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- Wallén-Mackenzie, Åsa, et al.
(författare)
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Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
- 2009
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Ingår i: The Journal of neuroscience : the official journal of the Society for Neuroscience. - 1529-2401 .- 0270-6474. ; 29:7, s. 2238-51
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Tidskriftsartikel (refereegranskat)abstract
- A major challenge in neuroscience is to resolve the connection between gene functionality, neuronal circuits, and behavior. Most, if not all, neuronal circuits of the adult brain contain a glutamatergic component, the nature of which has been difficult to assess because of the vast cellular abundance of glutamate. In this study, we wanted to determine the role of a restricted subpopulation of glutamatergic neurons within the forebrain, the Vglut2-expressing neurons, in neuronal circuitry of higher brain function. Vglut2 expression was selectively deleted in the cortex, hippocampus, and amygdala of preadolescent mice, which resulted in increased locomotor activity, altered social dominance and risk assessment, decreased sensorimotor gating, and impaired long-term spatial memory. Presynaptic VGLUT2-positive terminals were lost in the cortex, striatum, nucleus accumbens, and hippocampus, and a downstream effect on dopamine binding site availability in the striatum was evident. A connection between the induced late-onset, chronic reduction of glutamatergic neurotransmission and dopamine signaling within the circuitry was further substantiated by a partial attenuation of the deficits in sensorimotor gating by the dopamine-stabilizing antipsychotic drug aripiprazole and an increased sensitivity to amphetamine. Somewhat surprisingly, given the restricted expression of Vglut2 in regions responsible for higher brain function, our analyses show that VGLUT2-mediated neurotransmission is required for certain aspects of cognitive, emotional, and social behavior. The present study provides support for the existence of a neurocircuitry that connects changes in VGLUT2-mediated neurotransmission to alterations in the dopaminergic system with schizophrenia-like behavioral deficits as a major outcome.
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| 2. |
- Zhang, Xiaoqun, et al.
(författare)
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Neurokinin B/NK3 receptors exert feedback inhibition on L-DOPA actions in the 6-OHDA lesion rat model of Parkinson's disease
- 2008
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Ingår i: Neuropharmacology. - : Elsevier BV. - 0028-3908 .- 1873-7064. ; 54:7, s. 1143-1152
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Tidskriftsartikel (refereegranskat)abstract
- Neurokinin B (NKB) and substance P (SP) act via NK(3) and NK(1) receptors. Using the unilateral 6-hydroxydopamine (6-OHDA) lesion rat model of Parkinson's disease (PD), it was found that chronic, but not acute, administration of L-DOPA increases striatal NKB expression in the dopamine-depleted hemisphere. In contrast, both acute and chronic administrations of L-DOPA restore reduced levels of SP mRNA. Co-treatment with the NK(3) receptor antagonist, SB222200, and L-DOPA increased contralateral rotations compared to L-DOPA alone in L-DOPA primed rats. The NK(3)R agonist, senktide, increased the phosphorylation of tyrosine hydroxylase (TH) at Ser(19)-TH, a CaMKII site, and of Thr(286)-CaMKII in striatal slices. Senktide had no effect on P-Ser(31)-TH, a MAPK site, but reduced P-Ser(217/221)-MEK. Amperometry demonstrated that senktide increased evoked dopamine release. SB222200 blocked the effects of senktide. In striatal slices prepared from 6-OHDA-lesioned rats repeatedly treated with L-DOPA, senktide no longer increased P-Thr(286)-CaMKII, suggesting a role of NK(3)R on dopamine terminals under normal conditions. SB222200 increased P-Ser(217/221)-MEK only in dopamine-depleted slices, indicating an increased NK(3)R tone under Parkinsonism conditions. Altogether, these data demonstrate a differential regulation of NKB and SP by L-DOPA in an animal model of PD and indicate a unique role of NKB in long-term effects of L-DOPA. Behavioural, biochemical and amperometric data indicate that NKB/NK(3)R signalling stimulates dopamine transmission at the presynaptic site, but inhibits it at the postsynaptic site. The inhibitory influence of NKB/NK(3)R on dopamine transmission dominates in an animal model of PD and provides a feedback inhibition on actions mediated via L-DOPA.
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