Age-dependent memory loss, synaptic pathology and altered brain plasticity in the Drosophila mutant cardinal accumulating 3-hydroxykynurenine

Abstract

A search for Drosophila mutants with phenotypes similar to human diseases might help to unravel evolutionary conserved genes implicated in polygenic human disorders. Among these are neurodegenerative diseases, characterized by a late onset disturbance of memory, synaptic and glial pathology, structural brain impairments and altered content of the intermediates of the kynurenine pathway, the modulators of glutamate excito- and oxidative toxicity. This pathway is conserved in insects, in rodents, and in humans. We tested the Drosophila mutants cardinal (3-hydroxykynurenine excess) and cinnabar (kynurenic acid excess) for age-dependent changes in memory, synaptic pathology, structural brain plasticity and glial immunoreactivity. The mutant cardinal demonstrated a decline in learning and memory from the 12th to the 29th day of life in a paradigm of conditioned courtship suppression. Memory decline was accompanied by a sharp decrease in immunoreactivity to the synaptic cysteine string protein, and alterations in volumetric parameters of the mushroom bodies, the brain structures implicated in memory.

Ethyl-Eicosapentaenoic Acid in First-Episode Psychosis. A 1H-MRS Study

“…The latter is in line with a recent study suggesting that atypical antipsychotic medication may protect the brain of firstepisode schizophrenia patients from gray matter loss . The positive correlation between age and change of in vivo brain metabolites may indicate an advantage for younger FEP patients with neuroprotective treatment strategies, indicating that the potential for a restoration of synaptic integrity may decrease with adulthood (Nakamura et al, 1999;Savvateeva et al, 2000). While this would have particular importance for early intervention strategies of psychotic disorders, it needs to be confirmed by additional clinical trials.…”

Crystal structure of the Anopheles gambiae 3-hydroxykynurenine transaminase

“…3-HK-triggered damage is not restricted to mammalian cells. Indeed, several invertebrate species, which depend on the kynurenine pathway for dietary tryptophan oxidation, are highly sensitive to perturbations in the physiological balance of its intermediate metabolites (13,14). In particular, the exogenous administration of 3-HK in adult insects profoundly affects locomotive activity and can culminate in irreversible paralysis and death (15,16).…”

The influence of D. melanogaster mutations of the kynurenine pathway of tryptophan metabolism on locomotor behavior and expression of genes belonging to glutamatergic and cholinergic systems

“…У личинок 3-го возраста, так же как и у 5-суточных имаго, уровень 3-ГК сравнительно невелик. Токсическое действие 3-ГК у линии cd развивается лишь начиная с 12 суток имаги-нального периода (Savvateeva et al, 2000).…”

“…У 12-13-суточных cd объем каликсов грибовидных тел, ответственных за процес-сы обучения и памяти у имаго (Krashes, Waddell, 2008;Krashes et al, 2007), снижен сравнительно с 5-суточ-ными сd, а также 12-13-суточными CS и cn (Savvateeva et al, 2000). При этом α бунгаротоксин-чувствительные nAChR (к числу которых относятся dα7 и dα3) у взрос-лых дрозофил в большом количестве представлены именно в каликсах грибовидных тел имаго дрозофилы (Su, O'Dowd, 2003).…”

“…Оба эти мутанта в возрасте 5 суток не отличаются по пара-метрам обучения в парадигме условно-рефлекторного подавления ухаживания от CS (Savvateeva et al, 2000). Однако только у мутанта cd начиная с 13 суток прояв-ляется прогрессивная потеря среднесрочной памяти, за-канчиваясь полной потерей памяти в возрасте 29 суток (Savvateeva et al, 2000).…”