Neurobiology - Fragile X Syndrome

CELLULAR NEUROBIOLOGY

SDL : THE FIGHT AGAINST FRAGILE X SYNDROME

Introduction

Fragile X Syndrome (FXS) is the most prevalent inherited form of mental retardation. Intellectual disability, neurobehavioral problems, and even other non-CNS anomalies like macroorchidism are typical characteristics of the FXS phentoype. FXS is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) because of an expansion of a CGG polymorphism in the 5'UTR (Untranslated Region) of the FMR1 gene located on the X chromosome ((Oostra, B.A. et al.,2009) as cited in Levenga J et al., 2010)

(i) Synaptic Plasticity

Learning and memory involves the change in the transmission efficacy at synapses. And this is mediated by synaptic plasticity- the process whereby connections between functional neurons change in strength – whether it is potentiated (stronger) or depressed (weaker), and this is accompanied by changes in dendritic spine size and morphology.) A lasting change in synapse strength is dependent on local protein synthesis, and it is usually mediated through several parallel mechanisms – with the postsynaptic terminal containing much of the protein-synthesizing apparatus required to respond swiftly to synaptic activity. Long-term potentiation (LTP) and Long-term depression (LTD) occur in response to high-frequency stimulation, and prolonged low-frequency stimulation, respectively.

In this case, we will be focussing on LTD, specifically on the mGluR (Metabotropic glutamate receptors)-dependent LTD – which is displayed by the reduction in number of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors – a major class of ionotropic receptors which mediate fast excitatory neurotransmission (Huber, K.M., 2006). mGluR are a family of G-protein-coupled receptors whose primary action is to stimulate an intracellular biochemical response. Studies indicate that activation of the group 1 mGluR (including mGluR1 and mGluR5) by glutamate neurotransmitters in syanptoneurosomes leads to local protein synthesis, some of which stimulate the internalization of AMPA receptors – and hence, start LTD.

In a normal functioning neuron, activated mGluR1 or 5 also stimulates the formation of FMRP – which through its special binding domains, associate with polyribosomes, acts in a regulatory feedback manner, negatively regulating the translation of proteins that are responsible for the internalization of AMPA receptors (Figure 1). Prolonged and inflated LTD - which happens with the lack of FMRP leads to imbalance towards net AMPA receptor loss and synapse loss during the critical period