Katherine Roche, NINDS, National Institutes of Health, USA
Synaptic dysfunction and neurodevelopmental disorders: insights from rare variants
Neocortical networks must generate and maintain stable activity patterns despite perturbations induced by learning and experience- dependent plasticity. There is abundant theoretical and experimental evidence that network stability is achieved through homeostatic plasticity mechanisms that adjust synaptic and neuronal properties to stabilize some measure of average activity, and this process has been extensively studied in primary visual cortex (V1), where chronic visual deprivation induces an initial drop in activity and ensemble average firing rates (FRs), but over time activity is restored to baseline despite continued deprivation. Here I discuss recent work from the lab in which we followed this FR homeostasis in individual V1 neurons in freely behaving animals during a prolonged visual deprivation/eye-reopening paradigm. We find that - when FRs are perturbed by manipulating sensory experience - over time they return precisely to a cell-autonomous set-point. Finally, we find that homeostatic plasticity depends critically on normal levels of Shank3 (which is strongly associated with human Autism and intellectual disability), and is gated by changes in Shank3 phosphorylation. Loss of Shank3 in rodent models results in a breakdown of FRH within V1, and disrupts vision-dependent learning. These data suggest that loss of homeostatic plasticity is one primary cause of circuit disregulation in rodent models of Autism Spectrum Disorder. Together these studies illuminate the role of stabilizing plasticity mechanisms in the ability of neocortical circuits to recover robust function following challenges to their excitability through altered sensory experience and learning.
Dr. Roche is a Senior Investigator and Chief of the Receptor Biology Section within the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health (NIH) in Bethesda, Maryland. Over the last two decades, Dr. Roche has studied the molecular mechanisms that underlie synaptic plasticity at excitatory synapses. Her research program has focused on revealing the mechanisms that regulate the targeting of glutamate receptors and other postsynaptic proteins to synapses. More recently, her research program has shifted to emphasize findings from human genetics to better understand the synaptic dysfunction underlying neurodevelopmental disorders. In particular, the Roche lab investigates rare variants in NMDA receptors (GRINs), the neuroligin family of adhesion molecules (NLGNs), and postsynaptic scaffolding proteins (MAGUKs; SHANKs; TRIO). Using molecular and biochemical approaches, her lab characterizes protein and synaptic dysfunction and generates related mouse models to study in an in vivo context.