Schizophrenia-associated SAP97 mutations increase glutamatergic synapse strength in the dentate gyrus and impair contextual episodic memory in rats

Yuni Kay, Linda Tsan, Elizabeth A. Davis, Chen Tian, Léa Décarie-Spain, Anastasiia Sadybekov, Anna N. Pushkin, Vsevolod Katritch, Scott E. Kanoski and Bruce E. Herring ()
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Yuni Kay: University of Southern California
Linda Tsan: University of Southern California
Elizabeth A. Davis: University of Southern California
Chen Tian: University of Southern California
Léa Décarie-Spain: University of Southern California
Anastasiia Sadybekov: University of Southern California
Anna N. Pushkin: University of Southern California
Vsevolod Katritch: University of Southern California
Scott E. Kanoski: University of Southern California
Bruce E. Herring: University of Southern California

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Mutations in the putative glutamatergic synapse scaffolding protein SAP97 are associated with the development of schizophrenia in humans. However, the role of SAP97 in synaptic regulation is unclear. Here we show that SAP97 is expressed in the dendrites of granule neurons in the dentate gyrus but not in the dendrites of other hippocampal neurons. Schizophrenia-related perturbations of SAP97 did not affect CA1 pyramidal neuron synapse function. Conversely, these perturbations produce dramatic augmentation of glutamatergic neurotransmission in granule neurons that can be attributed to a release of perisynaptic GluA1-containing AMPA receptors into the postsynaptic densities of perforant pathway synapses. Furthermore, inhibiting SAP97 function in the dentate gyrus was sufficient to impair contextual episodic memory. Together, our results identify a cell-type-specific synaptic regulatory mechanism in the dentate gyrus that, when disrupted, impairs contextual information processing in rats.

Date: 2022
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DOI: 10.1038/s41467-022-28430-5

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