Huibert Mansvelder

Huibert Mansvelder, PhD
Principal Investigator
Rhiannon M. Meredith, PhD
Postdoctoral Fellow
University of Amsterdam
The Netherlands

FRAXA Awards:
  $40,000 in 2008

Improvement of neuronal maturation and synaptic connectivity in Fragile X mice: targeting the role of Group 1 metabotropic glutamate receptors

By Huibert Mansvelder, 5/2008

Development of cognitive function requires the formation of cortical neuronal networks and synaptic connectivity during early postnatal life. In Fragile X syndrome, impairments in behaviour and cognition along with differences in neuronal spine morphology are observed early on in development. Fragile X mental retardation protein (FMRP) is expressed in the brain before birth and reduction or absence of this protein, as occurs in Fragile X syndrome, most likely affects the formation and refinement of neuronal networks in prenatal and early postnatal cortex development.

Our research project will firstly study patterns of activity across neuronal networks from juvenile brains of young Fmr1 KO (Fragile X) mice and measure the effects of lack of FMRP upon the functional activity of hundreds of neurons simultaneously. These patterns of neuronal activity are a key feature of newly-forming networks and depend upon glutamatergic signalling in the cortex. Metabotropic glutamate receptors (mGluRs) are already expressed in the brain before birth and a wealth of data from morphology, cellular and behavioural experiments show alterations in signalling via a particular type of these receptors, mGluR5. We will test whether application of drug compounds targeting the mGluR5 receptors during these critical early periods of network development can have a beneficial effect upon the early connectivity and function of the networks in Fmr1 KO mice. Furthermore, we will test the effects of specific mGluR drugs on activity during later periods of development.

Our aim is that the outcome of these experiments will directly assess the effects of mGluR-targeting compounds, which are potential viable candidates for clinical trials, on the function of networks of neurons during critical early periods and subsequent maturation of the brain in Fragile X.