Postnatal transient connectivity in brain development and implications in fragile x syndrome

ABSTRACT Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorders. Autism symptoms in FXS patients typically manifest during early infancy when children actively interact with their environment and form sensory-cognitive associations. During this stage, the neocortex undergoes extensive

experience-dependent synaptogenesis and synaptic pruning to either maintain or eliminate, so-called transient, neuronal circuits. Several studies suggest that both sensory and neuromodulatory inputs to the cortex can establish transient connections with specific cell-types, and subsequently contribute to the maturation of proper

adult cortical circuits. Given that early behavioral therapy is widely considered to be the most effective treatment for children with autism, pharmacological manipulations of sensory and neuromodulatory transient connectivity at the early onset of the disorders could potentially mimic or synergize with the effects of such beneficial

behavioral therapies. However, to date, the role and mechanisms of transient connectivity in normal and FXS- associated cortical maturation remain largely unknown. To address this knowledge gap, we propose to investigate the mechanisms of transient connectivity underlying sensory- and neuromodulatory-dependent cortical maturation in control mice and in a mouse model

of FXS. Sensory experiences are encoded in the cortex by thalamocortical (TC) neurons forming transient connections with a subset of inhibitory neurons, the somatostatin (SST) cells. These transient connections are believed to control maturation of excitation/inhibition (E/I) balance in the cortex, which is altered in the mature

brain of FXS mice or patients. Our mouse data indicate that, in parallel to sensory TC inputs, SST neurons receive cholinergic modulatory inputs associated with the early development of TC pathways. Therefore, we hypothesize that the synergy between TC and cholinergic transient connectivity to SST neurons is an instructive

mechanism that triggers cortical maturation and that this mechanism is impaired in FXS. Our previous research using combinatorial mouse genetics and viral chemogenetic approaches showed that metabotropic signaling controls the formation of transient TC inputs to SST neurons. Based on this data, we propose that cortical E/I

maturation results from metabotropic signaling that transiently transduces sensory cues and neuromodulation onto SST neurons. To test this hypothesis, we will employ multidisciplinary approaches to investigate whether transient TC connectivity governs healthy and FXS cortical maturation (Aim 1), elucidate the role of cholinergic

inputs in the maturation of healthy and FXS cortical circuits (Aim 2), and characterize metabotropic molecular pathways underlying transient connectivity (Aim 3). Overall, our work will provide novel insights into the role of transient connectivity on sensory and cognitive experience-dependent cortical maturation and lay the foundations for exploring approaches targeting the onset

of circuit dysfunctions in FXS.