Neuronal computation evoked by extra-large spines (Obi-Nagata et al., 2023)

Human genetics strongly support the involvement of synaptopathy in psychiatric disorders. However, trans-scale causality linking synapse pathology to behavioral changes is lacking. To address this question, we examined the effects of synaptic inputs on dendrites, cells, and behaviors of mice with knockdown of SETD1A and DISC1, which are validated animal models of schizophrenia. Both models exhibited an overrepresentation of extra-large (XL) synapses, which evoked supralinear dendritic and somatic integration, resulting in increased neuronal firing. The probability of XL spines correlated negatively with working memory, and the optical prevention of XL spine generation restored working memory impairment. Furthermore, XL synapses were significantly more abundant in the postmortem brains of schizophrenia patients than in those of matched controls. Our findings suggest that working memory performance, a pivotal aspect of psychiatric symptoms, is shaped by distorted dendritic and somatic integration via extra-large spines.

Model Type: Neuron or other electrically excitable cell

Region(s) or Organism(s): Prefrontal cortex (PFC)

Cell Type(s): Neocortex L2/3 pyramidal GLU cell

Currents: I Calcium; I K,Ca; I K; I Na,t

Model Concept(s): Action Potentials; Synaptic Integration

Simulation Environment: NEURON


Obi-Nagata K et al. (2023). Distorted neurocomputation by a small number of extra-large spines in psychiatric disorders Science Advances. 9(23) [PubMed]

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