Anantha Shekhar

Switch and maintenance of task set in schizophrenia

Task set maintenance and switching deficits are robust in schizophrenia. However, little is known about how these constructs are related to one another. The development of an improved understanding of set switching and maintenance deficits in schizophrenia requires that these constructs be explicated in terms of elementary cognitive processes rather than grouped into broad psychological concepts like executive functioning. A relevant dichotomy has been proposed in which sensory and perceptual (attentional) processes are distinguished from decisional (intentional) processes in task maintenance and switching; however, the contributions these processes make to performance deficits in schizophrenia is not known. In the present study, 30 participants with schizophrenia and 27 healthy comparisons completed a cued attentional set switching task. In addition to analyses of mean response times, the contributions of attentional and intentional processes to task performance were estimated using an ex-Gaussian distributional analysis. Schizophrenia was associated with a set maintenance deficit that was accounted for by an attentional, rather than intentional, dysfunction. Both groups showed significant switch costs that could be attributed to attentional processes, but there was no evidence for an attentional set switching deficit in schizophrenia. The findings suggest that set switching and set maintenance may reflect distinct cognitive deficits in schizophrenia and that they may be associated with unique information processing mechanisms.

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

Children with neurofibromatosis type 1 (NF1) are increasingly recognized as having a high prevalence of social difficulties and autism spectrum disorders (ASDs). We demonstrated a selective social learning deficit in mice with deletion of a single Nf1 allele (Nf1+/−), along with greater activation of the mitogen-activated protein kinase pathway in neurons from the amygdala and frontal cortex, structures that are relevant to social behaviors. The Nf1+/− mice showed aberrant amygdala glutamate and GABA neurotransmission, deficits in long-term potentiation and specific disruptions in the expression of two proteins that are 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 the additional deletion of the 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 insights and therapeutic targets for patients with NF1 and ASDs.

Neurofibromatosis type 1 as a model system to study molecular mechanisms of autism spectrum disorder symptoms

Neurofibromatosis type 1 (NF1) is monogenic neurodevelopmental disorder caused by mutation of NF1 gene, which leads to increased susceptibility to various tumors formations. Additionally, majority of patients with NF1 are experience high incidence of cognitive deficits. Particularly, we review the growing number of reports demonstrated a higher incidence of autism spectrum disorder (ASD) in individuals with NF1. In this review we also discuss face validity of preclinical Nf1 mouse models. Then we describe discoveries from these animal models that have uncovered the deficiencies in the regulation of Ras and other intracellular pathways as critical mechanisms underlying the Nf1 cognitive problems. We also summarize and interpret recent preclinical and clinical studies that point toward potential pharmacological therapies for NF1 patients.