Learning, Memory, and Transcription Factors

Abstract

The following article is the second in this series. It reviews genes and metabolic pathways involved in learning and memory in lower animals and in humans. These new, exciting studies will contribute to greater understanding of the molecular abnormalities responsible for cognitive disorders in children. Cognitive disorders in children have traditionally been described in terms of clinical phenotypes or syndromes, chromosomal lesions, metabolic disorders, or neuropathology. Relatively little is known about how these disorders affect the chemical reactions involved in learning and memory. Experiments in fruit flies, snails, and mice have revealed some highly conserved pathways that are involved in learning, memory, and synaptic plasticity, which is the primary substrate for memory storage. These can be divided into short-term memory storage through local changes in synapses, and long-term storage mediated by activation of transcription to translate new proteins that modify synaptic function. This review summarizes evidence that disruptions in these pathways are involved in human cognitive disorders, including neurofibromatosis type I, Coffin-Lowry syndrome, Rubinstein-Taybi syndrome, Rett syndrome, tuberous sclerosis-2, Down syndrome, X-linked ␣-thalassemia/ mental retardation, cretinism, Huntington disease, and lead poisoning. More than a thousand types of mental retardation are listed currently in Online Mendelian Inheritance in Man (OMIM, 2002) and many milder learning disorders are seen in clinical practice. Many of these disorders are associated with syndromes, chromosomal disorders, or metabolic diseases, but it is unclear how most of them disrupt the brain's chemical machinery for learning and memory. Experimental work over several decades makes it clear that long-term memory storage, which is essential for cognition, involves activity-dependent synaptic plasticity and transcription of genes to synthesize synaptic proteins (1, 2). Recently, several genetic forms of mental retardation have been linked to mutations in intracellular pathways that mediate synaptic plasticity, learning, and memory in lower animals (3). These discoveries suggest that a Alvin Zipursky Editor-in-Chief

Altered neurodevelopment associated with mutations of RSK2: a morphometric MRI study of Coffin–Lowry syndrome

“…Decreased brain volume in CLS is likely to stem from disruption of core RSK2 protein functions associated with mutations of this gene. The RSK2 protein activates the transcription factor cyclic AMP response element binding protein (CREB) [17,18], which in turn, regulates neuronal survival factors and is required for axonal growth, neuro-protection, and synaptic plasticity associated with long-term memory.…”

“…Persistent neuronal stimulation activates a cascade of molecular components that results in transcription and translation of new proteins, which strengthen and increase the number of synapses [18,22]. The RSK2 protein is directly involved in these signaling pathways [23,24].…”

Snoezelen: A controlled multi-sensory stimulation therapy for children recovering from severe brain injury

“…Impaired plasticity refers to situations in which genetic or acquired disorders disrupt molecular plasticity pathways, for example in genetic and acquired disorders such as TBI that cause cognitive impairment [46]. The Snoezelen environment may be an enriched environment that is beneficial for children with disruption in the signalling cascades that have been shown to mediate learning, memory and other forms of neuronal plasticity in animal models [47,48]. It has been reported that children who have severe or moderate mental retardation may find their immediate environment chaotic, frightening, confusing and unstimulating [46].…”

Plasticity and injury in the developing brain

“…The common theme for these disorders is that they disrupt specific steps in the pathways that lead to changes in numbers of synapses or in the strength of synapses based on synaptic activity (24). For example, neurofibromatosis type 1 (NF-1) is caused by a mutation in the tumor suppressor gene for the protein neurofibromin, which is a GTPase activating protein (GAP) (25).…”