Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by tumor growth and neuropsychological symptoms such as autistic behavior, developmental delay, and epilepsy. While research has shed light on the biochemical and genetic etiology of TSC, the pathogenesis of the neurologic and behavioral manifestations remains poorly understood. TSC patients have a greatly increased risk of developmental delay and autism spectrum disorder, rendering the relationship between the two sets of symptoms an extremely pertinent issue for clinicians. We have expanded on previous observations of aberrant vocalizations in Tsc2+/？ mice by testing vocalization output and developmental milestones systematically during the early postnatal period. In this study, we have demonstrated that Tsc2 haploinsufficiency in either dams or their pups results in a pattern of developmental delay in sensorimotor milestones and ultrasonic vocalizations. 1. Introduction Tuberous sclerosis complex (TSC) is an autosomal dominant disease presenting with hamartomatous tumor development and neurological symptoms, including autism spectrum disorder, epilepsy, and developmental delays [1]. TSC results from mutation in either the TSC1 or TSC2 genes, which encode for hamartin and tuberin, respectively. These two proteins inhibit the pathway of the mammalian target of rapamycin (mTOR) through negative regulation of the GTPase Rheb [2]. The mTOR pathway plays essential roles in protein synthesis and translation that are necessary for cell proliferation [3, 4]. Approximately 25–50% of TSC patients are diagnosed with autism spectrum disorder (ASD), a developmental disorder presenting with stereotyped behavioral patterns, social impairments, and communication deficits？[5]. This represents a significantly increased risk for ASD among TSC patients as compared to individuals without TSC. The neuropathology and etiology of autism remain undefined although the relationship between TSC and associated autistic symptoms continues to be explored [6]. Several studies have suggested that the neurological disruption evoked by infantile spasms as well as the presence of cortical tubers or cerebellar abnormalities increases the risk for development of ASD [7–10]. Emerging evidence from neuroimaging studies also indicates that hypomyelination, a common phenotype in the TSC brain, may be correlated with neurocognitive disabilities in patients (reviewed in [3]). TSC patients also show an increased incidence of intellectual disability, with up to 80% of patients experiencing developmental delay [11].
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