Molecular and cellular mechanisms of learning disabilities: a focus on NF1

Abstract

Neurofibromatosis Type I (NF1) is a single-gene disorder characterized by a high incidence of complex cognitive symptoms, including learning disabilities, attention deficit disorder, executive function deficits, and motor coordination problems. Because the underlying genetic cause of this disorder is known, study of NF1 from a molecular, cellular, and systems perspective has provided mechanistic insights into the etiology of higher-order cognitive symptoms associated with the disease. In particular, studies of animal models of NF1 indicated that disruption of Ras regulation of inhibitory networks is critical to the etiology of cognitive deficits associated with NF1. Animal models of Nf1 identified mechanisms and pathways that are required for cognition, and represent an important complement to the complex neuropsychological literature on learning disabilities associated with this condition. Here, we review findings from NF1 animal models and human populations affected by NF1, highlighting areas of potential translation and discussing the implications and limitations of generalizing findings from this single-gene disease to idiopathic learning disabilities.

Figure 1

Schematic representation of human and mouse Nf1. (a) Human Nf1 on chromosome 17 encodes a 2818--amino acid protein called neurofibromin. Small boxes represent exons. Black boxes indicate exons 21 to 27a that encode the GAP-related domain (GRD). Alternatively spliced exons are marked by arrows. Disease-causing mutations are widely distributed throughout the entire Nf1 gene and most of those result in loss of function of its protein product. (b) Top: the mouse Nf1 gene on chromosome 11 has a structure very similar to that of human Nf1 gene and encodes a protein with 98% identity to human NF1. Middle: Nf1 null mutant mice were generated by inserting a neomycin cassette in exon 31 (Jacks et al. 1994). Gray box indicates exon 31 including the neo gene. Bottom: conditional mutants were engineered by inserting loxP sites flanking exons 31 and 32 (Zhu et al. 2001). loxP sites are indicated by triangles. Delivery of Cre recombinase by crossing with Cre-expressing transgenic line or viral vector enables cell type-- specific deletion of Nf1.

Figure 2

Neurofibromin and cell signaling. Neurofibromin (NF1) is a GTPase activating protein (GAP) that functions as a negative regulator of Ras-MAPK signaling cascade. Guanine-nucleotide exchange factors (GEFs), such as SOS, may counteract the GAP function of NF1. On the other hand, NF1 acts as an activator of adenylate cyclase (AC). Note that the key pathways are grossly simplified in this diagram. For example, phosphatidylinositol 3-kinase (PI3K)-AKT-mTOR cascade is also modulated by NF1, but is omitted in the diagram. Arrows and barred lines indicate activation and suppression, respectively. MEK, mitogen-activated protein kinase or extracellular signal-regulated kinase kinase; NMDAR, N-methyl-D-aspartate receptor; GPCR, G proteincoupled receptor; RTK, receptor tyrosine kinase; PKA, protein kinase A; PKC, protein kinase C; SHP2, Src homology 2-containing tyrosine phosphatase.

Figure 3

Proposed cellular mechanism underlying learning deficits of Nf1 mutant mice. (a) Learning triggers interneuronal Ras signaling leading to increased GABA release. MAPKdependent phosphorylation of synapsin I (SynI) plays a critical role in GABA release. Wild-type NF1 restricts the increase in GABA release within an appropriate range that modulates learning. (b) In Nf1 mutants, reduced NF1 activity leads to abnormal hyperactivation of Ras signaling in inhibitory interneurons during learning, resulting in abnormally high GABA release. This increased activity-dependent GABA release shifts the balance between excitatory and inhibitory processes in neuronetworks of the mutant mice and impairs synaptic plasticity needed for learning and memory.