SH2B1 Tunes Hippocampal ERK Signaling to Influence Fluid Intelligence in Humans and Mice.

Fluid intelligence is a cognitive domain that encompasses general reasoning, pattern recognition, and problem-solving abilities independent of task-specific experience. Understanding its genetic and neural underpinnings is critical yet challenging for predicting human development, lifelong health, and well-being. One approach to address this challenge is to map the network of correlations between intelligence and other constructs. In the current study, we performed a genome-wide association study using fluid intelligence quotient scores from the UK Biobank to explore the genetic architecture of the associations between obesity risk and fluid intelligence. Our results revealed novel common genetic loci (SH2B1, TUFM, ATP2A1, and FOXO3) underlying the association between fluid intelligence and body metabolism. Surprisingly, we demonstrated that SH2B1 variation influenced fluid intelligence independently of its effects on metabolism but partially mediated its association with bilateral hippocampal volume. Consistently, selective genetic ablation of Sh2b1 in the mouse hippocampus, particularly in inhibitory neurons, but not in excitatory neurons, significantly impaired working memory, short-term novel object recognition memory, and behavioral flexibility, but not spatial learning and memory, mirroring the human intellectual performance. Single-cell genetic profiling of Sh2B1-regulated molecular pathways revealed that Sh2b1 deletion resulted in aberrantly enhanced extracellular signal-regulated kinase (ERK) signaling, whereas pharmacological inhibition of ERK signaling reversed the associated behavioral impairment. Our cross-species study thus provides unprecedented insight into the role of SH2B1 in fluid intelligence and has implications for understanding the genetic and neural underpinnings of lifelong mental health and well-being.

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.

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.

Quercetin Reduces Cortical GABAergic Transmission and Alleviates MK-801-Induced Hyperactivity.

An imbalance between neuronal excitation and inhibition represents a core feature in multiple neuropsychiatry disorders, necessitating the development of novel strategies to calibrate the excitatory-inhibitory balance of therapeutics. Here we identify a natural compound quercetin that reduces prefrontal cortical GABAergic transmission and alleviates the hyperactivity induced by glutamatergic N-methyl-d-aspartate receptor antagonist MK-801. Quercetin markedly reduced the GABA-activated currents in a noncompetitive manner in cultured cortical neurons, and moderately inhibited spontaneous and electrically-evoked GABAergic inhibitory postsynaptic current in mouse prefrontal cortical slices. Notably, systemic and prefrontal-specific delivery of quercetin reduced basal locomotor activity in addition to alleviated the MK-801-induced hyperactivity. The effects of quercetin were not exclusively dependent on α5-subunit-containing A type GABA receptors (GABAARs), as viral-mediated, region-specific genetic knockdown of the α5-subunit in prefrontal cortex improved the MK-801-evoked psychotic symptom but reserved the pharmacological responsivity to quercetin. Both interventions together completely normalized the locomotor activity. Together, quercetin as a negative allosteric GABAAR modulator exerted antipsychotic activity, facilitating further therapeutic development for the excitatory-inhibitory imbalance disorders.