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.

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.