Molecular and Cellular Basis of Learning Difficulties in Genetic Disorders

Abstract

Recent advances have revealed a plethora of genes, signalling pathways, cellular and circuit processes involved in learning and memory. Convergent evidence demonstrates that molecular mechanisms that regulate long‐lasting changes in synaptic function are critical for learning and memory. This evidence has had a key role in unraveling mechanisms responsible for learning disabilities. For example, mutations in the neurofibromatosis type I (NF1) gene are a common genetic cause for learning disabilities. Studies in mice revealed that these learning deficits are caused by increases in Ras signalling leading to enhancements in synaptic inhibition and synaptic plasticity deficits. These deficits can be reversed by manipulations that target Ras signalling or inhibition. Current clinical trials are testing the efficacy of these treatments in NF1. Studies in other genetic causes for learning disabilities have shown that it is possible to develop mechanism‐based treatments for these disorders in mice that are effective even when they are started in adulthood.

Key Concepts:

  • The molecular mechanisms that regulate long‐lasting changes in synaptic function are critical for learning and memory.

  • Our growing understanding of mechanisms of memory has been effectively used to unravel the causes for memory deficits associated with animal models of several key genetic disorders, including NF1, tuberous sclerosis and fragile X.

  • It is possible to develop mechanism‐based treatments for developmental disorders that are effective even when treatment is started in adulthood.

Keywords: synaptic plasticity; NF1; LTP; Ras

Figure 1.

Overview of the RAS‐MAPK pathway and associated disorders. Binding of a growth factor to a receptor tyrosine kinase (RTK) activates RAS proteins by the action of guanosine nucleotide exchange factors (GEFs) such as SOS which catalyse guanosine nucleotide exchange. RAS‐GTP activates RAF and downstream effectors. Signalling is terminated when RAS‐GTP is hydrolysed to RAS‐GDP either by the action of GAPs neurofibromin or p120 GAP. Responsible proteins for autoimmune lymphoproliferative syndrome (ALPS), capillary malformation‐arteriovenous malformation (CM‐AVM), neurofibromatosis type 1 (NF1), Costello, Noonan, LEOPARD, cardiofaciocutaneous (CFC) and NF1‐like syndrome are indicated. Reproduced from Denayer et al., with permission from BMJ Publishing Group Ltd.

Figure 2.

Rescue by Lovastatin of attention deficits in nf1+/− mice. (a) nf1+/− mice have deficits compared to wt animals in the 0.5 ms target stimulus duration condition of the lateralised reaction time test. The deficit is rescued by lovastatin treatment. (b) The deficit is seen only at the most difficult interval. Longer intervals produce equivalent performance between the groups (wt=10, nf1+/−=14, wt with lovastatin=7, nf1+/− with lovastatin=7). Error bars represent ±1 standard error. Reproduced from Li et al., with permission from Elsevier.

Figure 3.

Lovastatin rescue of spatial learning deficits in nf1+/− mice. (a) Per cent time spent in each quadrant during a water maze probe trial on day 5. (b) Per cent time spent in each quadrant during a probe trial on day 7. Quadrants are target quadrant (TQ), adjacent left, opposite quadrant (OP) and adjacent right (wt=24, nf1+/−=21, wt with lovastatin=21, nf1+/− with lovastatin=20). Error bars represent ±1 standard error. Reproduced from Li et al., with permission from Elsevier.

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Further Reading

Lee YS and Silva AJ (2009) The molecular and cellular biology of enhanced cognition. Nature Reviews. Neuroscience 10(2): 126–140.

Shilyansky C, Lee YS and Silva AJ (2010) Molecular and cellular mechanisms of learning disabilities: a focus on NF1. Annual Review of Neuroscience 33: 221–243.

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Crego, Cortney, Landreth, Anthony, and Silva, Alcino J(Apr 2011) Molecular and Cellular Basis of Learning Difficulties in Genetic Disorders. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0022480]