A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson's Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway.

Parkinson's disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.

Celecoxib impairs heart development via inhibiting cyclooxygenase-2 activity in zebrafish embryos.

BACKGROUND: Celecoxib, a cyclooxygenase-2 inhibitor, is a commonly ingested drug that is used by some women during pregnancy. Although use of celecoxib is associated with increased cardiovascular risk in adults, its effect on fetal heart development remains unknown. METHODS: Zebrafish embryos were exposed to celecoxib or other relevant drugs from tailbud stage (10.3-72 h postfertilization). Heart looping and valve formation were examined at different developmental stages by in vivo confocal imaging. In addition, whole mount in situ hybridization was performed to examine drug-induced changes in the expression of heart valve marker genes. RESULTS: In celecoxib-treated zebrafish embryos, the heart failed to undergo normal looping and the heart valve was absent, causing serious blood regurgitation. Furthermore, celecoxib treatment disturbed the restricted expression of the heart valve markers bone morphogenetic protein 4 and versican-but not the cardiac chamber markers cardiac myosin light chain 2, ventricular myosin heavy chain, and atrial myosin heavy chain. These defects in heart development were markedly relieved by treatment with the cyclooxygenase-2 downstream product prostaglandin E2, and mimicked by the cyclooxygenase-2 inhibitor NS398, implying that celecoxib-induced heart defects were caused by the inhibition of cyclooxygenase-2 activity. CONCLUSIONS: These findings provide the first in vivo evidence that celecoxib exposure impairs heart development in zebrafish embryos by inhibiting cyclooxygenase-2 activity.

Development of light response and GABAergic excitation-to-inhibition switch in zebrafish retinal ganglion cells.

The zebrafish retina has been an important model for studying morphological development of neural circuits in vivo. However, its functional development is not yet well understood. To investigate the functional development of zebrafish retina, we developed an in vivo patch-clamp whole-cell recording technique in intact zebrafish larvae. We first examined the developmental profile of light-evoked responses (LERs) in retinal ganglion cells (RGCs) from 2 to 9 days post-fertilization (dpf). Unstable LERs were first observed at 2.5 dpf. By 4 dpf, RGCs exhibited reliable light responses. As the GABAergic system is critical for retinal development, we then performed in vivo gramicidin perforated-patch whole-cell recording to characterize the developmental change of GABAergic action in RGCs. The reversal potential of GABA-induced currents (E(GABA)) in RGCs gradually shifted from depolarized to hyperpolarized levels during 2-4 dpf and the excitation-to-inhibition (E-I) switch of GABAergic action occurred at around 2.5 dpf when RGCs became light sensitive. Meanwhile, GABAergic transmission upstream to RGCs also became inhibitory by 2.5 dpf. Furthermore, down-regulation of the K(+)/Cl() co-transporter (KCC2) by the morpholino oligonucleotide-based knockdown approach, which shifted RGC E(GABA) towards a more depolarized level and thus delayed the E-I switch by one day, postponed the appearance of RGC LERs by one day. In addition, RGCs exhibited correlated giant inward current (GICs) during 2.5-3.5 dpf. The period of GICs was shifted to 3-4.5 dpf by KCC2 knockdown. Taken together, the GABAergic E-I switch occurs coincidently with the emergence of light responses and GICs in zebrafish RGCs, and may contribute to the functional development of retinal circuits.