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Author(s): Sungkun Chun [1]; Fei Du [1]; Joby J Westmoreland [1]; Seung Baek Han [1]; Yong-Dong Wang [2]; Donnie Eddins [1]; Ildar T Bayazitov [1]; Prakash Devaraju [1]; Jing Yu [...], Although 22q11.2 deletion syndrome (22q11DS) is associated with early-life behavioral abnormalities, affected individuals are also at high risk for the development of schizophrenia symptoms, including psychosis, later in life. Auditory thalamocortical (TC) projections recently emerged as a neural circuit that is specifically disrupted in mouse models of 22q11DS (hereafter referred to as 22q11DS mice), in which haploinsufficiency of the microRNA (miRNA)-processing-factor-encoding gene Dgcr8 results in the elevation of the dopamine receptor Drd2 in the auditory thalamus, an abnormal sensitivity of thalamocortical projections to antipsychotics, and an abnormal acoustic-startle response. Here we show that these auditory TC phenotypes have a delayed onset in 22q11DS mice and are associated with an age-dependent reduction of miR-338-3p, a miRNA that targets Drd2 and is enriched in the thalamus of both humans and mice. Replenishing depleted miR-338-3p in mature 22q11DS mice rescued the TC abnormalities, and deletion of Mir338 (which encodes miR-338-3p) or reduction of miR-338-3p expression mimicked the TC and behavioral deficits and eliminated the age dependence of these deficits. Therefore, miR-338-3p depletion is necessary and sufficient to disrupt auditory TC signaling in 22q11DS mice, and it may mediate the pathogenic mechanism of 22q11DS-related psychosis and control its late onset.

Objective: Epothilone D (EpoD), microtubule (MT) stabilizing agent, demonstrated promising results in the animal models of Alzheimer's disease, Parkinson's disease and schizophrenia. The present study sought to investigate preventive effects of EpoD on altered changes of MT related proteins and endoplasmic reticulum (ER) stress proteins induced by social defeat stress (SDS)., Methods: We measured protein expression levels of α-tubulin and its post-translational modifications, MT-associated protein 2, stathmin1 and 2 with their phosphorylated forms, and ER stress markers, 78-kDa glucose-regulated protein (GRP-78) and CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) in the prefrontal cortex (PFC) and hippocampus (HIP) of C57BL/6J strain mice treated with EpoD (2 mg/kg) or its vehicle, dimethylsulfoxide (DMSO), and exposed to SDS., Results: We observed lower levels of acetylated α-tubulin, MAP2, p-STMN (Ser16), and GRP-78 in the PFC of the EpoD-Con group when compared to the DMSO-Con group. On the other hand, in the HIP, there were significantly higher levels of tyrosinated α-tubulin and GRP-78 in the EpoD-Defeat group compared to the DMSO-Defeat group. Furthermore, the level of MAP2 in the HIP was found to be lower in the EpoD-Con group compared to the DMSO-Con group., Conclusion: Our results suggest that EpoD exhibits a dual impact, manifesting both beneficial and detrimental effects on the aberrant changes of MT-related proteins and ER stress proteins induced by SDS, depending on the brain regions. These findings underscore the complexity of EpoD's effects, necessitating further exploration to understand its intricate mechanisms in cellular pathways linked to SDS.

In this study, we used a novel α-L-arabinopyranosidase (AbpBs) obtained from ginsenoside-converting Blastococcus saxobsidens that was cloned and expressed in Escherichia coli BL21 (DE3), and then applied it in the biotransformation of ginsenoside Rb 2 into Rd. The gene, termed AbpBs , consisting of 2,406 nucleotides (801 amino acid residues), and with a predicted translated protein molecular mass of 86.4 kDa, was cloned into a pGEX4T-1 vector. A BLAST search using the AbpBs amino acid sequence revealed significant homology with a family 2 glycoside hydrolase (GH2). The over-expressed recombinant AbpBs in Escherichia coli BL21 (DE3) catalyzed the hydrolysis of the arabinopyranose moiety attached to the C-20 position of ginsenoside Rb2 under optimal conditions (pH 7.0 and 40°;C). Kinetic parameters for α-Larabinopyranosidase showed apparent K m and V max values of 0.078 ± 0.0002 micrometer and 1.4 ± 0.1 μmol/min/mg of protein against p -nitrophenyl-α-L-arabinopyranoside. Using a purified AbpBs (1 μg/ml), 0.1% of ginsenoside Rb 2 was completely converted to ginsenoside Rd within 1 h. The recombinant AbpBs could be useful for high-yield, rapid, and low-cost preparation of ginsenoside Rd from Rb 2 .

Cortical maps in sensory cortices are plastic, changing in response to sensory experience. The cellular site of such plasticity is currently debated. Thalamocortical (TC) projections deliver sensory information to sensory cortices. TC synapses are currently dismissed as a locus of cortical map plasticity because TC synaptic plasticity is thought to be limited to neonates, whereas cortical map plasticity can be induced in both neonates and adults. However, in the auditory cortex (ACx) of adults, cortical map plasticity can be induced if animals attend to a sound or receive sounds paired with activation of cholinergic inputs from the nucleus basalis. We now show that, in the ACx, long-term potentiation (LTP), a major form of synaptic plasticity, is expressed at TC synapses in both young and mature mice but becomes gated with age. Using single-cell electrophysiology, two-photon glutamate uncaging, and optogenetics in TC slices containing the auditory thalamus and ACx, we show that TC LTP is expressed postsynaptically and depends on group I metabotropic glutamate receptors. TC LTP in mature ACx can be unmasked by cortical disinhibition combined with activation of cholinergic inputs from the nucleus basalis. Cholinergic inputs passing through the thalamic radiation activate M1 muscarinic receptors on TC projections and sustain glutamate release at TC synapses via negative regulation of presynaptic adenosine signaling through A1 adenosine receptors. These data indicate that TC LTP in the ACx persists throughout life and therefore can potentially contribute to experience-dependent cortical map plasticity in the ACx in both young and adult animals.