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Lysosomal amino acid accumulation is implicated in several diseases, but its role in insulin resistance, the central mechanism to type 2 diabetes and many metabolic diseases, is unclear. In this study, we show the hepatic expression of lysosomal membrane protein solute carrier family 7 member 14 (SLC7A14) is increased in insulin-resistant mice. The promoting effect of SLC7A14 on insulin resistance is demonstrated by loss- and gain-of-function experiments. SLC7A14 is further demonstrated as a transporter resulting in the accumulation of lysosomal γ-aminobutyric acid (GABA), which induces insulin resistance via inhibiting mTOR complex 2 (mTORC2)'s activity. These results establish a causal link between lysosomal amino acids and insulin resistance and suggest that SLC7A14 inhibition may provide a therapeutic strategy in treating insulin resistance-related and GABA-related diseases and may provide insights into the upstream mechanisms for mTORC2, the master regulator in many important processes. [Display omitted] • Hepatic SLC7A14 regulates insulin sensitivity • SLC7A14 is a transporter for importing GABA to lysosomes • The increased lysosomal GABA mediates SLC7A14-induced insulin resistance • mTORC2 is involved in lysosomal GABA accumulation-induced insulin resistance Jiang et al. find SLC7A14 as a GABA transporter, resulting in the accumulation of lysosomal γ-aminobutyric acid (GABA), which induces insulin resistance via inhibiting mTOR complex 2 (mTORC2)'s activity. These results establish a causal link between lysosomal amino acids and insulin sensitivity and provide drug targets for insulin-resistance-related diseases. [ABSTRACT FROM AUTHOR]

Summary A critical step in understanding the neural basis of human cognitive functions is to identify neuronal types in the neocortex. In this study, we performed whole-cell recording from human cortical slices and found a distinct subpopulation of neurons with intrinsic persistent activity that could be triggered by single action potentials (APs) but terminated by bursts of APs. This persistent activity was associated with a depolarizing plateau potential induced by the activation of a persistent Na + current. Single-cell RT-PCR revealed that these neurons were inhibitory interneurons. This type of neuron was found in different cortical regions, including temporal, frontal, occipital, and parietal cortices in human and also in frontal and temporal lobes of nonhuman primate but not in rat cortical tissues, suggesting that it could be unique to primates. The characteristic persistent activity in these inhibitory interneurons may contribute to the regulation of pyramidal cell activity and participate in cortical processing. [ABSTRACT FROM AUTHOR]

Enhanced beta oscillations within the cortico-basal ganglia-thalamic (CBT) network are correlated with motor deficits in Parkinson's disease (PD), whose generation has been associated recently with amplified network dynamics in the striatum. However, how distinct striatal cell subtypes interact to orchestrate beta oscillations remains largely unknown. Here, we show that optogenetic suppression of dopaminergic control over the dorsal striatum (DS) elevates the power of local field potentials (LFPs) selectively at beta band (12–25 Hz), accompanied by impairments in locomotion. The amplified beta power originates from a striatal loop driven by somatostatin-expressing (SOM) interneurons and constituted by choline acetyltransferase (ChAT)-expressing interneurons and dopamine D2 receptor (D2R)-expressing medium spiny neurons (iMSNs). Moreover, closed-loop intervention selectively targeting striatal iMSNs or ChATs diminishes beta oscillations and restores motor function. Thus, we reveal a striatal microcircuit motif that underlies beta oscillation generation and accompanied motor deficits upon perturbation of dopaminergic control over the striatum. [Display omitted] • Inhibition of DANs selectively enhances beta oscillations and produces motor deficits • SOMs function as the downstream effectors for DANs in beta oscillation generation • The amplified beta power originates from a striatal SOM-driven ChAT-iMSN loop • Closed-loop inhibition iMSNs or ChATs reduces beta power and improves motor deficits Qian et al. demonstrate that photoinhibition of substantia nigra pars compacta (SNc) dopaminergic terminals in striatum enhances beta oscillations, accompanied by impairment in locomotion. Specifically, the enhancement in beta power originates from a loop circuit driven by somatostatin interneurons and constituted by cholinergic interneuron and D2R medium spiny neurons. [ABSTRACT FROM AUTHOR]

Abstract Fragile X mental retardation protein (FMRP), a key determinant of normal brain development and neuronal plasticity, plays critical roles in nucleocytoplasmic shuttling of mRNAs. However, the factors involved in FMRP nuclear localization remain to be determined. Using cross-species sequence comparison, we show that an aspartate in position 132 (D132), located within the conserved nuclear localization signal (NLS) of FMRP, appears in human and other mammals, while glutamate 132 (E132) appears in rodents and birds. Human FMRP-D132E alters the secondary structure of the protein and reduces its nuclear localization, while the reciprocal substitution in mouse FMRP-E132D promotes its nuclear localization. Human FMRP could interact with poly(A)-binding protein 1 (PABP1) which is impeded by the D132E mutation. Reversely, mouse FMRP could not interact with PABP1, but the E132D mutation leads to the FMRP-PABP1 interaction. We further show that overexpression of human FMRP-D132E mutant promotes the formation of cytoplasmic aggregates of PABP1 in human cells, but not of mouse FMRP-E132D in mouse cells. PABP1 knockdown reduces the nuclear localization of human FMRP, but not mouse FMRP. Furthermore, RNase A treatment decreases the PABP1 levels in the anti-V5-immunoprecipitates using the V5-hFMRP-transfected cells, suggesting an interaction between human FMRP and PABP1 in an RNA-dependent fashion. Thus, our data suggest that the FMRP protein with the human-used D132 accommodates a novel protein-RNA-protein interaction which may implicate a connection between FMRP residue transition and neural evolution. Graphical abstract Unlabelled Image Highlights • The position 132 on the NLS of FMRP is a species-correlated transitional site. • Human FMRP D132E mutation alters the protein structure and reduces its nuclear localization. • FMRP interacts with PABP1 in an RNA-dependent fashion and D132E reduces the interaction. • PABP1 knockdown reduces the nuclear localization of human FMRP, but not mouse FMRP. [ABSTRACT FROM AUTHOR]

Ionotropic GABA A receptors expressing at the axon initial segment (AIS) of glutamatergic pyramidal cell (PC) in the cortex plays critical roles in regulating action potential generation. However, it remains unclear whether these receptors also express at the AIS of cortical GABAergic interneurons. In mouse prefrontal cortical slices, we performed experiments at the soma and AIS of the two most abundant GABAergic interneurons: parvalbumin (PV) and somatostatin (SST) positive neurons. Local application of GABA at the perisomatic axonal regions could evoke picrotoxin-sensitive currents with a reversal potential near the Cl − equilibrium potential. Puffing agonists to outside-out patches excised from AIS confirmed the expression of GABA A receptors. Further pharmacological experiments revealed that GABA A receptors in AIS of PV neurons contain α1 subunits, different from those containing α2/3 in AIS and α4 in axon trunk of layer-5 PCs. Cell-attached recording at the soma of PV and SST neurons revealed that the activation of AIS GABA A receptors inhibits the action potential generation induced by synaptic stimulation. Together, our results demonstrate that the AIS of PV and SST neurons express GABA A receptors with distinct subunit composition, which exert an inhibitory effect on neuronal excitability in these inhibitory interneurons. [ABSTRACT FROM AUTHOR]

Midbrain dopamine neurons (DANs) regulate various brain functions such as motor control and motivation. Alteration of spiking activities of these neurons could contribute to severe brain disorders including Parkinson's disease and depression. Previous studies showed important roles of somatodendritic voltage-gated K+ channels (Kv) of DANs in governing neuronal excitability and dopamine release. However, it remains largely unclear about the biophysical properties and the function of Kv channels distributed at DAN axons. We performed whole-cell recordings from the axons of DANs in acute mouse midbrain and striatal slices. We detected both rapidly activating/inactivating Kv current (i.e. A-current) and rapidly activating but slowly inactivating current (i.e. D-current) in DAN axons. Pharmacological experiments with channel blockers revealed that these currents are predominantly mediated by Kv1.4 and Kv1.2 subunits, respectively. Blocking these currents could substantially prolong axonal action potentials (APs) via a reduction of their repolarization slope. Together, our results show that Kv channels mediating A- and D-currents shape AP waveforms in midbrain DAN axons, through this regulation they may control dopamine release at the axonal terminals. Therefore, these axonal Kv channels could be drug targets for brain disorders with abnormal dopamine release. • Dopamine neuron axons express Kv channels mediating both A- and D-currents. • A- and D-currents are predominantly mediated by Kv1.4 and Kv1.2 subunits, respectively. • Axonal Kv channels determine the duration of axonal AP waveform. • Axonal depolarization inactivates Kv channels and thus prolongs AP duration. [ABSTRACT FROM AUTHOR]