Social learning and amygdala disruptions in Nf1 mice are rescued by blocking p21-activated kinase

Abstract

Children with Neurofibromatosis type 1 (NF1) are increasingly recognized to have high prevalence of social difficulties and autism spectrum disorders (ASD). We demonstrated selective social learning deficit in mice with deletion of a single Nf1 gene (Nf1+/−), along with greater activation of mitogen activated protein kinase pathway in neurons from amygdala and frontal cortex, structures relevant to social behaviors. The Nf1+/− mice showed aberrant amygdala glutamate/GABA neurotransmission; deficits in long-term potentiation; and specific disruptions in expression of two proteins associated with glutamate and GABA neurotransmission: a disintegrin and metalloprotease domain 22 (ADAM22) and heat shock protein 70 (HSP70), respectively. All of these amygdala disruptions were normalized by co-deletion of p21 protein-activated kinase (Pak1) gene. We also rescued the social behavior deficits in Nf1+/− mice with pharmacological blockade of Pak1 directly in the amygdala. These findings provide novel insights and therapeutic targets for NF1 and ASD patients.

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

“…However, in contrast to the previous findings (Cui et al, 2008;Shilyansky et al, 2010a), Molosh and colleagues reported that glutamatergic transmission is also altered in the amygdala of Nf1 +/-mice (Molosh et al, 2014). This discrepancy might be due to the differences in genetic backgrounds of the mutants: an F1 hybrid (C57Bl/6 x 129S6) was used in the previous studies (Cui et al, 2008;Shilyansky et al, 2010a) whereas a C57Bl/6 background was used by Molosh et al (2014). Nevertheless, these results clearly show that NF1 regulates neurotransmitter release from GABAergic inhibitory neurons (Fig.…”

“…A recent study also reported deficits in social behavior, increased GABAergic synaptic transmission, and impaired amygdala LTP in the Nf1 +/-mice (Molosh, Johnson, Spence, Arendt, Federici, Bernabe et al, 2014). However, in contrast to the previous findings (Cui et al, 2008;Shilyansky et al, 2010a), Molosh and colleagues reported that glutamatergic transmission is also altered in the amygdala of Nf1 +/-mice (Molosh et al, 2014). This discrepancy might be due to the differences in genetic backgrounds of the mutants: an F1 hybrid (C57Bl/6 x 129S6) was used in the previous studies (Cui et al, 2008;Shilyansky et al, 2010a) whereas a C57Bl/6 background was used by Molosh et al (2014).…”

“…Shilyansky and colleagues further showed that GABA-mediated inhibition is also increased in the cortex of the Nf1 +/-mice, which may result in working memory deficits associated with NF1 (Shilyansky et al, 2010a). A recent study also reported deficits in social behavior, increased GABAergic synaptic transmission, and impaired amygdala LTP in the Nf1 +/-mice (Molosh, Johnson, Spence, Arendt, Federici, Bernabe et al, 2014). However, in contrast to the previous findings (Cui et al, 2008;Shilyansky et al, 2010a), Molosh and colleagues reported that glutamatergic transmission is also altered in the amygdala of Nf1 +/-mice (Molosh et al, 2014).…”

Decrease of SYNGAP1 in GABAergic cells impairs inhibitory synapse connectivity, synaptic inhibition and cognitive function

“…Decrease of Nf1 induces deficits in hippocampal-dependent spatial learning, amygdala dependent-social learning and prefrontal cortex-dependent working memory by increasing GABA release in these different areas of the brain through the activation of the Ras–ERK pathway61626364. The increase of Ras thus appears to produce opposite effects on GABA neurotransmission depending upon whether it is associated with Syngap1 or Nf1 haploinsufficiency.…”

Perfusion Single Photon Emission Computed Tomography in a Mouse Model of Neurofibromatosis Type 1: Towards a Biomarker of Neurologic Deficits

“…Recently, Molosh et al 16 identified the amygdala as a key structure involved in social learning deficits in NF1+/ − mice. They found aberrant glutamate and GABA neurotransmission in BLA (basolateral amygdala nuclei) neurons in NF1+/ − mice resulting in functional changes in amygdala networks.…”