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SUMMARYThe lateral hypothalamic area (LHA) regulates food intake and energy expenditure. Although LHA neurons innervate adipose tissues, the identity of neurons that regulate fat is undefined. Here we identify that Gabra5-positive neurons in LHA (GABRA5LHA) polysynaptically project to brown and white adipose tissues in the periphery. GABRA5LHA are a distinct subpopulation of GABAergic neurons and show decreased pacemaker firing in diet-induced obesity (DIO) mouse model. Chemogenetic inhibition of GABRA5LHA suppresses energy expenditure and increases weight gain, whereas gene-silencing of Gabra5 in LHA decreases weight gain. In DIO mouse model, GABRA5LHA are tonically inhibited by nearby reactive astrocytes releasing GABA, which is synthesized by MAOB. Gene-silencing of astrocytic MAOB in LHA reduces weight gain significantly without affecting food intake, which is recapitulated by administration of a MAOB inhibitor, KDS2010. We propose that firing of GABRA5LHA facilitates energy expenditure and selective inhibition of astrocytic GABA is a molecular target for treating obesity.

Alzheimers disease (AD) is one of the foremost neurodegenerative diseases, characterized by beta-amyloid (Aβ) plaques and significant progressive memory loss. In AD, astrocytes are known to take up and clear Aβ plaques. However, how Aβ induces pathogenesis and memory impairment in AD remains elusive. We report that normal astrocytes show non-cyclic urea metabolism, whereas Aβ-treated astrocytes show switched-on urea cycle with upregulated enzymes and accumulated entering-metabolite aspartate, starting-substrate ammonia, end-product urea, and side-product putrescine. Gene-silencing of astrocytic ornithine decarboxylase-1 (ODC1), facilitating ornithine-to-putrescine conversion, boosts urea cycle and eliminates aberrant putrescine and its toxic by-products ammonia, H2O2, and GABA to recover from reactive astrogliosis and memory impairment in AD model. Our findings implicate that astrocytic urea cycle exerts opposing roles of beneficial Aβ detoxification and detrimental memory impairment in AD. We propose ODC1-inhibition as a promising therapeutic strategy for AD to facilitate removal of toxic molecules and prevent memory loss.

The Golgi apparatus is a critical intracellular organelle that is responsible for modifying, packaging, and transporting proteins to their destinations. Golgi homeostasis involving the acidic pH, ion concentration, and membrane potential, is critical for proper functions and morphology of the Golgi. Although transporters and anion channels that contribute to Golgi homeostasis have been identified, the molecular identity of cation channels remains unknown. Here we identify TMEM87A as a novel Golgi-resident cation channel that contributes to pH homeostasis and rename it as GolpHCat (Golgi pH-sensitive Cation channel). The genetic ablation of GolpHCat exhibits an impaired resting pH in the Golgi. Heterologously expressed GolpHCat displays voltage- and pH-dependent, non-selective cationic, and inwardly rectifying currents, with potent inhibition by gluconate. Furthermore, reconstitution of purified GolpHCat in liposomes generates functional channel activities with unique voltage-dependent gating and ion permeation. GolpHCat is expressed in various cell types such as neurons and astrocytes in the brain. In the hippocampus, GolpHCat-knockout mice show dilated Golgi morphology and altered glycosylation and protein trafficking, leading to impaired spatial memory with significantly reduced long-term potentiation. We elucidate that GolpHCat, by maintaining Golgi membrane potential, regulates ionic and osmotic homeostasis, protein glycosylation/trafficking, and brain functions. Our results propose a new molecular target for Golgi-related diseases and cognitive impairment.

Autism spectrum disorders (ASD) represent neurodevelopmental disorders characterized by social deficits, repetitive behaviors, and various comorbidities, including epilepsy. ANK2, which encodes a neuronal scaffolding protein, is frequently mutated in ASD, but its in vivo functions and disease-related mechanisms are largely unknown. Here, we report that mice with Ank2 knockout restricted to cortical and hippocampal excitatory neurons (Ank2-cKO mice) show ASD-related behavioral abnormalities and juvenile seizure-related death. Ank2-cKO cortical neurons show abnormally increased excitability and firing rate. These changes accompanied decreases in the total level and function of the Kv7.2/KCNQ2 and Kv7.3/KCNQ3 potassium channels and the density of these channels in the enlengthened axon initial segment. Importantly, the Kv7 agonist, retigabine, rescued neuronal excitability, juvenile seizure-related death, and hyperactivity in Ank2-cKO mice. These results suggest that Ank2 regulates neuronal excitability by regulating the length of and Kv7 density in the AIS and that Kv7 channelopathy is involved in Ank2-related brain dysfunctions.

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