Deficits in Morphofunctional Maturation of Hippocampal Mossy Fiber Synapses in a Mouse Model of Intellectual Disability

Abstract

The grik2 gene, coding for the kainate receptor subunit GluK2 (formerly GluR6), is associated with autism spectrum disorders and intellectual disability. Here, we tested the hypothesis that GluK2 could play a role in the appropriate maturation of synaptic circuits involved in learning and memory. We show that both the functional and morphological maturation of hippocampal mossy fiber to CA3 pyramidal cell (mf-CA3) synapses is delayed in mice deficient for the GluK2 subunit (GluK2 Ϫ/Ϫ ). In GluK2 Ϫ/Ϫ mice this deficit is manifested by a transient reduction in the amplitude of AMPA-EPSCs at a critical time point of postnatal development, whereas the NMDA component is spared. By combining multiple probability peak fluctuation analysis and immunohistochemistry, we have provided evidence that the decreased amplitude reflects a decrease in the quantal size per mf-CA3 synapse and in the number of active synaptic sites. Furthermore, we analyzed the time course of structural maturation of CA3 synapses by confocal imaging of YFP-expressing cells followed by tridimensional (3D) anatomical reconstruction of thorny excrescences and presynaptic boutons. We show that major changes in synaptic structures occur subsequently to the sharp increase in synaptic transmission, and more importantly that the course of structural maturation of synaptic elements is impaired in GluK2 Ϫ/Ϫ mice. This study highlights how a mutation in a gene linked to intellectual disability in the human may lead to a transient reduction of synaptic strength during postnatal development, impacting on the proper formation of neural circuits linked to memory.

N-linked glycosylation of cortical N-methyl-D-aspartate and kainate receptor subunits in schizophrenia

“…GluR6 containing KA receptors have been demonstrated to be important in generation of brain oscillatory activity[22]. The expression of a nonfunctional GluR6 subunit has been proposed to disrupt development and lead to cognitive dysfunction[23,24]. …”

Imbalance of synaptic actin dynamics as a key to fragile X syndrome?

“…This allows single granule cells to precisely time the activity of CA3 pyramidal neurons and thereby provide the necessary depolarization needed for Hebbian plasticity at the associational/commissural inputs in the stratum radiatum and stratum oriens (see also Henze et al 2000). Mutations in a different gene (grik2, coding for the kainate receptor subunit GluK2) are also associated with ASD and intellectual disability and have been shown to influence LMT-TE development (Lanore et al 2012). Moreover, a key role of the mossy fibre synapse in mediating homeostatic synaptic plasticity was reported in mature hippocampal neurons (Lee et al 2013).…”

“…Mutations in a different gene ( grik2 , coding for the kainate receptor subunit GluK2) are also associated with ASD and intellectual disability and have been shown to influence LMT‐TE development (Lanore et al . ). Moreover, a key role of the mossy fibre synapse in mediating homeostatic synaptic plasticity was reported in mature hippocampal neurons (Lee et al .…”

A Subset of Autism-Associated Genes Regulate the Structural Stability of Neurons

“…KAR subunits, in particular GluK2, interacts with structural elements of the synapse; such as the PSD-95 and SAP-102 scaffolding molecules, as well as the N -cadherin and β-catenin adhesion molecules (Carta et al, 2014; Pahl et al, 2014), indicating that Grik genes are involved in processes that regulate synapse architecture and stability. Indeed, GluK2 regulates hippocampal synapse maturation and stability (Huettner, 2003; Contractor et al, 2011; Lanore et al, 2012; Lerma and Marques, 2013). Animals with deficient GluK2 proteins exhibit a delay in the postnatal maturation of synaptic contacts between MF-CA3 in the hippocampus, suggesting that the expression of the GluK2 is important for the establishment of normal morphology and function of synaptic networks in the hippocampus (Contractor et al, 2001; Lanore et al, 2012).…”

“…Indeed, GluK2 regulates hippocampal synapse maturation and stability (Huettner, 2003; Contractor et al, 2011; Lanore et al, 2012; Lerma and Marques, 2013). Animals with deficient GluK2 proteins exhibit a delay in the postnatal maturation of synaptic contacts between MF-CA3 in the hippocampus, suggesting that the expression of the GluK2 is important for the establishment of normal morphology and function of synaptic networks in the hippocampus (Contractor et al, 2001; Lanore et al, 2012). Expression of the GluK4 is mainly restricted to mossy fiber synapses in the hippocampal CA3 region where it co-assembles with GluK2 in functional pre- and postsynaptic GluK2/4 receptor complexes (Darstein et al, 2003).…”