Spine development and activity-dependent plasticity in the hippocampus of a mouse model of the Fragile X Syndrome

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The Fragile X syndrome (FXS) is the leading monogenetic cause of cognitive impairment and autism. Patients with FXS can show attention deficits and autism spectrum disorder (ASD) symptoms like stereotypic behavior and excessive adherence to patterns which can be associated with perturbed hippocampal networks. The hippocampus is indeed crucially involved in pattern separation/ completion during memory formation. In this respect the CA3 region is of special interest because of the auto-associative nature of the recurrent inputs. Unlike most other cells in the cortex, these cells actually are connected to a high degree to themselves. In contrast to this, the exceptionally strong and sparse mossy fiber input onto CA3 neurons is described as a ‘detonator’ synapse, directing plasticity and the information processing in the recurrent network.A hallmark of FXS is an immature spine profile which can be found in patients as well as in the FXS mouse model (fmr1 KO). We could recently uncover a novel role of FMRP in restricting synapse development of mossy fiber inputs as the postsynaptic thorny excrescences (TEs) on CA3 neurons are premature during development in fmr1 KO mice. In contrast to this, analysis of the recurrent inputs displayed the well documented immature spine. Our preliminary data provide therefore evidence for a strong dysregulation of synapse maturation in a synapse-type specific manner in the CA3 subregion. Most likely associated with a detrimental outcome for information processing in CA3 neurons and for hippocampal function as a whole.In our current project we would like to determine the precise development of these synaptic phenotypes and to what extent they persist into adulthood both under normal laboratory conditions and in an enriched environment as a potential treatment for FXS. We will use general hippocampus-dependent and specifically CA3-dependent learning paradigms to study the behavioral outcome of synaptic alterations in CA3 neurons in juvenile and adult mice. High-resolution imaging and electrophysiological techniques will allow us to combine knowledge about structure and function of the respective synapse type under naïve conditions as well as following rearing in an enriched environment or memory training at different stages during development to reveal the underlying cellular mechanisms for behavioral impairments. Our experiments will help to understand the structure-function-relationship and the role for behavioral outcome of two important synapses in the mouse hippocampus and how this is altered in an FXS mouse model. In order to understand the role of the CA3 region for FXS it is important to combine knowledge about both synapses throughout development to understand how alterations in one or both synapse types affects information processing. This will not only contribute to a better understanding of the cellular mechanisms underlying FXS but also reveal details about hippocampal function in general.