Reduced expression of the psychiatric risk gene DLG2 (PSD93) impairs hippocampal synaptic integration and plasticity

• Published in: Neuropsychopharmacology (New York, N.Y.) N.Y.), 2022-06, Vol.47 (7), p.1367-1378
• Main Authors: Griesius, Simonas, O'Donnell, Cian, Waldron, Sophie, Thomas, Kerrie L, Dwyer, Dominic M, Wilkinson, Lawrence S, Hall, Jeremy, Robinson, Emma S J, Mellor, Jack R
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (muscarinic); Agonists; Allosteric properties; Animals; Autism; Autism Spectrum Disorder - metabolism; Cognitive ability; Computational neuroscience; Copy number; Cytoskeleton; Electrophysiology; Excitability; Glutamic acid receptors (ionotropic); Guanylate Kinases - metabolism; Hippocampal plasticity; Hippocampus; Hippocampus - metabolism; Integration; Intellectual disabilities; Long-term potentiation; Long-Term Potentiation - genetics; Membrane Proteins - metabolism; Mental disorders; N-Methyl-D-aspartic acid receptors; Neuronal Plasticity - genetics; Phenotypes; Postsynaptic density proteins; Potassium; Potassium channels; Potassium Channels - metabolism; Rats; Receptors, N-Methyl-D-Aspartate - metabolism; Schizophrenia; Synapses - physiology; Synaptic Transmission - physiology; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0893-133X; 1740-634X
• DOI: 10.1038/s41386-022-01277-6

Copy number variants indicating loss of function in the DLG2 gene have been associated with markedly increased risk for schizophrenia, autism spectrum disorder, and intellectual disability. DLG2 encodes the postsynaptic scaffolding protein DLG2 (PSD93) that interacts with NMDA receptors, potassium channels, and cytoskeletal regulators but the net impact of these interactions on synaptic plasticity, likely underpinning cognitive impairments associated with these conditions, remains unclear. Here, hippocampal CA1 neuronal excitability and synaptic function were investigated in a novel clinically relevant heterozygous Dlg2+/- rat model using ex vivo patch-clamp electrophysiology, pharmacology, and computational modelling. Dlg2+/- rats had reduced supra-linear dendritic integration of synaptic inputs resulting in impaired associative long-term potentiation. This impairment was not caused by a change in synaptic input since NMDA receptor-mediated synaptic currents were, conversely, increased and AMPA receptor-mediated currents were unaffected. Instead, the impairment in associative long-term potentiation resulted from an increase in potassium channel function leading to a decrease in input resistance, which reduced supra-linear dendritic integration. Enhancement of dendritic excitability by blockade of potassium channels or activation of muscarinic M1 receptors with selective allosteric agonist 77-LH-28-1 reduced the threshold for dendritic integration and 77-LH-28-1 rescued the associative long-term potentiation impairment in the Dlg2+/- rats. These findings demonstrate a biological phenotype that can be reversed by compound classes used clinically, such as muscarinic M1 receptor agonists, and is therefore a potential target for therapeutic intervention.