Social deficits via dysregulated Rac1-dependent excitability control of prefrontal cortical neurons and increased GABA/glutamate ratios.

Identifying symptom-specific convergent mechanisms for neurodevelopmental disorders is a promising strategy in advancing therapies. Here, we show that bidirectional dysregulation of Rac1 activity in the medial prefrontal cortex (mPFC) dictates shared social deficits in mice. Selective upregulation or downregulation of Rac1 activity in glutamatergic or fast-spiking GABAergic neurons results in excessive or inadequate control of excitability combined with a decrease in glutamate or an increase in GABA concentrations and an increase in the GABA/glutamate ratio, which is responsible for social deficits. Notably, the autism model of Shank3B knockout mice exhibits aberrantly enhanced Rac1 activity, reduced glutamate concentrations, and pyramidal neuron excitability in mPFC accompanied with social deficits, which were corrected by either excitatory-neuron-specific downregulation of Rac1 activity or upregulation of neuronal excitability. Thus, this work shows a convergence between genetic autism risk factors, dysregulation of Rac1 signaling, and excitation-inhibition imbalance, enabling mechanism-based stratification of patients with social deficits.

Nanoformulated Bumetanide Ameliorates Social Deficiency in BTBR Mice Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder with few medication options. Bumetanide, an FDA-approved diuretic, has been proposed as a viable candidate to treat core symptoms of ASD, however, neither the brain region related to its effect nor the cell-specific mechanism(s) is clear. The availability of nanoparticles provides a viable way to identify pharmacological mechanisms for use in ASD. Here, we found that treatment with bumetanide, in a systemic and medial prefrontal cortex (mPFC) region-specific way, attenuated social deficits in BTBR mice. Furthermore, using poly (ethylene glycol)-poly(l-lactide) (PEG-PLA) nanoparticles [NP(bumetanide)], we showed that the administration of NP(bumetanide) in a mPFC region-specific way also alleviated the social deficits of BTBR mice. Mechanistically, the behavioral effect of NP(bumetanide) was dependent on selective microglia-specific targeting in the mPFC. Pharmacological depletion of microglia significantly reduced the effect of nanoencapsulation and depletion of microglia alone did not improve the social deficits in BTBR mice. These findings suggest the potential therapeutic capabilities of nanotechnology for ASD, as well as the relevant link between bumetanide and immune cells.

Drug-induced liver injury: Oltipraz and C2-ceramide intervene HNF-1α/GSTA1 expression via JNK signaling pathway.

Drug-induced liver injury (DILI) is a serious and frequently occurring issue in drug development. The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in many diseases; hepatocyte nuclear factor-1α (HNF-1α) and glutathione S-transferase A1 (GSTA1) are important in regulating liver-specific genes expressions and affecting drug metabolism. Oltipraz is used to treat liver cirrhosis by improving liver function, and C2-ceramide is a pro-apoptotic lipid that regulates multiple signaling pathways. In this study, we investigated the function of the JNK signaling pathway with HNF-1α and GSTA1 in a cellular model of DILI and whether oltipraz and C2-ceramide exert effects via the JNK pathway. The results showed that inhibiting JNK could ameliorate APAP-induced hepatocyte injury, reduced oxidative stress, suppressed JNK and c-Jun activation, and hepatocyte apoptosis. Meanwhile, the mRNA and protein expressions of HNF-1α and GSTA1 were increased significantly compared to control conditions. The effect of oltipraz (8 µmol/L) was similar to a JNK inhibitor and significantly increased HNF-1α/GSTA1 expression, but oltipraz combined with JNK inhibitor did not show a synergistic effect. Although C2-ceramide (8 µmol/L) aggravated hepatocyte injury and apoptosis, exacerbated oxidative stress, increased phosphorylation of JNK and c-Jun, and markedly decreased HNF-1α/GSTA1 expression, C2-ceramide combined with JNK inhibitor could partially alleviate these alterations. These results demonstrated that the JNK signaling pathway with HNF-1α/GSTA1 are involved in the process of DILI. Inhibiting JNK up-regulated HNF-1α and GSTA1 expressions which could attenuate hepatocyte injury. Oltipraz and C2-ceramide might affect the expression of HNF-1α/GSTA1 though JNK signaling.

Reconsolidation of a post-ingestive nutrient memory requires mTOR in the central amygdala.

The central control of feeding behavior and metabolic homeostasis has been proposed to involve a form of post-ingestive nutrient learning independent of the gustatory value of food. However, after such learning, it is unknown which brain regions or circuits are activated to retrieve the stored memory and whether this memory undergoes reconsolidation that depends on protein synthesis after its reactivation through retrieval. In the present study, using a conditioned-flavor-preference paradigm by associating flavors with intra-gastric infusion of glucose to minimize the evaluation of the taste of food, we show that retrieval of the post-ingestive nutrient-conditioned flavor memory stimulates multiple brain regions in mice, including the central nucleus of the amygdala (CeA). Moreover, memory retrieval activated the mammalian target of rapamycin complex 1 (mTORC1) in the CeA, while site-specific or systemic inhibition of mTORC1 immediately after retrieval prevented the subsequent expression of the post-ingestive nutrient-associated flavor memory, leading to a long-lasting suppression of reinstatement. Taken together, our findings suggest that the reconsolidation process of a post-ingestive nutrient memory modulates food preferences.

Long-Term NMDAR Antagonism Correlates Weight Loss With Less Eating.

Memantine hydrochloride is an uncompetitive N-methyl-D-aspartate (NMDA) antagonist for treatment of moderate-to-severe Alzheimer's disease. Several studies have shown that memantine can significantly correct the binge-like eating behavior in human and animal models. People with overeating behavior are more likely to be obese. Therefore, we suppose that memantine would be a good candidate for the treatment of obesity. In this study, memantine was shown to increase weight loss in obese mice induced by high fat diet. Memantine was shown to decrease food intake without inducing abdominal discomfort and anxiety, suggesting that this compound would be a good candidate drug for obesity control.

Methyleugenol counteracts anorexigenic signals in association with GABAergic inhibition in the central amygdala.

Feeding can be inhibited by satiety, sickness, or food unpalatability. The central nucleus of the amygdala (CeA) has been considered the key region for processing multiple anorexigenic signals, although the detailed cellular and molecular mechanisms remain largely unclear. Here we identify that methyleugenol (ME), a novel agonist of A type ionotropic γ-aminobutyric acid receptors (GABAARs), significantly counteracts the anorexigenic effects caused by satiety or sickness in association with GABAergic inhibition in the CeA. Electrophysiologically, ME enhanced GABAergic transmission and repressed neuronal excitability of the CeA. Behaviorally, ME increased feeding but not affect locomotor activity and basal anxiety in naïve mice. Notably, both systemic and CeA-specific delivery of ME significantly rescued satiety- or sickness-induced inhibition of feeding. The effects of ME were mainly dependent on the GABAARs in the CeA. Indeed, viral-mediated, the CeA region-specific genetic knockdown of the γ2 subunit of GABAARs largely abolished the above pharmacological effects, while its re-expression in a subpopulation of GABAergic neurons in the CeA, that produce protein kinase C-δ (PKC-δ), recovered the effects of ME on anorexigenic signals. Taken together, these results reveal a novel molecular mechanism for counter-anorexigenic signals dependent on GABAergic inhibition in the CeA, suggesting the possibility of ME as a leading compound for anorexia treatment.