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Answer added in Synaptic Plasticity9 Is there any way to understand the neurotransmitter uptake ability through receptors using imaging or biochemical assays in mammalian cell lines?Neurotransmitter uptake cannnot be evaluated efectively through receptor function in mammalian cell lines; these are different processes in neurotrans... [more]
Publications (139) View all
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Article: The effects of brain serotonin deficiency on behavioural disinhibition and anxiety-like behaviour following mild early life stress.
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ABSTRACT: Aberrant serotonin (5-HT) signalling and exposure to early life stress have both been suggested to play a role in anxiety- and impulsivity-related behaviours. However, whether congenital 5-HT deficiency × early life stress interactions influence the development of anxiety- or impulsivity-like behaviour has not been established. Here, we examined the effects of early life maternal separation (MS) stress on anxiety-like behaviour and behavioural disinhibition, a type of impulsivity-like behaviour, in wild-type (WT) and tryptophan hydroxylase 2 (Tph2) knock-in (Tph2KI) mice, which exhibit ∼60-80% reductions in the levels of brain 5-HT due to a R439H mutation in Tph2. We also investigated the effects of 5-HT deficiency and early life stress on adult hippocampal neurogenesis, plasma corticosterone levels and several signal transduction pathways in the amygdala. We demonstrate that MS slightly increases anxiety-like behaviour in WT mice and induces behavioural disinhibition in Tph2KI animals. We also demonstrate that MS leads to a slight decrease in cell proliferation within the hippocampus and potentiates corticosterone responses to acute stress, but these effects are not affected by brain 5-HT deficiency. However, we show that 5-HT deficiency leads to significant alterations in SGK-1 and GSK3β signalling and NMDA receptor expression in the amygdala in response to MS. Together, these findings support a potential role for 5-HT-dependent signalling in the amygdala in regulating the long-term effects of early life stress on anxiety-like behaviour and behavioural disinhibition.The International Journal of Neuropsychopharmacology 05/2013; · 4.58 Impact Factor -
Article: Disruption of Arp2/3 Results in Asymmetric Structural Plasticity of Dendritic Spines and Progressive Synaptic and Behavioral Abnormalities.
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ABSTRACT: Despite evidence for a strong genetic contribution to several major psychiatric disorders, individual candidate genes account for only a small fraction of these disorders, leading to the suggestion that multigenetic pathways may be involved. Several known genetic risk factors for psychiatric disease are related to the regulation of actin polymerization, which plays a key role in synaptic plasticity. To gain insight into and test the possible pathogenetic role of this pathway, we designed a conditional knock-out of the Arp2/3 complex, a conserved final output for actin signaling pathways that orchestrates de novo actin polymerization. Here we report that postnatal loss of the Arp2/3 subunit ArpC3 in forebrain excitatory neurons leads to an asymmetric structural plasticity of dendritic spines, followed by a progressive loss of spine synapses. This progression of synaptic deficits corresponds with an evolution of distinct cognitive, psychomotor, and social disturbances as the mice age. Together, these results point to the dysfunction of actin signaling, specifically that which converges to regulate Arp2/3, as an important cellular pathway that may contribute to the etiology of complex psychiatric disorders.Journal of Neuroscience 04/2013; 33(14):6081-6092. · 7.11 Impact Factor -
Dataset: Intrinsic pulsatile secretory activity of immortalized luteinizing hormone-releasing hormone-secreting neurons (dye-coupling/synapse-like connections/immortalized cells)
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ABSTRACT: Mammalian reproduction is dependent upon intermittent delivery of luteinizing hormone-releasing hor-mone (LHRH) to the anterior pituitary. This mode of secretion is required to sensitize maximally the gonadotrophs to LHRH stimulation and to regulate gonadotropin gene expression. While LHRH secretion is pulsatile in nature, the origin of the pulse generator is unknown. In this report, we show that this oscillator could be located within the LHRH neuronal network. When immortalized LHRH neurons are placed into a perifu-sion system, LHRH is secreted into the medium in a pulsatile fashion under basal conditions. LHRH secretion and the num-ber of LHRH pulses are reduced when calcium is removed from the medium. Perifusion also influences pro-LHRH processing, since the molar ratio of its processed products varies dramat-ically when the cells are transferred from a static system. Several different cellular mechanisms may underlie these changes in secretion and processing. Lucifer yellow experi-ments reveal that some cells are dye-coupled. Hence, these cells could be electrically coupled through gap junctions such that secretion from individual cells could be coordinated. Secretion could also be synchronized through the observed synapse-like contacts. These contacts could perform a negative-feedback role to regulate not only the amount of LHRH released but also the molecular forms secreted. The organization of LHRH neurons into interconnected clusters could serve to coordinate LHRH secretion from individual cells and, thereby, orches-trate functions in vivo as diverse as the onset of puberty, the timing of ovulation, and the duration of lactational infertility. Luteinizing hormone (LH)-releasing hormone (LHRH) is a major regulator of reproduction in mammals (1-3). While LHRH neuronal cell bodies are scattered throughout the anterior hypothalamic region, their nerve terminals converge on the median eminence. LHRH is secreted into the hy-pophysial portal circulation, where it is transported to the anterior pituitary to stimulate the release of LH and follicle-stimulating hormone. In all mammalian species studied so far, secretion of LH into blood is episodic in nature (1, 4-8). Interestingly, LHRH is secreted into the hypophysial portal blood in a pulsatile manner (9-11), and LH pulses are preceded by LHRH release (1, 10, 11). In addition, LH pulsatile secretion is lost either after passive immunization with LHRH antiserum (12) or with administration of a LHRH antagonist (13). Lesions of either the medial basal hypothalamus or the arcuate nucleus also eradicate LH pulses (1). By comparison, continuous infusion of LHRH, which desensitizes the gonadotropes through down-regulation of the LHRH receptor (14), also -
Article: Emergence of anxiety-like behaviours in depressive-like Cpefat/fat mice.
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ABSTRACT: Cpefat/fat mice have a point mutation in carboxypeptidase E (Cpe), an exopeptidase that removes C-terminal basic amino acids from intermediates to produce bioactive peptides. The mutation renders the enzyme inactive and unstable. The absence of Cpe activity in these mutants leads to abnormal processing of many peptides, with elevated levels of intermediates and greatly reduced levels of the mature peptides. Cpefat/fat mice develop obesity, diabetes and infertility in adulthood. We examined whether anxiety- and/or depressive-like behaviours are also present. Anxiety-like responses are not evident in young Cpefat/fat mice (∼60 d), but appear in older animals (>90 d). These behaviours are reversed by acute treatment with diazepam or fluoxetine. In contrast, increased immobilities in forced swim and tail suspension are evident in all age groups examined. These behaviours are reversed by acute administration of reboxetine. In comparison acute treatments with fluoxetine or bupropion are ineffective; however, immobility times are normalized with 2 wk treatment. These data demonstrate that Cpefat/fat mice display depressive-like responses aged ∼60 d, whereas anxiety-like behaviours emerge ∼1 month later. In tail suspension, the reboxetine findings show that noradrenergic actions of antidepressants are intact in Cpefat/fat mice. The ability of acute fluoxetine treatment to rescue anxiety-like while leaving depressive-like responses unaffected suggests that serotonin mechanisms underlying these behaviours are different. Since depressive-like responses in the Cpefat/fat mice are rescued by 2 wk, but not acute, treatment with fluoxetine or bupropion, these mice may serve as a useful model that resembles human depression.The International Journal of Neuropsychopharmacology 02/2013; · 4.58 Impact Factor -
Article: Automated design of ligands to polypharmacological profiles.
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ABSTRACT: The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.Nature 12/2012; 492(7428):215-20. · 36.28 Impact Factor
