Early developmental processes underlying sensory deficits in neurodevelopmental disorders

Autism spectrum disorder (ASD) represents a group of complex neurodevelopmental disorder of strikingly high incidence. ASD patients often suffer from altered sensory reactivity, which is thought to contribute to other clinical features of ASD such weaknesses in social communicative abilities and restricted interests and repetitive behaviors. Animal studies indicate that sensory processing dysfunction may follow disruption of activity-dependent fine-tuning of synaptic connections in the thalamocortical system, but the precise causal relationship remains unclear. In this project, we aim to directly test how altered synaptic development disrupts the development of brain activity in sensory cortex and, vice versa, how aberrant activity impairs synaptic maturation during early postnatal stages. We will start from findings in the mouse model of Fragile X Mental Retardation (FraX), one of the most studied monogenetic ASD models with established sensory dysfunctioning, and expand the impact of our findings to a broad spectrum of pervasive neurodevelopmental disorders. A precise developmental sequence in changes of neuronal activity patterns is essential for the refinement of synaptic function, as network activity directs the wiring of cortical circuits during development. At the same time, activity pattern is also shaped by the synaptic connections in the network. However, it is not understood how early activity and synaptic function precisely determine network function later in life. The Lohmann group has recently found that early activity patterns in the visual cortex are disturbed in Fragile X Mental Retardation (FraX), a well described model of autism and cognitive impairment. We propose here to test the hypothesis that sensory information processing deficits in FraX are a consequence of early aberrations in neuronal activity patterns and related synaptic deficits. To this end, we will experimentally induce - in wild type mice –aberrant brain activity patterns and synaptic deficits observed in the FraX model and test directly their consequences for synaptic connections, circuit activity and ultimately sensory processing defects. More specifically, we will: 1. use optogenetic and pharmacogenetic manipulations to change spontaneous activity patterns in wild type mice before the onset of sensation (postnatal weeks 1 and 2) to simulate the errors observed by us and others in the FraX mouse model. More specifically, we express channelrhodopsin in L2/3 cells in visual cortex to promote cortically driven activity, and to reduce thalamical input we express an inhibitory DREADD in thalamic cells. 2. manipulate excitatory and inhibitory synaptic function in wild type mice before the onset of sensation (postnatal weeks 1 and 2) to mimic synaptic errors of the FraX mouse model. More specifically, we will overexpress nkcc1 in L2/3 cells in visual cortex to simulate immature GABAergic transmission, and we will reduce NMDA function in these cells to simulate immature excitatory transmission. Subsequently, we will test the effects of this postnatal manipulations on early activity patterns at P12-14, synaptic function at P20-25 and sensory processing capacities in adult mice. In addition, we will test the contribution of inhibitory synaptic maldevelopment to adult sensory processing by pre-sensation treatment of FraX mice with bumetanide. Our results will provide answers to the chicken and egg puzzle of aberrant brain activity and synaptic development and how their pathological interaction may cause pervasive defects in sensory information processing. Our research is fundamental in nature, but its outcome will be of interest to a broad audience and will be of benefit to society. Our findings will have immediate consequences for the understanding of sensory processing disorders in ASD and related disorders. Through this project we will establish a powerful collaboration of excellent researchers with expertise on developmental activity patterns (Lohmann), inhibitory synaptic plasticity (Wierenga) and sensory processing and behaviour (Kas & Bruining). Together, we propose here to combine the strengths of our groups to further pioneer approaches for manipulating and interrogating specific disease processes with the highest possible spatial-temporal precision. This strategy will allow us to test individual processes in isolation and thus dissect their specific contribution to ASD, which is much harder in the disease model alone, because of the complexity of the interacting factors. Specifically, by linking early disturbances in activity patterns and network development to later sensory deficits, we may fill a crucial gap in ASD knowledge. If successful, the field can directly make use of our findings and design targeted interventions based upon a novel neurophysiological framework.