In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome

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.

Mechanisms underlying auditory processing deficits in Fragile X syndrome

“…In Fmr1 knockout animals, a smaller proportion of calyxes in the MNTB display simple morphology, which is associated with synaptic depression . Additionally, in vivo juxtacellular recordings detected only minor changes in excitatory spiking activity . In vitro slice physiology on the inhibitory inputs has also revealed no significant changes in most of the parameters examined for both glycinergic and GABAergic transmission .…”

“…These include KCa1.1 (BK), Kv4.2, and HCN channels, which shape the excitability of many types of neurons in the auditory system, but their roles in auditory processing in FXS have not been investigated. Because FXS is a neurodevelopmental disorder, it is likely that there exist compensatory mechanisms that act over time to alter the excitability and synaptic transmission in the patients and in animal models of the disease …”

“…Proportionally fewer Fmr1 knockout than wild-type neurons showed this pattern. In Fmr1 knockout animals, a smaller proportion of calyxes in the MNTB display simple morphology, 58 which is associated with synaptic depression. 59 Additionally, in vivo juxtacellular recordings detected only minor changes in excitatory spiking activity.…”

Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome

“…In FXS, where it is thought that there is hyperexcitability of sensory systems due to imbalances in the excitation and inhibition (Rubenstein & Merzenich, ), impairments in MNTB processing may be particularly pronounced. However, recently it has been shown that despite changes in calyx morphology, there were no obvious changes in synaptic transmission in vivo in Fmr1 −/− mice (Wang, de Kok, Willemsen, Elgersma, & Borst, ). There was however a trend towards longer synaptic latencies in the Fmr1 −/− mice and this study did not specifically target the medial or lateral MNTB where we have seen (along with others, Strumbos et al, ) potential tonotopic differences in the MNTB of Fmr1 −/− mice.…”

Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders

“…The homozygous Hras G12V knock-in mice generated by Schuhmacher and colleagues showed altered anxiety and mild deficits in the hidden-platform version of the Morris water maze (Viosca, Schuhmacher, Guerra, & Barco, 2009). This mutant also did not show deficits in in vivo synaptic transmission and short-term plasticity at the calyx of Held synapse (Wang, de Kok, Willemsen, Elgersma, & Borst, 2015). Testing behavioral and electrophysiological phenotypes in the other Hras G12V knock-in mutants, which showed more severe phenotypes such as development of papillomas and angiosarcomas, would be of interest (Chen et al, 2009).…”