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1. Adeno-associated viral overexpression of neuroligin 2 in the mouse hippocampus enhances GABAergic synapses and impairs hippocampal-dependent behaviors.

   https://doi.org/10.1016/j.bbr.2018.12.052  

   Van Zandt, M ; Weiss, E ; Almyasheva, A ; Lipior, S ; Maisel, S ; Naegele, J. ( January 2019 , Behavioural brain research)

   The cell adhesion molecule neuroligin2 (NLGN2) regulates GABAergic synapse development, but its role inneural circuit function in the adult hippocampus is unclear. We investigated GABAergic synapses and hippo-campus-dependent behaviors following viral-vector-mediated overexpression of NLGN2. Transducing hippo-campal neurons with AAV-NLGN2 increased neuronal expression of NLGN2 and membrane localization ofGABAergic postsynaptic proteins gephyrin and GABAARγ2, and presynaptic vesicular GABA transporter protein(VGAT) suggesting trans-synaptic enhancement of GABAergic synapses. In contrast, glutamatergic postsynapticdensity protein-95 (PSD-95) and presynaptic vesicular glutamate transporter (VGLUT) protein were unaltered.Moreover, AAV-NLGN2 significantly increased parvalbumin immunoreactive (PV+) synaptic boutons co-loca-lized with postsynaptic gephyrin+puncta. Furthermore, these changes were demonstrated to lead tomore »cognitiveimpairments as shown in a battery of hippocampal-dependent mnemonic tasks and social behaviors.« less
2. Early life adversity promotes resilience to opioid addiction-related phenotypes in male rats and sex-specific transcriptional changes

   https://doi.org/10.1073/pnas.2020173118  

   Ordoñes Sanchez, Evelyn ; Bavley, Charlotte C. ; Deutschmann, Andre U. ; Carpenter, Rachel ; Peterson, Drew R. ; Karbalaei, Reza ; Flowers, II, James ; Rogers, Charleanne M. ; Langrehr, Miranda G. ; Ardekani, Cory S. ; et al ( February 2021 , Proceedings of the National Academy of Sciences)

   Experiencing some early life adversity can have an “inoculating” effect that promotes resilience in adulthood. However, the mechanisms underlying stress inoculation are unknown, and animal models are lacking. Here we used the limited bedding and nesting (LBN) model of adversity to evaluate stress inoculation of addiction-related phenotypes. In LBN, pups from postnatal days 2 to 9 and their dams were exposed to a low-resource environment. In adulthood, they were tested for addiction-like phenotypes and compared to rats raised in standard housing conditions. High levels of impulsivity are associated with substance abuse, but in males, LBN reduced impulsive choice compared tomore »controls. LBN males also self-administered less morphine and had a lower breakpoint on a progressive ratio reinforcement schedule than controls. These effects of LBN on addiction-related behaviors were not found in females. Because the nucleus accumbens (NAc) mediates these behaviors, we tested whether LBN altered NAc physiology in drug-naïve and morphine-exposed rats. LBN reduced the frequency of spontaneous excitatory postsynaptic currents in males, but a similar effect was not observed in females. Only in males did LBN prevent a morphine-induced increase in the AMPA/NMDA ratio. RNA sequencing was performed to delineate the molecular signature in the NAc associated with LBN-derived phenotypes. LBN produced sex-specific changes in transcription, including in genes related to glutamate transmission. Collectively, these studies reveal that LBN causes a male-specific stress inoculation effect against addiction-related phenotypes. Identifying factors that promote resilience to addiction may reveal novel treatment options for patients.

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3. Rapid exchange of synaptic and extrasynaptic NMDA receptors in hippocampal CA1 neurons

   https://doi.org/10.1152/jn.00458.2019  

   McQuate, Andrea ; Barria, Andres ( March 2020 , Journal of Neurophysiology)

   N-methyl-d-aspartate receptors (NMDARs) are fundamental coincidence detectors of synaptic activity necessary for the induction of synaptic plasticity and synapse stability. Adjusting NMDAR synaptic content, whether by receptor insertion or lateral diffusion between extrasynaptic and synaptic compartments, could play a substantial role defining the characteristics of the NMDAR-mediated excitatory postsynaptic current (EPSC), which in turn would mediate the ability of the synapse to undergo plasticity. Lateral NMDAR movement has been observed in dissociated neurons; however, it is currently unclear whether NMDARs are capable of lateral surface diffusion in hippocampal slices, a more physiologically relevant environment. To test for lateral mobility inmore »rat hippocampal slices, we rapidly blocked synaptic NMDARs using MK-801, a use-dependent and irreversible NMDAR blocker. Following a 5-min washout period, we observed a strong recovery of NMDAR-mediated responses. The degree of the observed recovery was proportional to the amount of induced blockade, independent of levels of intracellular calcium, and mediated primarily by GluN2B-containing NMDA receptors. These results indicate that lateral diffusion of NMDARs could be a mechanism by which synapses rapidly adjust parameters to fine-tune synaptic plasticity. NEW & NOTEWORTHY N-methyl-d-aspartate-type glutamate receptors (NMDARs) have always been considered stable components of synapses. We show that in rat hippocampal slices synaptic NMDARs are in constant exchange with extrasynaptic receptors. This exchange of receptors is mediated primarily by NMDA receptors containing GluN2B, a subunit necessary to undergo synaptic plasticity. Thus this lateral movement of synaptic receptors allows synapses to rapidly regulate the total number of synaptic NMDARs with potential consequences for synaptic plasticity.« less
4. Multiplexed and high-throughput neuronal fluorescence imaging with diffusible probes

   https://doi.org/10.1038/s41467-019-12372-6  

   Guo, Syuan-Ming ; Veneziano, Remi ; Gordonov, Simon ; Li, Li ; Danielson, Eric ; Perez de Arce, Karen ; Park, Demian ; Kulesa, Anthony B. ; Wamhoff, Eike-Christian ; Blainey, Paul C. ; et al ( September 2019 , Nature Communications)

   Synapses contain hundreds of distinct proteins whose heterogeneous expression levels are determinants of synaptic plasticity and signal transmission relevant to a range of diseases. Here, we use diffusible nucleic acid imaging probes to profile neuronal synapses using multiplexed confocal and super-resolution microscopy. Confocal imaging is performed using high-affinity locked nucleic acid imaging probes that stably yet reversibly bind to oligonucleotides conjugated to antibodies and peptides. Super-resolution PAINT imaging of the same targets is performed using low-affinity DNA imaging probes to resolve nanometer-scale synaptic protein organization across nine distinct protein targets. Our approach enables the quantitative analysis of thousands ofmore »synapses in neuronal culture to identify putative synaptic sub-types and co-localization patterns from one dozen proteins. Application to characterize synaptic reorganization following neuronal activity blockade reveals coordinated upregulation of the post-synaptic proteins PSD-95, SHANK3 and Homer-1b/c, as well as increased correlation between synaptic markers in the active and synaptic vesicle zones.

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5. NMDAR-dependent long-term depression is associated with increased short term plasticity through autophagy mediated loss of PSD-95

   https://doi.org/10.1038/s41467-021-23133-9  

   Compans, Benjamin ; Camus, Come ; Kallergi, Emmanouela ; Sposini, Silvia ; Martineau, Magalie ; Butler, Corey ; Kechkar, Adel ; Klaassen, Remco V. ; Retailleau, Natacha ; Sejnowski, Terrence J. ; et al ( December 2021 , Nature Communications)

   Abstract Long-term depression (LTD) of synaptic strength can take multiple forms and contribute to circuit remodeling, memory encoding or erasure. The generic term LTD encompasses various induction pathways, including activation of NMDA, mGlu or P2X receptors. However, the associated specific molecular mechanisms and effects on synaptic physiology are still unclear. We here compare how NMDAR- or P2XR-dependent LTD affect synaptic nanoscale organization and function in rodents. While both LTDs are associated with a loss and reorganization of synaptic AMPARs, only NMDAR-dependent LTD induction triggers a profound reorganization of PSD-95. This modification, which requires the autophagy machinery to remove the T19-phosphorylatedmore »form of PSD-95 from synapses, leads to an increase in AMPAR surface mobility. We demonstrate that these post-synaptic changes that occur specifically during NMDAR-dependent LTD result in an increased short-term plasticity improving neuronal responsiveness of depressed synapses. Our results establish that P2XR- and NMDAR-mediated LTD are associated to functionally distinct forms of LTD.« less