Translational Neuroscience Facility
Translational Neuroscience Facility
Tadros S.F.,Translational Neuroscience Facility |
Kim Y.,Translational Neuroscience Facility |
Phan P.A.B.,Translational Neuroscience Facility |
Housley G.D.,Translational Neuroscience Facility
Histochemistry and Cell Biology | Year: 2010
Canonical transient receptor potential (TRPC) subunits assemble as tetramers to form ion channels with high calcium (Ca2+) permeability. Here, we investigated the possibility that TRPC3 ion channels are broadly expressed in the adult guinea pig and mouse cochleae. Using immunofluorescence, pronounced labeling occurred in the spiral ganglion (SG) neurons, inner hair cells (IHC), outer hair cells (OHC) and epithelial cells lining scala media. TRPC3 expression was homogeneous in the SG throughout the cochlea. In contrast, there was marked spatial variation in the immunolabeling in the cochlear hair cells with respect to location. This likely relates to the tonotopy of these cells. TRPC3 immunolabeling was more pronounced in the IHC than OHC. Both basal region IHC and OHC had higher TRPC3 expression levels than the corresponding cells from the apical region of the cochlea. These data suggest that TRPC3 ion channels contribute to Ca2+ homeostasis associated with the hair cells, with higher ionfluxes in more basal regions of the cochlea, and may also be a signiflcant pathway for Ca2+ entry associated with auditory neurotransmission via the SG neurons. TRPC3 expression was also identifled within the spiral limbus region, inner and outer sulcus, but without evidence for spatial variation in expression level. Expression in these gap junction-coupled epithelial cells lining scala media is indicative of a contribution of TRPC3 channels to cochlear electrochemical homeostasis. © Springer-Verlag 2009.
Harasta A.E.,Translational Neuroscience Facility |
Power J.M.,Translational Neuroscience Facility |
Von Jonquieres G.,Translational Neuroscience Facility |
Karl T.,Neuroscience Research Australia |
And 5 more authors.
Neuropsychopharmacology | Year: 2015
Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are a key component of the satiety signaling system, and long-acting GLP-1 analogs have been approved for the treatment of type-2 diabetes mellitus. Previous reports demonstrate that GLP-1 regulates glucose homeostasis alongside the rewarding effects of food. Both palatable food and illicit drugs activate brain reward circuitries, and pharmacological studies suggest that central nervous system GLP-1 signaling holds potential for the treatment of addiction. However, the role of endogenous GLP-1 in the attenuation of reward-oriented behavior, and the essential domains of the mesolimbic system mediating these beneficial effects, are largely unknown. We hypothesized that the central regions of highest Glp-1r gene activity are essential in mediating responses to drugs of abuse. Here, we show that Glp-1r-deficient (Glp-1r -/-) mice have greatly augmented cocaine-induced locomotor responses and enhanced conditional place preference compared with wild-type (Glp-1r +/+) controls. Employing mRNA in situ hybridization we located peak Glp-1r mRNA expression in GABAergic neurons of the dorsal lateral septum, an anatomical site with a crucial function in reward perception. Whole-cell patch-clamp recordings of dorsal lateral septum neurons revealed that genetic Glp-1r ablation leads to increased excitability of these cells. Viral vector-mediated Glp-1r gene delivery to the dorsal lateral septum of Glp-1r -/- animals reduced cocaine-induced locomotion and conditional place preference to wild-type levels. This site-specific genetic complementation did not affect the anxiogenic phenotype observed in Glp-1r -/- controls. These data reveal a novel role of GLP-1R in dorsal lateral septum function driving behavioral responses to cocaine. © 2015 American College of Neuropsychopharmacology.
PubMed | University of New South Wales and Translational Neuroscience Facility
Type: Journal Article | Journal: European journal of human genetics : EJHG | Year: 2015
Williams-Beuren Syndrome (WBS) is a rare genetic condition caused by a hemizygous deletion involving up to 28 genes within chromosome 7q11.23. Among the spectrum of physical and neurological defects in WBS, it is common to find a distinctive response to sound stimuli that includes extreme adverse reactions to loud, or sudden sounds and a fascination with certain sounds that may manifest as strengths in musical ability. However, hearing tests indicate that sensorineural hearing loss (SNHL) is frequently found in WBS patients. The functional and genetic basis of this unusual auditory phenotype is currently unknown. Here, we investigated the potential involvement of GTF2IRD1, a transcription factor encoded by a gene located within the WBS deletion that has been implicated as a contributor to the WBS assorted neurocognitive profile and craniofacial abnormalities. Using Gtf2ird1 knockout mice, we have analysed the expression of the gene in the inner ear and examined hearing capacity by evaluating the auditory brainstem response (ABR) and the distortion product of otoacoustic emissions (DPOAE). Our results show that Gtf2ird1 is expressed in a number of cell types within the cochlea, and Gtf2ird1 null mice showed higher auditory thresholds (hypoacusis) in both ABR and DPOAE hearing assessments. These data indicate that the principal hearing deficit in the mice can be traced to impairments in the amplification process mediated by the outer hair cells and suggests that similar mechanisms may underpin the SNHL experienced by WBS patients.