Dominique Moreira Fernandes - CNC, University of Coimbra
Title: Autism-associated Caspr2 regulates synaptic AMPA receptors in the context of homeostatic synaptic plasticity
Abstract:
During development and learning/memory-related events, the mammalian brain undergoes constant changes that can compromise its function. To prevent this, homeostatic synaptic plasticity mechanisms come into play, allowing experience-based adaptations to occur while maintaining the activity of neuronal networks in-balance for proper brain function. One fundamental mechanism to achieve neuronal homeostasis is the dynamic regulation of AMPA receptors at glutamatergic synapses.
Herein, we describe a novel role for the cell-adhesion molecule Caspr2, implicated in autism and other neuropsychiatric disorders, in the regulation of synaptic AMPARs in the context of homeostatic plasticity. We demonstrate that loss of Caspr2 not only decreases the basal synaptic content of GluA1-containing AMPARs in cortical neurons, but also hinders the triggering of homeostatic mechanisms that upscale synaptic AMPARs during prolonged periods of neuronal inactivity. Accordingly, Caspr2 is further required for experience dependent plasticity in vivo, since its loss in the mouse visual cortex (V1) prevents the scaling of AMPAR-mediated mEPSC amplitudes following paradigms of chronic visual deprivation. Caspr2 is also a target antigen in autoimmune synaptic encephalitis. Remarkably, in vitro or in vivo incubation with patient-purified Caspr2 autoantibodies significantly decreases synaptic GluA1-AMPARs in cortical cultures and mEPSC amplitudes in V1.
Overall, we uncover a novel function for autism-associated Caspr2 in the regulation of synaptic AMPARs and homeostatic plasticity. Importantly, this evidence hints at a potential disruption of neuronal homeostasis following Caspr2 dysfunction in the context of disease, which is consistent with accumulating data implicating glutamatergic synapse dysfunction and impaired neuronal homeostasis as common underlying pathologies of several cognitive disorders, including autism.
Title: Autism-associated Caspr2 regulates synaptic AMPA receptors in the context of homeostatic synaptic plasticity
Abstract:
During development and learning/memory-related events, the mammalian brain undergoes constant changes that can compromise its function. To prevent this, homeostatic synaptic plasticity mechanisms come into play, allowing experience-based adaptations to occur while maintaining the activity of neuronal networks in-balance for proper brain function. One fundamental mechanism to achieve neuronal homeostasis is the dynamic regulation of AMPA receptors at glutamatergic synapses.
Herein, we describe a novel role for the cell-adhesion molecule Caspr2, implicated in autism and other neuropsychiatric disorders, in the regulation of synaptic AMPARs in the context of homeostatic plasticity. We demonstrate that loss of Caspr2 not only decreases the basal synaptic content of GluA1-containing AMPARs in cortical neurons, but also hinders the triggering of homeostatic mechanisms that upscale synaptic AMPARs during prolonged periods of neuronal inactivity. Accordingly, Caspr2 is further required for experience dependent plasticity in vivo, since its loss in the mouse visual cortex (V1) prevents the scaling of AMPAR-mediated mEPSC amplitudes following paradigms of chronic visual deprivation. Caspr2 is also a target antigen in autoimmune synaptic encephalitis. Remarkably, in vitro or in vivo incubation with patient-purified Caspr2 autoantibodies significantly decreases synaptic GluA1-AMPARs in cortical cultures and mEPSC amplitudes in V1.
Overall, we uncover a novel function for autism-associated Caspr2 in the regulation of synaptic AMPARs and homeostatic plasticity. Importantly, this evidence hints at a potential disruption of neuronal homeostasis following Caspr2 dysfunction in the context of disease, which is consistent with accumulating data implicating glutamatergic synapse dysfunction and impaired neuronal homeostasis as common underlying pathologies of several cognitive disorders, including autism.