specific way (37, 38), and also that galanin is prodepres...

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Electrophysiological evidence for a hyperpolarizing, galanin (1-15)-selective receptor on hippocampal CA3 pyramidal neurons

Abstract: coexistence ͉ locus coeruleus ͉ neuropeptide ͉ noradrenaline

Cited by 34 publications

References 58 publications

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

Alterations in the neuropeptide galanin system in major depressive disorder involve levels of transcripts, methylation, and peptide

Modulatory Effects of Galanin in the Lateral Bed Nucleus of the Stria Terminalis on Behavioral and Neuroendocrine Responses to Acute Stress

Depression-like behavior in rat: Involvement of galanin receptor subtype 1 in the ventral periaqueductal gray

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