Co-expression of serotonin 5-HT1B and 5-HT4 receptors in p11 containing cells in cerebral cortex, hippocampus, caudate-putamen and cerebellum

Egeland, Martin; Warner-Schmidt, Jennifer L.; Greengard, Paul; Svenningsson, Per

doi:10.1016/j.neuropharm.2011.01.046

Cited by 47 publications

(47 citation statements)

References 40 publications

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“…Previous work has shown that constitutive p11KO mice, which lack p11 in the whole brain and body, have both a depressive-like phenotype and are less sensitive to antidepressant treatment (7). p11 is normally expressed in a variety of cell types throughout the central nervous system (31). The current study demonstrates that p11 in NAC cholinergic interneurons is sufficient for regulating anhedonia and behavioral despair, identifying these cells as modulators of mood.…”

Section: Discussionsupporting

confidence: 55%

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

Warner-Schmidt¹,

Schmidt

Marshall³

et al. 2012

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

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A large number of studies have demonstrated that the nucleus accumbens (NAC) is a critical site in the neuronal circuits controlling reward responses, motivation, and mood, but the neuronal cell type(s) underlying these processes are not yet known. Identification of the neuronal cell types that regulate depression-like states will guide us in understanding the biological basis of mood and its regulation by diseases like major depressive disorder. Taking advantage of recent findings demonstrating that the serotonin receptor chaperone, p11, is an important molecular regulator of depression-like states, here we identify cholinergic interneurons (CINs) as a primary site of action for p11 in the NAC. Depression-like behavior is observed in mice after decrease of p11 levels in NAC CINs. This phenotype is recapitulated by silencing neuronal transmission in these cells, demonstrating that accumbal cholinergic neuronal activity regulates depression-like behaviors and suggesting that accumbal CIN activity is crucial for the regulation of mood and motivation.he nucleus accumbens (NAC) has been identified as a critical site in the neuronal circuits controlling reward responses, motivation, and mood (1-3). For example, in major depressive disorder (MDD): (i) NAC activity is reduced in response to positive stimuli (4) and (ii) MDD symptoms can be reversed by deep brain stimulation in the NAC (5, 6). Although these regional studies implicate the NAC, the cell type(s) responsible for the pathophysiology remain to be elucidated. In the case of MDD, it is crucial that we determine which neuronal cell types regulate depressive-like behaviors to eventually develop highly targeted antidepressants that could be both faster acting and have fewer off-site effects. MDD is a debilitating psychiatric condition characterized by anhedonia (defined as a loss of interest in pleasurable things), loss of motivation, negative affect, behavioral despair, and changes in cognition and basic drives such as eating and sleeping. Despite its complexity, central features of the disease, such as anhedonia and behavioral despair, can be modeled in rodents to probe the underlying neuronal circuitry.The serotonin receptor (5HTR) interacting protein p11 is a small intracellular protein that regulates the localization of certain 5HTRs, including 5HTR1B and 5HTR4 (7,8), at the cellular surface. Constitutive p11 knockout (KO) mice show both anhedonia (e.g., reduced sucrose preference) and increased behavioral despair (e.g., increased immobility) (7-9). Recently, we identified the NAC as a key brain region in which loss of p11 induces depression-like behaviors (9). The NAC is composed of several different cell types (10). Approximately 95% of the neurons in this region are medium spiny neurons (MSNs), the projection neurons of the NAC. The cholinergic interneurons have a characteristically large soma and make up less than 1% of the neurons in the striatum (10). Cholinergic interneurons primarily target MSNs via muscarinic and nicotinic acetylcholine receptors, a...

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Section: Discussionsupporting

confidence: 55%

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

Warner-Schmidt¹,

Schmidt

Marshall³

et al. 2012

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

Self Cite

152

159

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“…3B). IT-CStr neurons also appear to have higher expression than PT neurons of 5HT-1B and 5HT-4 receptors 71 . As discussed later, differential IT/PT serotonin signaling has significant disease implications.…”

Section: Neuromodulationmentioning

confidence: 86%

Corticostriatal connectivity and its role in disease

2013

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Corticostriatal projections are essential components of forebrain circuits widely involved in motivated behavior. These axonal projections are formed by two distinct classes of cortical neurons, intratelencephalic (IT) and pyramidal tract (PT) type neurons. Convergent evidence points to IT/PT differentiation of the corticostriatal system at all levels of functional organization, from cellular signaling mechanisms to circuit topology. There is also growing evidence for IT/PT imbalance as an etiological factor in neurodevelopmental, neuropsychiatric, and movement disorders – autism, amyotrophic lateral sclerosis, obsessive-compulsive disorder, schizophrenia, Huntington’s and Parkinson’s diseases, and major depression are highlighted here.

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“…However, the use of the 5-HT 4 receptor as a novel antidepressant target may be hampered by the fact that it also has important roles outside the central nervous system, for example, in the heart, gastrointestinal tract, adrenal gland, and urinary bladder (Tonini and Pace, 2006), which may prevent its development as an effective anxiolytic/antidepressant drug (Bockaert et al, 2004(Bockaert et al, , 2008. Thus, signaling molecules that interact with the 5-HT 4 receptor such as P11 (Egeland et al, 2011;WarnerSchmidt et al, 2009) may represent novel targets for fastacting anxiolytic/antidepressant treatments. There is indeed recent evidence that cortical neurons that express both P11 and 5-HT 4 receptors are involved in the behavioral effects of SSRIs (Schmidt et al, 2012), and that chronic treatment with fluoxetine results in an increase in 5-HT 4 receptor expressions in cortical neurons (Schmidt et al, 2012).…”

Section: Neurogenesisindependentmentioning

confidence: 99%

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

Mendez‐David

David

Darcet

et al. 2013

Neuropsychopharmacol

142

152

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Selective serotonin reuptake inhibitors (SSRIs) display a delayed onset of action of several weeks. Past work in naive rats showed that 5-HT 4 receptor agonists had rapid effects on depression-related behaviors and on hippocampal neurogenesis. We decided to investigate whether 5-HT 4 receptor stimulation was necessary for the effects of SSRIs in a mouse model of anxiety/depression, and whether hippocampal neurogenesis contributed to these effects. Using the mouse corticosterone model of anxiety/depression, we assessed whether chronic treatment with a 5-HT 4 receptor agonist (RS67333, 1.5 mg/kg/day) had effects on anxiety-and depression-related behaviors, as well as on hippocampal neurogenesis in comparison with chronic fluoxetine treatment (18 mg/kg/day). Then, using our anxiety/depression model combined with ablation of hippocampal neurogenesis, we investigated whether neurogenesis was necessary for the behavioral effects of subchronic (7 days) or chronic (28 days) RS67333 treatment. We also assessed whether a 5-HT 4 receptor antagonist (GR125487, 1 mg/kg/day) could prevent the behavioral and neurogenic effects of fluoxetine. Chronic treatment with RS67333, similar to fluoxetine, induced anxiolytic/antidepressant-like activity and stimulated adult hippocampal neurogenesis, specifically facilitating maturation of newborn neurons. However, unlike fluoxetine, anxiolytic effects of RS67333 were already present after 7 days and did not require hippocampal neurogenesis. Chronic treatment with GR125487 prevented both anxiolytic/antidepressant-like and neurogenic effects of fluoxetine, indicating that 5-HT 4 receptor activation is necessary for these effects of SSRIs. 5-HT 4 receptor stimulation could represent an innovative and rapid onset therapeutic approach to treat depression with comorbid anxiety.

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Co-expression of serotonin 5-HT1B and 5-HT4 receptors in p11 containing cells in cerebral cortex, hippocampus, caudate-putamen and cerebellum

Cited by 47 publications

References 40 publications

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior

Corticostriatal connectivity and its role in disease

Rapid Anxiolytic Effects of a 5-HT4 Receptor Agonist Are Mediated by a Neurogenesis-Independent Mechanism

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