Tachykinins and excitotoxicity in cerebellar granule cells.
ABSTRACT The tachykinins represent an important group of neuropeptides that are widely distributed both in the central and peripheral nervous system where they perform several functions connected with neuronal modulation, often in synergy with glutamate excitatory transmission. While a great deal of data is available on their distribution and many studies have been performed by molecular, biochemical, and immunohistochemical techniques, much less is known about their physiological role, in particular in the cerebellum. This review is an attempt to summarize the diverse evidence suggesting a role for tachykinins in cerebellar granule neurons.
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ABSTRACT: The classic theorem of Fitts (1954) asserts that the combined effects of movement amplitude and target width (index of difficulty: ID) define movement times (MTs) for goal-directed reaches. Moreover, Fitts' theorem states that reaches yielding the same ID produce equivalent MTs regardless of the response's amplitude and width combination. However, most work providing direct support for Fitts' theorem has employed short movement amplitudes and small target widths. Thus, no direct evidence supports the unitary nature of MT/ID relations across a range of amplitudes and widths used in contemporary studies of goal-directed reaching. To that end, we contrasted MT/ID relations for discrete reaches equated for movement ID but differing with respect to their amplitude (15.5, 19, 25.5, and 38 cm) and width (2, 3, 4, and 5 cm) requirements. Results show that amplitude and width manipulations yielded robust linear MT/ID relations; however, the slope of the MT/ID function was markedly steeper in the former (amplitude=92 ms; width=13 ms). Such findings indicate that the constituent elements of movement ID are dissociable and that the fixed parameter nature of Fitts' theorem cannot be applied to a continuous range of veridical movement amplitudes and target widths.Canadian Journal of Experimental Psychology 07/2011; 65(4):259-68. DOI:10.1037/a0023618 · 1.02 Impact Factor
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ABSTRACT: Substance P (SP), a neuropeptide member of the tachykinin (TK) family, has a functional role both in physiological and pathological conditions, including Amyotrophic Lateral Sclerosis disease. One hypothesis of the selective motor neuron death in ALS involves the excitatory neurotransmitter glutamate, because these neurons are extremely susceptible to excessive stimulation of AMPA receptors. It has been reported that SP exerts its action against a variety of insults including excitotoxicity, and that altered levels of SP have been observed in the cerebrospinal fluid (CSF) of patients with ALS. Here we have analyzed the interaction between SP and AMPA receptor functionality, both in Control cortical neurons in culture and in those obtained from a genetic mouse model of ALS (G93A). Our studies demonstrate that SP reduces the kainate-activated currents in Control and G93A neurons and that this reduction is significantly higher in the mutated neurons. SP effect is mediated by its receptor NK1 because GR 82334 (5 μM), a NK1 competitive antagonist, is able to suppress the current reduction. Analysis of miniature excitatory postsynaptic currents (mEPSCs) in Control and G93A neurons indicates that SP (200 nM) is able to significantly decrease the mEPSC amplitudes in G93A neurons, whereas it is ineffective on Control mEPSCs. Western blotting experiments in cultures and cortical tissues show a higher NK1 expression level in G93A mice compared to that of Control. This is also confirmed by immunocytochemistry experiments in cultured neurons. In addition, the amount of GluR1 subunit AMPA receptors is not modified following SP exposure, indicating a non internalization of the AMPA receptors. Finally, toxicity experiments have revealed that SP is able to rescue G93A cortical cells whereas it is ineffective on those of Control. These findings provide the first evidence of SP having a physiological and protective role in the G93A mouse model of ALS, and may suggest the possible use of SP as a clinical therapeutic treatment.Neurobiology of Disease 10/2011; 44(1):92-101. DOI:10.1016/j.nbd.2011.06.008 · 5.20 Impact Factor
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ABSTRACT: Reduced levels of Substance P (SP), an endogenous neuropeptide endowed with neuroprotective and anti-apoptotic properties, have been found in brain and spinal fluid of Alzheimer's disease (AD) patients. Potassium (K(+)) channel dysfunction is implicated in AD development and the amyloid-β (Aβ)-induced up-regulation of voltage-gated potassium channel subunits could be considered a significant step in Aβ brain toxicity. The aim of this study was to evaluate whether SP could reduce, in vivo, Aβ-induced overexpression of Kv subunits. Rats were intracerebroventricularly infused with amyloid-β 25-35 (Aβ25-35, 20 µg) peptide. SP (50 µg/Kg, i.p.) was daily administered, for 7 days starting from the day of the surgery. Here we demonstrate that the Aβ infused rats showed impairment in cognitive performances in the Morris water maze task 4 weeks after Aβ25-35 infusion and that this impairing effect was prevented by SP administration. Kv1.4, Kv2.1 and Kv4.2 subunit levels were quantified in hippocampus and in cerebral cortex by Western blot analysis and immunofluorescence. Interestingly, SP reduced Kv1.4 levels overexpressed by Aβ, both in hippocampus and cerebral cortex. Our findings provide in vivo evidence for a neuroprotective activity of systemic administration of SP in a rat model of AD and suggest a possible mechanism underlying this effect.PLoS ONE 11/2013; 8(11):e78036. DOI:10.1371/journal.pone.0078036 · 3.53 Impact Factor