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The GluN3A subunit of N-methyl-D-aspartate receptors (NMDARs) plays an established role in synapse development, but its contribution to neural circuits in the adult brain is less clear. Recent work has demonstrated that in select cell populations, GluN3A assembles with GluN1 to form GluN1/GluN3A receptors that are insensitive to glutamate and instead serve as functional excitatory glycine receptors (eGlyRs). Our understanding of these eGlyRs, and how they contribute to intrinsic excitability and synaptic communication within relevant networks of the developing and the mature brain, is only beginning to be uncovered. Here, using male and female mice, we demonstrate that GluN3A subunits are enriched in the adult ventral hippocampus (VH), where they localize to synaptic and extrasynaptic sites and can assemble as functional eGlyRs on CA1 pyramidal cells. GluN3A expression was barely detectable in the adult dorsal hippocampus (DH). We also observed a high GluN2B content in the adult VH, characterized by slow NMDAR current decay kinetics and a high sensitivity to the GluN2B-containing NMDAR antagonist ifenprodil. Interestingly, the GluN2B enrichment in the adult VH was dependent on GluN3A as GluN3A deletion accelerated NMDAR decay and reduced ifenprodil sensitivity in the VH, suggesting that GluN3A expression can regulate the balance of conventional NMDAR subunit composition at synaptic sites. Lastly, we found that GluN3A knock-out also enhanced both NMDAR-dependent calcium influx and NMDAR-dependent long-term potentiation in the VH. Together, these data reveal a novel role for GluN3A and eGlyRs in the control of ventral hippocampal circuits in the mature brain. [ABSTRACT FROM AUTHOR]

Histone deacetylase (HDAC) plays a role in synaptic plasticity and long-term memory formation. We hypothesized that trichostatin-A (TSA), an HDAC inhibitor, would promote long-term odor preference memory and maintain enhanced GluA1 receptor levels that have been hypothesized to support memory. We used an early odor preference learning model in neonate rat pups that normally produces only 24-h memory to test behavior and examine receptor protein expression. Our behavioral studies showed that intrabulbar infusion of TSA, prior to pairing of the conditioned stimulus (peppermint odor) with the unconditioned stimulus (tactile stimulation), prolonged 24-h odor preference memory for at least 9 d. The prolonged odor preference memory was selective for the paired odor and was also observed using a specific HDAC6 inhibitor, tubacin, supporting a role for histone acetylation in associative memory. Immunoblot analysis showed that GluA1 receptor membrane expression in the olfactory bulbs of the TSA-treated group was significantly increased at 48 h unlike control rats without TSA. Immunohistochemistry revealed significant increase of GluA1 expression in olfactory bulb glomeruli 5 d after training. These results extend previous evidence for a close relationship between enhanced GluA1 receptor membrane expression and memory expression. Together, these findings provide a new single-trial appetitive model for understanding the support and maintenance of memories of varying duration.

Early odor preference learning occurs in one-week-old rodents when a novel odor is paired with a tactile stimulation mimicking maternal care. ß-Adrenoceptors and L-type calcium channels (LTCCs) in the anterior piriform cortex (aPC) are critically involved in this learning. However, whether ß-adrenoceptors interact directly with LTCCs in aPC pyramidal cells is unknown. Here we show that pyramidal cells expressed significant LTCC currents that declined with age. ß-Adrenoceptor activation via isoproterenol age-dependently enhanced LTCC currents. Nifedipine-sensitive, isoproterenol enhancement of calcium currents was only observed in post-natal day 7-10 mice. APC ß-adrenoceptor activation induced early odor preference learning was blocked by nifedipine coinfusion.

Here we demonstrate metaplastic effect of a change in NMDA receptor (NMDAR) number in the anterior piriform cortex (aPC) in rat induced by a 10 min pairing of peppermint odor stroking, which significantly modifies later learning and memory. Using isolated synaptoneurosomes, we found NR1 receptor downregulation 3 h after training and upregulation at 24 h. Consistent with the NR1 pattern, the NMDAR-mediated EPSP was smaller at 3 h and larger at 24 h. Subunit composition was unchanged. Whereas LTP was reduced at both times by training, LTD was facilitated only at 3 h. Behaviorally, pups, given a pairing of peppermint stroking 3 h after an initial peppermint stroking training, lost the normally acquired peppermint preference 24 h later. To probe the pathway specificity of this unlearning effect, pups were trained first with peppermint and then, at 3 h, given a second training with peppermint or vanillin. Pups given peppermint training at both times lost the learned peppermint preference. Pups given vanillin retraining at 3 h had normal peppermint preference. Downregulating NR1 with siRNA prevented odor preference learning. Finally, the NMDAR antagonist MK-801 blocked the LTD facilitation seen 3 h after training, and giving MK-801 before the second peppermint training trial eliminated the loss of peppermint odor preference. Atraining-associated reduction inNMDARsfacilitates LTD3 h later; training at the time of LTD facilitation reverses an LTP-dependent odor preference. Experience-dependent, pathway-specific metaplastic effects in a cortical structure have broad implications for the optimal spacing of learning experiences. [ABSTRACT FROM AUTHOR]

Amyloid accumulation in Alzheimer's disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD ( App NL-G-F /hMapt ), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.