Neuroscience
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The Ts65Dn (TS) mouse model of Down syndrome (DS) displays a number of behavioral, neuromorphological and neurochemical phenotypes of the syndrome. Altered GABAergic transmission appears to contribute to the mechanisms responsible for the cognitive impairments in TS mice. Increased functional expression of the trisomic gene encoding an inwardly rectifying potassium channel, subfamily J, member 6 (KCNJ6) has been reported in DS and TS mice, along with the consequent impairment in GAB Aergic function. ⋯ Also, ETH and GAB did not induce anxiety in the open field or plus maze tests, did not alter performance in the Morris water maze, and did not affect cued - or context - fear conditioning. Our results thus suggest that KCNJ6 may not be a promising drug target candidate in DS. As a corollary, they also show that long-term use of ETH and GAB is devoid of adverse behavioral and cognitive effects.
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Spinal muscular atrophy (SMA), a fatal genetic motor disorder of infants, is caused by diminished full-length survival of motor neuron (SMN) protein levels. Normally involved in small nuclear ribonucleoprotein (snRNP) assembly and pre-mRNA splicing, recent studies suggest that SMN plays a critical role in regulating apoptosis. Interestingly, the anti-apoptotic Bcl-x isoform, Bcl-xL, is reduced in SMA. ⋯ We also found that exogenous SMN expression increased full-length SMN transcripts, possibly by promoting exon 7 inclusion. Finally, co-expression of SMN and Bcl-xL produced an additive anti-apoptotic effect following PI3-kinase inhibition in SH-SY5Y cells. Our findings implicate Bcl-xL as another potential target in SMA therapeutics, and indicate that therapeutic increases in SMN may arise from modest increases in total SMN.
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Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease. One of the proposed disease mechanisms is excitotoxicity, in which excessive cytosolic calcium causes neuronal death. ⋯ In vitro, dantrolene provides a significant protection to motor neurons exposed to a brief excitotoxic insult. However, daily administration of dantrolene to mice overexpressing superoxide dismutase 1 glycine to alanine at position 93 (SOD1(G93A)) does affect neither survival nor the number of motor neurons and ubiquitin aggregates indicating that calcium release through RyRs does not contribute to the selective motor neuron death in this animal model for ALS.
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Extracellular nucleotides exert their actions via two subfamilies of purinoceptors: P2X and P2Y. Eight mammalian P2Y receptor subtypes (P2Y(1,2,4,6,11,12,13,14)) have been identified. In this work, the localization of P2Y(6) was studied in rat retina using double immunofluorescence labeling and confocal scanning microscopy. ⋯ Moreover, P2Y(6) immunoreactivity was seen in almost all ganglion cells, labeled by Brn3a. In Müller glial cells, stained by cellular retinaldehyde binding protein (CRALBP), however, no P2Y(6) expression was found in both somata and processes. We speculate that P2Y(6) may be involved in retinal information processing in different ways, probably by regulating the release of transmitters and/or modulating the radial flow of visual signals and lateral interaction mediated by horizontal and amacrine cells.
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The amygdala and serotonergic innervations thereunto are considered to cooperatively modulate affective behaviors. By whole-cell recording, the present study examined effects of serotonin (5-HT) on synaptic transmission in the rat basolateral amygdala (BLA) complex, which is the amygdalar entrance for sensory information. Application of 5-HT-attenuated excitatory postsynaptic currents at synapses from the lateral amygdala (LA) to the BLA proper, and also at synapses from putative thalamic afferents to LA principal neurons, both depending on 5-HT(2) receptors. ⋯ Reduction of potassium currents was identified as a major ionic mechanism for this sADPs. We thus revealed that 5-HT usually reduces overall synaptic transmission in the whole BLA complex, but enables sADPs to occur, thereby increasing synaptic responsiveness of LA neurons in a positive feedback manner. With this duality of 5-HT actions in operation, a weak input to the BLA complex would be usually eliminated, but could be selected were it associated with sufficiently large depolarization.