Synaptic Alterations in a Transgenic Model of Tuberous Sclerosis Complex: Relevance to Autism Spectrum Disorders.

Grzegorz A Czapski,Magdalena Gąssowska-Dobrowolska,Magdalena Cieślik,Lidia Babiec,Karolina Zajdel,Henryk Jęśko,Marta Matuszewska,Agata Adamczyk,Małgorzata Frontczak-Baniewicz

doi:10.3390/ijms221810058

Abstract

Tuberous sclerosis complex (TSC) is a rare, multi-system genetic disease with serious neurological and mental symptoms, including autism. Mutations in the TSC1/TSC2 genes lead to the overactivation of mTOR signalling, which is also linked to nonsyndromic autism. Our aim was to analyse synaptic pathology in a transgenic model of TSC: two-month-old male B6;129S4-Tsc2tm1Djk/J mice with Tsc2 haploinsufficiency. Significant brain-region-dependent alterations in the expression of several synaptic proteins were identified. The most prominent changes were observed in the immunoreactivity of presynaptic VAMP1/2 (ca. 50% increase) and phospho-synapsin-1 (Ser62/67) (ca. 80% increase). Transmission electron microscopy demonstrated serious ultrastructural abnormalities in synapses such as a blurred structure of synaptic density and a significantly increased number of synaptic vesicles. The impairment of synaptic mitochondrial ultrastructure was represented by excessive elongation, swelling, and blurred crista contours. Polyribosomes in the cytoplasm and swollen Golgi apparatus suggest possible impairment of protein metabolism. Moreover, the delamination of myelin and the presence of vacuolar structures in the cell nucleus were observed. We also report that Tsc2+/− mice displayed increased brain weights and sizes. The behavioural analysis demonstrated the impairment of memory function, as established in the novel object recognition test. To summarise, our data indicate serious synaptic impairment in the brains of male Tsc2+/− mice.

Highlights

Introduction published maps and institutional affilTuberous sclerosis complex (TSC) is an autosomal, dominant genetic disease evoked by the mutation of either the TSC1 or TSC2 gene; these genes encode the proteins Tsc1(hamartin) and Tsc2, respectively
Tuberous sclerosis complex (TSC) is an autosomal, dominant genetic disease evoked by the mutation of either the TSC1 or TSC2 gene; these genes encode the proteins Tsc1 and Tsc2, respectively
In the strain B6;129S4-Tsc2tm1Djk/J, the gene Tsc2 was inactivated by the insertion of the neo cassette into exon 2 [20]

Summary

Introduction

Introduction published maps and institutional affilTuberous sclerosis complex (TSC) is an autosomal, dominant genetic disease evoked by the mutation of either the TSC1 or TSC2 gene; these genes encode the proteins Tsc1(hamartin) and Tsc (tuberin), respectively. Hamartin and tuberin have been implicated in the control of cortical lamination, the regulation of dendritic arborization, neuronal migration, polarization, axonal outgrowth, and spine formation [2,3]. Pathological mutations in these genes disrupt the interaction between hamartin and tuberin and affect cell function via the improper regulation of the mechanistic/mammalian target of rapamycin (mTOR). Signalling cascade and multiple downstream effectors responsible for the modulation of key cellular processes, including protein synthesis, autophagy, cell growth, and proliferation [4].

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