Alumni speakers (l-r) Aniko Ludanyi, Albert Chiang and Ana Vanesa Torbidoni
The IBRO alumni symposium and social held on 18 October during SfN 2009 in Chicago attracted 200 participants. Alumni Chair Susan Sara introduced the evening, followed by IBRO Secretary-General Marina Bentivoglio and President Carlos Belmonte, who emphasized the importance of the alumni community and its networking. There followed three short talks by alumni on their research, after which participants enjoyed an evening of discussion and socializing. The three speakers were recipients of funding to attend Cold Spring Harbor Laboratory (CSHL) courses in 2007 or 2008.
Ana Vanesa Torbidoni (Institute for Research on Genetic Engineering and Molecular Biology (INGEBI), CONICET, Buenos Aires, Argentina) spoke about her recent work on "Shaping auditory pathways: Effect of a mutation in the nicotinic cholinergic receptor of hair cells on central auditory pathways". A synopsis of her work follows:
Introduction: There are two different types of hair cells in the Organ of Corti of the cochlea: inner hair cells (IHCs) that transform the sound information into electrical signals and outer hair cells (OHCs) known as the cochlear amplifier, because they increase the sound-evoked motions of the organ of Corti. Sound processing is modulated by efferent terminals, one of them synapsing with OHCs. These terminals release acetylcholine (ACh) that acting on heteromeric nicotinic receptor α9/α10 (nAChR) of the OHCs, inhibits amplification and thus reduces cochlear sensitivity. In the Dr A. Belén Elgoyhen's laboratory, where I am working as a postdoc, a knock-in mouse with a mutation at 9 position of α9 subunit of the α9/α10 receptor (L9'T knock-in, Ki) has been generated. This change determined a gain in the receptor function (Taranda et al. 2009).
Purpose: analyze if this cochlear modification in the nAChR could induce molecular changes at any of the different nuclei of the central auditory pathways.
Material and Methods: Wild type (WT) and L9'T Ki mice of postnatal day 11 and 20 (P11 and P20), before and after onset of hearing respectively. We used immunohistochemistry of brainstem cryosections to analyze the Medial Nucleus of the Trapezoid Body (MNTB), an important nucleus in sound processing and localization. We study Voltage-sensitive K channels (Kv1.1), particularly important in determining the discharge patterns of neurons. We measured the immunoreactivity to Kv1.1 along the medial-lateral axe dividing the MNTB it in three areas: lateral, intermediate and medial.
Results: We found that the Kv1.1 immunoreactivity was present in all neurons along the medial lateral axe of the MNTB in both types of animals. There was a week correlation between the intensity of the immunoreactivity to Kv1.1 with the area along the medial-lateral axe in WT animals, being stronger in lateral areas than in medial. At P11, we observed a decrease in the Kv1.1 immunoreactivity in L9'T Ki animals (p<0,05) in all areas measured. After the onset of hearing these differences were still detected.
Future: Test the differences in Kv1.1 between WT and L9'T Ki by other techniques (Western blot, RT-PCR). Analyze other molecules such us: NMDA, AMPA, GABA-R. Perform electrophysiology of the MNTB. Analyze other relay centers of the auditory pathway.
Conclusions: Kv1.1 channels are concentrated in neurons of the MNTB. The modification of the activity the nAChR of OHC induced a reduction in the intensity of Kv1.1 immunoreactivity in the MNTB in P11 and P20.
Albert Chiang (National Centre for Biological Sciences (NCBS), Bangalore, India) talked about his work on "Mechanisms of synapse maintenance in Drosophila olfactory circuits":
The mechanisms involved in the maintenance of an animal's nervous system architecture post-developmentally are poorly understood, despite their potential relevance to neurodegeneration. During development, neuronal activity and cell signaling pathways collaborate to eliminate neurons or synaptic connections (Cohen-Cory, 2002; Katz and Shatz, 1996). However, little is known about the mechanisms underlying the maintenance of mature neurons in an established circuit, or, indeed, whether there is any active requirement at all for maintenance. Using the Drosophila olfactory sensory map, we have demonstrated that maintenance of adult olfactory sensory neurons (OSNs) requires cell-autonomous neuronal activity (Chiang et al., 2009). When activity is silenced, development occurs normally, but OSNs degenerate in adulthood. This inactivity-induced neurodegeneration can be rescued by downregulating Glycogen synthase kinase-3β (Gsk-3β). We also found that neural activity increased the amount of the Wnt ligand Wingless (Wg) present in the antennal lobe (olfactory bulb), and a series of experiments with activated and dominant-negative forms of Wnt pathway components showed that signaling from Wg through Dishevelled (Dsh) to Gsk-3β protected inactive neurons from degeneration, whereas inhibiting Wnt signaling induced degeneration. Our study suggests that neuronal activity and Wnt signaling, each of which has been separately implicated in maintenance of neuronal circuits, may be mechanistically coupled (Chiang et al., 2009; VanHook, 2009). This work was carried out with my Ph.D. supervisor Professsor K. VijayRaghavan (National Centre for Biological Sciences (NCBS), Bangalore), in collaboration with Professor Veronica Rodrigues (Tata Institute for Fundamental Research (TIFR), Mumbai).
Aniko Ludanyi (Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary) was the third alumni to talk about her recent research, "CB1 cannabinoid receptor and related molecular elements are down-regulated in the hippocampus of epileptic patients":
Endocannabinoid system is a recently recognized synaptic signaling system. Compelling evidence show that its perturbation prones animals to development of epileptic seizures indicating that endocannabinoids play an intrinsic protective role in controlling neuronal excitability. To elucidate whether potential long-term reorganization of endocannabinoid signaling occurs in chronic epileptic patients, we carried out comparative expression profiling along with quantitative electron microscopic analysis of epileptic hippocampal samples surgically removed from patients with intractable temporal lobe epilepsy and control postmortem hippocampal samples.
Quantitative PCR measurements revealed that mRNA level of CB1 cannabinoid receptor was down-regulated in epileptic hippocampus. Likewise, the expression level of the cannabinoid receptor interacting protein 1a was decreased. mRNA level of diacylglycerol lipase alpha, the enzyme responsible for synthesis of 2-arachidonoylglycerol (2-AG), was also reduced. Parallel to the decline in CB1 mRNA, the density of CB1-immunolabeling was also decreased in the epileptic hippocampus, most robustly in the inner molecular layer of the dentate gyrus. Quantitative electron microscopic analysis uncovered reduction in the ratio of CB1-positive glutamatergic axon terminals, but no change could be observed on the CB1-positive GABAergic axon terminals.
These findings reveal that endogenous neuroprotective signaling mediated by endocannabinoids may be impaired in epileptic human hippocampus and imply that down-regulation of CB1 receptors and related molecular components of the endocannabinoid system at the glutamatergic axon terminals may be conducive to deleterious effects of increased network excitability.
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