Neuroligins (NLs) are critical for synapse formation and function. NL3 R451C is an autism-associated mutation. NL3 R451C knockin (KI) mice exhibit autistic behavioral abnormalities, including social novelty deficits. However, neither the brain regions involved in social novelty nor the underlying mechanisms are clearly understood. Here, we found decreased excitability of fast-spiking interneurons and dysfunction of gamma oscillation in the medial prefrontal cortex (mPFC), which contributed to the social novelty deficit in the KI mice. Neuronal firing rates and phase-coding abnormalities were also detected in the KI mice during social interactions. Interestingly, optogenetic stimulation of parvalbumin interneurons in the mPFC at 40 Hz nested at 8 Hz positively modulated the social behaviors of mice and rescued the social novelty deficit in the KI mice. Our findings suggest that gamma oscillation dysfunction in the mPFC leads to social deficits in autism, and manipulating mPFC PV interneurons may reverse the deficits in adulthood.
2+-dependent signaling and synaptic plasticity. Previous studies have suggested that the synaptic trafficking of NMDAR subtypes is differentially regulated, but the precise molecular mechanism is not yet clear. In this study, we demonstrated that Bip, an endoplasmic reticulum (ER) chaperone, selectively interacted with GluN2A and mediated the neuronal activity-induced assembly and synaptic incorporation of the GluN2A-containing NMDAR from dendritic ER. Furthermore, the GluN2A-specific synaptic trafficking was effectively disrupted by peptides interrupting the interaction between Bip and GluN2A. Interestingly, fear conditioning in mice was disrupted by intraperitoneal injection of the interfering peptide before training. In summary, we have uncovered a novel mechanism for the activity-dependent supply of synaptic GluN2A-containing NMDARs, and demonstrated its relevance to memory formation.
In the original publication of this article, the sentence in the Introduction, ''In addition, reduced gamma oscillations and sharp-wave ripples in the hippocampus are associated with decreased extinction of contextual fear memory in the NL3 R451C KI mouse (Polepalli et al., 2017),'' the term ''NL3 R451C KI mouse'' should be ''NL3 fl /PV-cre mouse.'' This has now been corrected in the article online.
Long term synaptic plasticity, such as long term potentiation (LTP), has been widely accepted as a cellular mechanism underlying memory. Recently, it has been unraveled that Shp2 plays a role in synaptic plasticity and memory in Drosophila and mice, revealing significant and conserved effects of Shp2 in cognitive function. However, the exact mechanism underlying this function of Shp2 in synaptic plasticity and memory still remains elusive. Here, we examine the regulation of Shp2 in hippocampal LTP and contextual fear conditioning. We find that Shp2 is rapidly recruited into spines after LTP induction. Furthermore, the phosphorylation level of Shp2 at Tyr-542 is elevated after LTP stimuli either in cultured hippocampal neurons or acute slices. Notably, contextual fear conditioning also regulates the phosphorylation level of Shp2 at Tyr-542, suggesting fine-tuned regulation of Shp2 in LTP and memory formation. By using a Shp2-specific inhibitor and adeno-associated virus-Cre mediated Shp2 knock-out in cultured neurons, we provide evidence that the phosphatase activity of Shp2 is critical for activity-dependent AMPA receptor surface trafficking. Collectively, our results have revealed a regulatory mechanism of Shp2 underlying LTP and memory, broadening our understanding of Shp2 in cognitive function.
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