Abstract
BackgroundReduced insulin/insulin-like growth factor signaling (IIS) is a major cause of symmetrical intrauterine growth retardation (IUGR), an impairment in cell proliferation during prenatal development that results in global growth defects and mental retardation. In Drosophila, chico encodes the only insulin receptor substrate. Similar to other animal models of IUGR, chico mutants have defects in global growth and associative learning. However, the physiological and molecular bases of learning defects caused by chico mutations, and by symmetrical IUGR, are not clear.ResultsIn this study, we found that chico mutations impair memory-associated synaptic plasticity in the mushroom bodies (MBs), neural centers for olfactory learning. Mutations in chico reduce expression of the rutabaga-type adenylyl cyclase (rut), leading to decreased cAMP synthesis in the MBs. Expressing a rut+ transgene in the MBs restores memory-associated plasticity and olfactory associative learning in chico mutants, without affecting growth. Thus chico mutations disrupt olfactory learning, at least in part, by reducing cAMP signaling in the MBs.ConclusionsOur results suggest that some cognitive defects associated with reduced IIS may occur, independently of developmental defects, from acute reductions in cAMP signaling.
Highlights
Reduced insulin/insulin-like growth factor signaling (IIS) is a major cause of symmetrical intrauterine growth retardation (IUGR), an impairment in cell proliferation during prenatal development that results in global growth defects and mental retardation
We found that chico mutants are defective for long-term enhancement (LTE), and have decreased expression of the rutabaga gene. rut encodes an adenylyl cyclase required for cAMP signaling during associative learning. rut mutants have impaired learning [10, 21], and we show that expression of a rut+ transgene in the mushroom bodies (MBs) restores both learning and LTE in chico mutants. rut+ expression restores learning and LTE without increasing numbers of MB neurons, indicating that learning defects in chico mutants are caused by reduced cAMP signaling, and not by reduced cell number
To determine whether they are defective for memoryassociated plasticity, we examined LTE in brains of chico mutants expressing the Ca2+ indicator G-CaMP 1.3 in the MBs (Fig. 1a). chico1 mutations consist of a P-element insertion 80 bp downstream from the translational start site, resulting in a complete loss of protein [6, 9]
Summary
Reduced insulin/insulin-like growth factor signaling (IIS) is a major cause of symmetrical intrauterine growth retardation (IUGR), an impairment in cell proliferation during prenatal development that results in global growth defects and mental retardation. The physiological and molecular bases of learning defects caused by chico mutations, and by symmetrical IUGR, are not clear. Symmetrical IUGR is caused by early intrauterine disruptions, which lead to global decreases in cell proliferation, reduced brain size and cognitive deficits [2]. In Drosophila, homozygous mutations in the chico gene, which encodes the only insulin receptor substrate in flies, decrease cell proliferation, reduce global body size and cause frequent death at birth [6,7,8]. Chico mutants display impaired associative learning [9], the physiological and molecular bases of learning defects caused by chico mutations are not clear
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