title: Increased Cortical Inhibition in Autism-Linked Neuroligin-3R451C Mice Is Due in Part to Loss of Endocannabinoid Signaling.
abstract: A single, maternally inherited, X-linked point mutation leading to an arginine to cysteine substitution at amino acid 451 (R451C) of Neuroligin 3 (NLGN3R451C) is a likely cause of autism in two brothers. Knockin mice expressing the Nlgn3R451C mutation in place of wild-type Nlgn3 demonstrate increased inhibitory synaptic strength in somatosensory cortex, resulting in an excitatory/inhibitory (E/I) imbalance that is potentially relevant for autism-associated behavioral deficits characteristic of these mice. We have replicated the increase in evoked inhibitory postsynaptic currents (eIPSCs) onto layer II/III cortical pyramidal neurons. We also find that increased frequency of spontaneous mIPSCs in Nlgn3R451C mice occurs in the absence of action potential-driven transmission. This suggests the E/I imbalance is due to changes at the synapse level, as opposed to the network level. Next, we use paired whole-cell recordings in an attempt to identify specific interneuron subtypes affected by the Nlgn3R451C mutation. Curiously, we observe no change in the amplitude of cell-to-cell, unitary IPSCs (uIPSCs) from parvalbumin-positive (PV) or somatostatin-positive (SOM) interneurons onto pyramidal neurons. We also observe no change in the number or density of PV and SOM interneurons in LII/III of somatosensory cortex. This effectively rules out a role for these particular interneurons in the increased inhibitory synaptic transmission, pointing to perhaps alternative interneuron subtypes. Lastly, impaired endocannabinoid signaling has been implicated in hippocampal synaptic dysfunction in Nlgn3R451C mice, but has not been investigated at cortical synapses. We find that bath application of the CB1 antagonist, AM 251 in WT mice eliminates the Nlgn3R451C increase in eIPSC amplitude and mIPSC frequency, indicating that increased inhibitory transmission in mutant mice is due, at least in part, to a loss of endocannabinoid signaling through CB1 receptors likely acting at interneurons other than PV or SOM.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Haley E
authors.initials: HE
authors.lastname: Speed
authors.affiliation: Quantitative Morphology Core, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Irene
authors.initials: I
authors.lastname: Masiulis
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Gibson
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America; Department of Psychiatry and Neuroscience Graduate Program, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000378:metabolism*; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D006624:Hippocampus / Q000502:physiology; D006801:Humans; D007395:Interneurons / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013003:Somatosensory Cortex / Q000503:physiopathology*; D009435:Synaptic Transmission
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D063388:Endocannabinoids; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D010880:Piperidines; D011720:Pyrazoles; C098004:neuroligin 3; C103505:AM 251