Effects of medial prefrontal cortex NMDA NR-1 subunit deletion in adult mice on spatial reference and working memory

Dysfunction of glutamate NMDA receptors may contribute to cognitive deficits in schizophrenia. In the present study, we examined the effects of chronic NMDA receptor dysfunction in the ventral medial prefrontal cortex (mPFC) on the acquisition of a spatial reference memory (SRM) and spatial working memory (SWM) radial maze task as employed by Niewoehner et al (2007). Localized NR1 gene deletions were induced in the ventral mPFC of floxed NR1 mice (DEL, n=10) using an AAV-Cre vector; control mice (CON, n=10) received sham deletions. In the SRM task, food was placed in 3 of 6 arms of an automated radial maze at the start of each trial. Mice were placed in the central chamber of the maze and allowed to enter any arm before returning to the center for a 10-s timeout. Only the previously unchosen arms were then made accessible. This sequence was continued until the mouse had entered all 3 baited arms or the trial was terminated (6 min). Thus, this phase of the task only assessed SRM errors, or entries to arms that were never baited. Following acquisition of the SRM task, a spatial working memory (SWM) component was added. During this phase mice were no longer prevented from re-entering a previously chosen arm. Re-entries were recorded as SWM errors. Performance was also assessed under conditions of a 5-s and 30-s timeout as well as rotation of the maze. NMDA receptor dysfunction in the ventral mPFC had no effect on acquisition of the SRM task or performance in the SWM component. Whereas reducing the timeout from 10-s to 5-s did not significantly alter SRM or SWM performance of either group, performance of both control and deleted mice was significantly impaired when the delay was extended from to 30-s or the maze was rotated to dissociate baited arms from the spatial cues. The most robust performance deficits were observed in response to the maze rotation, which increased SRM and SWM errors. This effect was potentiated in deleted mice where there was a tendency for deleted mice to exhibit a greater number of SWM errors than controls (4.0±1.1 and 2.8±0.8, respectively). These results suggest performance deficits associated with PFC NMDA receptor dysfunction reflect impairment of the ability to modify behavior in the presence of changes in the environment

Damaging variants in FOXI3 cause microtia and craniofacial microsomia

Q1Q1Pacientes con Microtia y Microsomía craneofacialPurpose: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown. Methods: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro. Results: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3. Conclusion: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.https://orcid.org/0000-0003-3822-7780https://orcid.org/0000-0002-0729-6866Revista Internacional - IndexadaA1N

Visualizing Nanoparticle Dissolution by Imaging Mass Spectrometry

We demonstrate the ability to visualize nanoparticle dissolution while simultaneously providing chemical signatures that differentiate between citrate-capped silver nanoparticles (AgNPs), AgNPs forced into dissolution via exposure to UV radiation, silver nitrate (AgNO₃), and AgNO₃/citrate deposited from aqueous solutions and suspensions. We utilize recently developed inkjet printing (IJP) protocols to deposit the different solutions/suspensions as NP aggregates and soluble species, which separate onto surfaces <i>in situ</i>, and collect mass spectral imaging data <i>via</i> time-of-flight secondary ion mass spectrometry (TOF-SIMS). Resulting 2D Ag⁺ chemical images provide the ability to distinguish between the different Ag-containing starting materials and, when coupled with mass spectral peak ratios, provide information-rich data sets for quick and reproducible visualization of NP-based aqueous constituents. When compared to other measurements aimed at studying NP dissolution, the IJP-TOF-SIMS approach offers valuable information that can potentially help in understanding the complex equilibria in NP-containing solutions and suspensions, including NP dissolution kinetics and extent of overall dissolution

Local connectivity and synaptic dynamics in mouse and human neocortex.

We present a unique, extensive, and open synaptic physiology analysis platform and dataset. Through its application, we reveal principles that relate cell type to synaptic properties and intralaminar circuit organization in the mouse and human cortex. The dynamics of excitatory synapses align with the postsynaptic cell subclass, whereas inhibitory synapse dynamics partly align with presynaptic cell subclass but with considerable overlap. Synaptic properties are heterogeneous in most subclass-to-subclass connections. The two main axes of heterogeneity are strength and variability. Cell subclasses divide along the variability axis, whereas the strength axis accounts for substantial heterogeneity within the subclass. In the human cortex, excitatory-to-excitatory synaptic dynamics are distinct from those in the mouse cortex and vary with depth across layers 2 and 3