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Kasture, A.

Publications and source records attributed to Kasture, A..

2 recordsLinked to original sources

An extraglomerular relay circuit for multimodal integration within the Drosophila antennal lobe

The central integration of sensory information within and between brain hemispheres is critical for efficient behavioral responses, but at which level of information processing multimodal integration occurs is poorly understood. In olfactory systems an array of receptor-specific synaptic glomeruli with corresponding projection neurons (PNs) form separate sensory channels within each hemisphere, which run in parallel with other sensory modalities to converge at higher brain regions. We recently identified a small cluster of commissural pioneer neurons (cPINs) in the Drosophila olfactory system, which controls the formation of bilateral sensory circuits to support interhemispheric integration at the first synaptic layer. Here we show that cPINs also mediate the integration of sensory channels by relaying class-specific input within the antennal lobe. Functional studies showed that medial cPINs converge olfactory amine/ammonia input with a class of non-olfactory PNs to trigger attraction. During olfactory circuit formation, growing cPINs specify separate dendritic input/output domains, which merge into distinct glomeruli of different sensory modalities. Mutant analysis of the Wnt5 pathway revealed that cPINs display an initial PN-related growth pattern, which becomes redirected to organize lateral relay between sensory channels. These results identified a small cluster of olfactory interneurons as a central coordinator for fast convergence of sensory information, providing a mechanistic model of neural circuit evolution.

neuroscience↗

A tropane-based ibogaine analog rescues folding-deficient SERT and DAT

Missense mutations that give rise to protein misfolding are rare, but collectively, defective protein folding diseases are consequential. Folding deficiencies are amenable to pharmacological correction (pharmacochaperoning), but the underlying mechanisms remain enigmatic. Ibogaine and its active metabolite noribogaine correct folding defects in the dopamine transporter (DAT), but they rescue only a very limited number of folding-deficient DAT mutants, which give rise to infantile Parkinsonism and dystonia. Herein, a series of analogs was generated by reconfiguring the complex ibogaine ring system and exploring the structural requirements for binding to wild type transporters, and for rescuing two equivalent synthetic folding-deficient mutants, SERT-PG601,602AA and DAT-PG584,585AA. The most active tropane-based analog (9b) was also an effective pharmacochaperone in vivo, in Drosophila harboring DAT-PG584,585AA and rescued six out of 13 disease-associated human DAT mutants in vitro. Hence, a novel lead pharmacochaperone has been identified that demonstrates medication development potential for patients harboring DAT mutants.

pharmacology and toxicology↗