NMDA receptor regulation of rapid scaling and spinal excitability in fragile X syndrome.

NMDA receptor regulation of rapid scaling and spinal excitability in fragile X syndrome. Abstract Identifying the mechanisms that control the maturation of network excitability during development will be crucial to understanding how these networks are established with dysregulated activity in cases of neurodevelopmental disorders such as autism spectrum disorder (ASD). We are proposing to study a guiding principle for the maturation of network excitability during neonatal development. We have just recently published work in the chick embryo spinal cord showing that blockade of NMDA receptors triggers rapid compensatory changes in the strength of glutamatergic and GABAergic synapses, referred to as synaptic scaling. This rapid form of synaptic scaling was previously characterized in a very different model system - rodent hippocampal cultures and slices. The observation that rapid scaling has been identified in 2 very different systems illustrates the fundamental importance of this form of plasticity. In the current application we will study rapid scaling in the neonatal mouse spinal cord, as we have preliminary results suggesting this plasticity exists in mouse spinal neurons, and that some inputs are altered more than others (nonuniform). In Aim 1 we will identify which classes of neonatal mouse spinal neurons express AMPAergic (excitatory) and GABAergic (inhibitory) rapid scaling and assess the uniformity of this scaling. We hypothesize that the homeostatic scaling capacity will be correlated with NMDAR content and will impact the excitatory to inhibitory (E/I) balance within the network and therefore maturation of excitability. Interestingly several different autism spectrum disorder (ASD) models experience altered NMDAR function and altered E/I balance. It is therefore reasonable to suggest that NMDA-dependent rapid scaling may indeed be altered in these models of autism, thus changing their excitability. ASD models have significant delays in motor development, yet spinal cord studies in these model systems are surprisingly rare. In Aim 2 we will test the hypothesis that rapid scaling is dependent on NMDAR content and that this is altered in a mouse model of Fragile X Syndrome (FXS), the most common monogenetic cause of ASD. By understanding the mechanisms of homeostatic plasticity during circuit formation, we will better understand the maturation of network excitability in neurodevelopmental disorders like ASD. Project Number: 1R21NS146918-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: PETER WENNER (+1 co-PI) | Institution: EMORY UNIVERSITY, ATLANTA, GA | Award Amount: $234,750 | Activity Code: R21 | Study Section: Neurodifferentiation, Plasticity, Regeneration and Rhythmicity Study Section[NDPR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11288244