Abstract
Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1+/- and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1+/- mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.
Highlights
Neurodevelopmental disorders with clinical overlap often share defects within the same intracellular signal transduction pathway
To address if the morphology of the calyx of Held synapse is altered in mouse models for tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), or Costello syndrome (CS), we electroporated axonal fibers in vivo at the midline with Alexa Fluor 594-labeled dextrans in young-adult animals (P28–P84)
Changes in morphology in the mouse models for TSC and FXS were not reflected in obvious changes in baseline synaptic transmission or short-term plasticity
Summary
Neurodevelopmental disorders with clinical overlap often share defects within the same intracellular signal transduction pathway. Synaptic transmission in intellectual disability neurodevelopmental disorders (Krab et al, 2008). We studied in vivo synaptic transmission in mouse models for four different monogenetic syndromes in which these two pathways are affected: tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome (CS). In TSC and FXS the mTOR pathway is upregulated (Ebrahimi-Fakhari and Sahin, 2015). The mTOR pathway plays a central role in synaptic plasticity, and its upregulation is linked to intellectual disability, autism spectrum disorder, seizures, and brain malformations (Swiech et al, 2008; Crino, 2011; Troca-Marín et al, 2012; Lasarge and Danzer, 2014). In NF1, FXS, and CS the Ras/ERK pathway is upregulated as well (Osterweil et al, 2013; Rauen, 2013). These four syndromes are characterized by abnormal synaptic plasticity and often abnormal synaptic morphology (Swiech et al, 2008; Stornetta and Zhu, 2011; Levenga and Willemsen, 2012; Rauen, 2013)
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