From Learning to Memory: What Flies Can Tell Us about Intellectual Disability Treatment

Abstract

Intellectual disability (ID), previously known as mental retardation, affects 3% of the population and remains without pharmacological treatment. ID is characterized by impaired general mental abilities associated with defects in adaptive function in which onset occurs before 18 years of age. Genetic factors are increasing and being recognized as the causes of severe ID due to increased use of genome-wide screening tools. Unfortunately drug discovery for treatment of ID has not followed the same pace as gene discovery, leaving clinicians, patients, and families without the ability to ameliorate symptoms. Despite this, several model organisms have proven valuable in developing and screening candidate drugs. One such model organism is the fruit fly Drosophila. First, we review the current understanding of memory in human and its model in Drosophila. Second, we describe key signaling pathways involved in ID and memory such as the cyclic adenosine 3',5'-monophosphate (cAMP)-cAMP response element binding protein (CREB) pathway, the regulation of protein synthesis, the role of receptors and anchoring proteins, the role of neuronal proliferation, and finally the role of neurotransmitters. Third, we characterize the types of memory defects found in patients with ID. Finally, we discuss how important insights gained from Drosophila learning and memory could be translated in clinical research to lead to better treatment development.

Keywords: Drosophila; clinical trials; fragile X; intellectual disability; learning; memory.

Figure 1

Intellectual disability and related co-morbid conditions. Intellectual disability is defined by the presence of cognitive defects (as measured usually by an intellectual quotient below 70) and the presence of adaptive dysfunction. These symptoms must have an onset before the patient is 18 years old to distinguish it from other conditions such as dementia. Several other conditions are frequently associated with ID, including sleep difficulties, obsessive-compulsive behaviors, anxiety, sensory-processing difficulties, autism, and epilepsy, which have significant effect on the cognitive and adaptive behaviors of the patients. In many patients, the effect of anxiety can be so prominent that it leads to underestimation of the true cognitive potential. Sensory-processing deficit is also very important in regulating the perception of sound, light and pain, and can contribute to the anxiety. Autism, which involves limited behavioral and social repertoire, will also affect the ability of the child to interact and thus impact his development. Epilepsy is much more common in ID (up to 30% as opposed to 3% in the general population) and can have detrimental effect on memory and daily functioning. In addition, drugs used to treat epilepsy (such as valproic acid) may have effects on memory themselves.

Figure 2

Fragile X Mental retardation protein regulates several cellular functions in the dendritic spine. Fragile X Mental retardation protein affects multiple aspects of neuronal metabolism. Even within a certain function like translational control, FMRP interacts with multiple pathways. Indeed, FMRP has been shown to regulate the AKT pathway via repression of PIKE. In addition, FMRP regulates CPEB that regulates translation via the poly A tail. FMRP also binds CYFIP and is part of the microRNA and short interfering pathway. FMRP also regulates the assembly of the ribosome to target RNA with the short RNA BC1. FMRP also interact with the cAMP–CREB pathway via the link with PKA but also because FMRP is produce in response to CREB activation. FMRP regulates cellular shape via actin remodeling using multiple molecules (profilin, cofilin, filamin) and receptors (Dscam, Receptor tyrosine kinase-RTK).

Figure 3

FMRP also acts at the nuclear level. FMRP has been shown to be produced in response to cAMP–CREB activation. Indeed, levels of FMRP are increased in PDE mutants. FMRP isoforms have been shown to have different role in short-term and long-term memory as was shown previously in NF1. The FMRP isoform lacking the Q/N rich domain is localized back to the nucleus and may participate in histone modification and splicing.

Figure 4

Scenarios of learning and memory defects in patients with ID. Several potential scenarios could be proposed to account for cognitive defects of patients with ID based on previous research findings. Depending on the gene tested or the method used, these various scenarios have been observed in ID patients. (A) In control, subjects without ID will be able to learn a task to criterion and then will present a lower performance in retest at 24 h. (B) In some rare cases, no learning and memory defects would be observed. (C) In some patients, defect in learning could be the sole manifestation. (D) In other patients, they can learn the information but would not be able to retain it. (E) Finally, in some patients, learning and long-term memory could be both impaired. The decreased level of learning, could be responsible for the defect in memory as the actual forgetting levels are the same as in controls. It should be noted that at this time, there is little systematic study aimed at identifying which model is most applicable to each specific genes. These hypothetical scenarios may provide a framework for the memory investigation in ID.