Neurofibromin regulates corticostriatal inhibitory networks during working memory performance

Abstract

Neurofibromatosis type I (NF1) is one of the most common singlegene causes of learning disabilities. Here, we use behavioral working memory probes and electrophysiological studies in a mouse model of NF1 (Nf1 heterozygous null mutants; Nf1 +/− ) to demonstrate that (i) Neurofibromin regulates prefrontal and striatal inhibitory networks, specifically activity-dependent GABA release and (ii) is required for working memory performance, with inhibitiondependent working memory deficits seen in Nf1 +/− mice. We find that increased inhibition in medial prefrontal cortex (mPFC) is sufficient to alter persistent activity in a biophysical model of an mPFC microcircuit, suggesting a possible mechanism for Nf1 +/− working memory deficits. Accordingly, working memory assays applied during functional MRI (fMRI) studies in human subjects with NF1 reveal hypoactivation of corticostriatal networks, which is associated with impaired working memory performance. Collectively, these integrative mouse and human studies reveal molecular and cellular mechanisms contributing to working memory deficits in NF1.GABA | Ras | prefrontal cortex | learning disability | neurofibromatosis type I N eurofibromatosis type 1 (NF1) is a valuable model for understanding mechanisms of learning disabilities (1). NF1 is a common genetic disorder (incidence 1:3,000) that results from mutations in a single gene (Nf1) that encodes the neurofibromin protein (2, 3). Specific deficits in the domains of visuospatial and executive functions are among the most common cognitive deficits associated with this syndrome (1,4,5). Previous mechanistic studies in a mouse model of NF1 (Nf1 heterozygous null mutants or Nf1 +/− ) demonstrated that neurofibromin modulates Rasdependent GABA release in the hippocampus, which in turn modulates long-term potentiation (LTP) and hippocampaldependent learning (6, 7). However, the mechanisms underlying frontal executive dysfunction in NF1, including prominent working memory deficits (5), are unknown. Therefore, to investigate mechanisms underlying working memory deficits associated with the NF1 mutation we carried out parallel experiments in mice and humans.Working memory is a cognitive construct involving the ability to hold and update information transiently in mind in the service of higher-order cognitive activities. Executive functions, including working memory, are thought to depend on common corticostriatal networks (8-11). Therefore, our experiments focused on frontal corticostriatal circuitry, with an emphasis on the dorsolateral prefrontal cortex (DLPFC) in humans, thought to be critical for working memory (12), and its functionally analogous structure in rodents, the medial prefrontal cortex (mPFC) (13,14).Here, we report Ras-dependent increases in GABA release in the mPFC and striatum of the Nf1 +/− mouse model. Increased GABAergic inhibition is likely to be responsible for the working memory deficits that we found in the Nf1 +/− mice because these deficits could be reversed with a drug that decreased inhibition. Further,...

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…Lee et al (2014) recently demonstrated that mice expressing either of two NS-associated mutations in PTPN11 show hippocampaldependent impairments in spatial learning tasks as well as deficits in hippocampal long-term potentiation. Other studies have reported that dysregulation of Ras can result in differences in maturation or functioning of frontal-subcortical circuitry involved in attention and cognitive control (Shilyansky et al 2010a). In a study of humans, Mainberger et al (2013) reported that, relative to a healthy comparison group, individuals with NS show reduced motor cortex plasticity (measured by changes in motor evoked potential amplitude) in response to paired peripheral electrical and transcranial magnetic stimulation.…”

“…Some research has indicated that Ras proteins (which are abnormally activated in these syndromes) may regulate interneuronal activity in prefrontal and striatal networks (Shilyansky et al 2010a). These regions of the brain are known to be critical for a number of higher-order cognitive processes such as working memory, response inhibition, and cognitive flexibility (Powell and Voeller 2004).…”

“…These regions of the brain are known to be critical for a number of higher-order cognitive processes such as working memory, response inhibition, and cognitive flexibility (Powell and Voeller 2004). Working memory abilities are known to be an area of weakness for children with other RASopathies, most notably NF1 (Rowbotham et al 2009;Shilyansky et al 2010a). In line with this finding, Pierpont et al (2013) reported that children with NS had weaker performance on a test assessing auditory and visual working memory than normative data, with 34 % showing significant impairment.…”

Mutant Mouse Models of Autism Spectrum Disorders

“…Mice with a heterozygous inactivating mutation in the Tsc genes (Tsc1 +/− and Tsc2 +/− mice) show deficits in learning, memory and contextual fear conditioning [56,68]. In addition to learning and memory deficits, Tsc1 +/− mice have reduced levels of social exploration, while Tsc2 +/− knockout mice show a normal social behavior [68,128] but altered ultrasonic vocalization [153]. In addition to behavioral changes, synaptic abnormalities are observed in the hippocampus of Tsc2 +/− and in mice with a conditional homozygous deletion of Tsc1 in astrocytes [56,68].…”

Neurofibromatosis: part 2 – clinical management

“…However, findings of brain abnormalities such as reduced white matter integrity, macrocephaly, abnormal gamma-aminobutyric acid activity, among others have provided converging evidences for impaired communication between the neural regions, and early myelin dysfunction in NF1 has been hypothesized to underlie cognitive deficits. In addition, the NF1 cognitive profile may be related with independently inherited genetic modifiers 30 and all cognitive impairments are considered a major source of decreased quality of life in NF1 childhood 31 .…”