Multiple Critical Periods for Rapamycin Treatment to Correct Structural Defects in Tsc-1-Suppressed Brain

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant neurogenetic disorder affecting the brain and other vital organs. Neurological symptoms include epilepsy, intellectual disability, and autism. TSC is caused by a loss-of-function mutation in the TSC1 or TSC2 gene. These gene products form a protein complex and normally suppress mammalian target of rapamycin (mTOR) activity. mTOR inhibitors have been used to treat subependymal glioma (SEGA) that is a brain tumor characteristic of TSC. However, neuropathology of TSC also involves dysregulated cortical circuit formation including neuronal migration, axodendritic differentiation, and synapse formation. It is currently unknown to what extent mTOR signaling inhibitors correct an alteration in neuronal morphology that have already formed prior to the treatment. Here, we address the efficacy of rapamycin treatment on neuronal migration and dendrite formation. Using in utero electroporation, we suppressed Tsc1 expression in a fraction of neuronal progenitor cells during the fetal period. In embryonic brain slices, we found that more Tsc1-suppressed cells remained within the periventricular zone, and rapamycin treatment facilitated neuronal migration. Postnatally, Tsc1-suppressed pyramidal neurons showed more complex branching of basal dendrites and a higher spine density at postnatal day (P) 28. Aberrant arborization was normalized by rapamycin administration every other day between P1 and P13 but not P15 and P27. In contrast, abnormal spine maturation improved by rapamycin treatment between P15 and P27 but not P1 and P13. Our results indicate that there are multiple critical windows for correcting different aspects of structural abnormalities in TSC, and the responses depend on the stage of neuronal circuit formation. These data warrant a search for an additional therapeutic target to treat neurological symptoms of TSC.

PTEN in Autism and Neurodevelopmental Disorders

“…Interestingly, during neuritogenesis, PTEN is mainly localized in the nucleus and sparsely found in dendrites, but retranslocates into mature dendrites to antagonize mTOR signaling, pause arborization, and promote synaptogenesis (Perandones et al 2004). These data overlap with the narrow time window, in which mTOR inhibitors are able to reverse aberrant outgrowth defects in a tuberous sclerosis complex (Tsc1 f/f ;Gfp-cre) model of autism (Cox et al 2018). Thus, a spatial regulation of PTEN localization is important for proper neuritogenesis, and constant PTEN (nuclear) depletion leads to increased axodendritogenesis with increased synaptogenesis possibly caused by hyperactive mTOR signaling.…”

Effect of rapamycin on aging and age-related diseases—past and future

“…Rapamycin (14 ppm) reduced anxiety-like behavior (thigmotaxis and elevated plus maze) and depressive-like behavior (floating and tail suspension test) in 4-and 12-month-old mice. As shown in Table 5, several studies report that rapamycin reduced behavioral deficits such as anxiety and depression in mouse models of autism [81][82][83][84]. However, Hadamitzky et al [85,86] reported that rapamycin (3 mg/kg, i.p.)…”

Renal Manifestations of Tuberous Sclerosis Complex

“…ADPKD accounts for fewer than 2% of TSC cases ( 33 , 34 ). The phenotypic intersection between TSC and ADPKD cases indicate the existence of a functional relationship between the respective genes that have been recently identified as the mTOR signal pathway ( 35 ).…”

“…In a large-scale study of 164 pediatric patients with TSC, who underwent serial renal ultrasonography or computed tomography (CT), the authors found that the rate of renal AML increased up to an excess of 50% after the age of five with no renal AMLs in the first year of life ( 65 ). In another longitudinal study involving 60 children, rates of renal AMLs increased from 48% in boys and 60% in girls at a mean age of 6.9 years to 76% in boys and 83% in girls at follow-up at a mean age of 10.5 years ( 33 ). By the time these patients reached adulthood, 33% of the AMLs stopped growing ( 61 ).…”

“…In most patients with TSC, renal cysts are asymptomatic with a limited number of cysts that are smaller ( 73 , 74 ). However, similar to AML, their prevalence increases with age ( 33 ). These types of cysts do not require regular surveillance imaging, but images should still be taken, as these patients are at risk for AML as they age.…”