Major depressive disorder with suicide behavior (sMDD) is a server mood disorder, bringing tremendous burden to family and society. Although reduced gamma amino butyric acid (GABA) level has been observed in postmortem tissues of sMDD patients, the molecular mechanism by which GABA levels are altered remains elusive. In this study, we generated induced pluripotent stem cells (iPSC) from five sMDD patients and differentiated the iPSCs to GABAergic interneurons (GINs) and ventral forebrain organoids. sMDD GINs exhibited altered neuronal morphology and increased neural firing, as well as weakened calcium signaling propagation, compared with controls. Transcriptomic sequencing revealed that a decreased expression of serotoninergic receptor 2C (5-HT2C) may cause the defected neuronal activity in sMDD. Furthermore, targeting 5-HT2C receptor, using a small molecule agonist or genetic approach, restored neuronal activity deficits in sMDD GINs. Our findings provide a human cellular model for studying the molecular mechanisms and drug discoveries for sMDD.

In the zebrafish midbrain, GABAergic neurons develop from precursors located in the nucleus of the medial longitudinal fasciculus (nMLF). However, the precise mechanisms that underline generation of the nMLF GABAergic neuron are poorly understood.
GABAergic neurons in the nMLF co-express transcription factors tal2, gata2a, gata3, and nkx1.2lb. The Nodal-related gene and shh signaling are required for differentiation of nMLF GABAergic neuron precursors. Tal2 is important for nMLF GABAergic neurogenesis. Disruption of Tal2, embryos completely lack the GABA-synthesizing enzyme glutamic acid decarboxylase 67 gene (gad67) expressing cells in the nMLF, and the whole nkx1.2lb expressing cells in the midbrain. Although almost all tal2-expressing cells in the diencephalon and/or nMLF are gata2a- and gata3-positive, simultaneous knockdown of gata2a and gata3 does not affect either tal2 or gad67 expression.
In the zebrafish midbrain, expression of tal2, gata2a, and/or gata3 is independent of each other. The function of gata2a and gata3 is dispensable for generation of GABAergic neuron in the nMLF. This suggests that the functional connections of the regulatory genes leading to generation of nMLF GABAergic neurons have diverged between mouse and zebrafish.

Excitatory projection neurons and inhibitory interneurons primarily accomplish the neural activity of the cerebral cortex, and an imbalance of excitatory-inhibitory neural networks may lead to neuropsychiatric diseases. Gamma-aminobutyric acid (GABA)ergic interneurons mediate inhibition, and the embryonic medial ganglionic eminence (MGE) is a source of GABAergic interneurons. After transplantation, MGE cells migrate to different brain regions, differentiate into multiple subtypes of GABAergic interneurons, integrate into host neural circuits, enhance synaptic inhibition, and have tremendous application value in diseases associated with interneuron disorders. In the current review, we describe the fate of MGE cells derived into specific interneurons and the related diseases caused by interneuron loss or dysfunction and explore the potential of MGE cell transplantation as a cell-based therapy for a variety of interneuron disorder-related diseases, such as epilepsy, schizophrenia, autism spectrum disorder, and Alzheimer\'s disease.

In mature mammalian brains, the endocannabinoid system (ECS) plays an important role in the regulation of synaptic plasticity and the functioning of neural networks. Besides, the ECS also contributes to the neurodevelopment of the central nervous system. Due to the increase in the medical and recreational use of cannabis, it is inevitable and essential to elaborate the roles of the ECS on neurodevelopment. GABAergic interneurons represent a group of inhibitory neurons that are vital in controlling neural network activity. However, the role of the ECS in the neurodevelopment of GABAergic interneurons remains to be fully elucidated. In this review, we provide a brief introduction of the ECS and interneuron diversity. We focus on the process of interneuron development and the role of ECS in the modulation of interneuron development, from the expansion of the neural stem/progenitor cells to the migration, specification and maturation of interneurons. We further discuss the potential implications of the ECS and interneurons in the pathogenesis of neurological and psychiatric disorders, including epilepsy, schizophrenia, major depressive disorder and autism spectrum disorder.

Kolmer-Agduhr (KA) cells are a subgroup of interneurons positioned adjacent to the neurocoele with cilia on the apical surface protruding into the central canal of the spinal cord. Although KA cells were identified almost a century ago, their development and functions are only beginning to be unfolded. Recent studies have revealed the characteristics of KA cells in greater detail, including their spatial distribution, the timing of their differentiation, and their specification via extrinsic signaling and a unique combination of transcription factors in zebrafish and mouse. Cell lineage-tracing experiments have demonstrated that two subsets of KA cells, named KA\' and KA\" cells, differentiate from motoneuronal progenitors and floor-plate precursors, respectively, in both zebrafish and mouse. Although KA\' and KA\" cells originate from different progenitors/precursors, they each share a common set of transcription factors. Intriguingly, the combination of transcription factors that promote the acquisition of KA\' cell characteristics differs from those that promote a KA\" cell identity. In addition, KA\' and KA\" cells exhibit separable neuronal targets and differential responses to bending of the spinal cord. In this review, we summarize what is currently known about the genetic programs defining the identities of KA\' and KA\" cell identities. We then discuss how these two subgroups of KA cells are genetically specified.

Phospho-tau accumulation and adult hippocampal neurogenesis (AHN) impairment both contribute importantly to the cognitive decline in Alzheimer\'s disease (AD), but whether and how tau dysregulates AHN in AD remain poorly understood. Here, we found a prominent accumulation of phosphorylated tau in GABAergic interneurons in the dentate gyrus (DG) of AD patients and mice. Specific overexpression of human tau (hTau) in mice DG interneurons induced AHN deficits but increased neural stem cell-derived astrogliosis, associating with a downregulation of GABA and hyperactivation of neighboring excitatory neurons. Chemogenetic inhibition of excitatory neurons or pharmacologically strengthening GABAergic tempos rescued the tau-induced AHN deficits and improved contextual cognition. These findings evidenced that intracellular accumulation of tau in GABAergic interneurons impairs AHN by suppressing GABAergic transmission and disinhibiting neural circuits within the neurogenic niche, suggesting a potential of GABAergic potentiators for pro-neurogenic or cell therapies of AD.

Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32-/- mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32-/- mouse is a novel autism model mouse.

Background: Mitophagy is the selective engulfment of mitochondria by autophagosomes and the subsequent mitochondrial catabolism by lysosomes. Evidence has suggested an important role for mitochondrial dynamics and mitophagic flux in the development of many different neurodegenerative diseases. Objectives: The potential role of the mechanism underlying mitochondrial dynamics and mitophagic flux as it may relate to neuropathic pain is not well understood. This is a disease that largely remains an area of mechanistic uncertainty. PINK1 is a PTEN-induced mitochondrial kinase that can be selectively activated under mitochondrial stress conditions and lead to the induction of mitophagy. Materials and methods: A neuropathic pain rat model was established via spinal nerve ligation (SNL) and nociception was assayed via the von Frey filament method. Increased expression of PINK1 and the mechanism of mitophagy was detected in GABAergic interneurons of dorsal horn neurons of mice that underwent L5 SNL in comparison to control mice counterparts (n=8, P<0.001) by Western blotting, immunohistochemistry and double immunofluorescence staining. Results: Elevated expression of PINK1 appeared to localize selectively to GABAergic interneurons, particularly within autophagic mitochondria as evidenced by co-localization studies of PINK1 with BECN1, LC3II and COX IV on immunofluorescent microscopy. Furthermore, we also detected a significant increase in autophagosomes in dorsal horn neurons of SNL mice and this was consistent with increased autophagic activity as measured by the p62 autophagic substrate. Conclusion: These results demonstrate that neuropathic pain causes aberrant mitophagic flux selectively in GABAergic interneurons and provide evidence implicating mitophagy as an important area of future molecular studies to enhance our understanding of neuropathic pain.

Fear behavior is under tight control of the prefrontal cortex, but the underlying microcircuit mechanism remains elusive. In particular, it is unclear how distinct subtypes of inhibitory interneurons (INs) within prefrontal cortex interact and contribute to fear expression. We employed a social fear conditioning paradigm and induced robust social fear in mice. We found that social fear is characterized by activation of dorsal medial prefrontal cortex (dmPFC) and is largely diminished by dmPFC inactivation. With a combination of in vivo electrophysiological recordings and fiber photometry together with cell-type-specific pharmacogenetics, we further demonstrated that somatostatin (SST) INs suppressed parvalbumin (PV) INs and disinhibited pyramidal cells and consequently enhanced dmPFC output to mediate social fear responses. These results reveal a previously unknown disinhibitory microcircuit in prefrontal cortex through interactions between IN subtypes and suggest that SST INs-mediated disinhibition represents an important circuit mechanism in gating social fear behavior.

Neuronal oscillations are fundamental to hippocampal function. It has been shown that GABAergic interneurons make an important contribution to hippocampal oscillations, but the underlying mechanism is not well understood. Here, using whole-cell recording in the complete hippocampal formation isolated from rats at postnatal days 14-18, we showed that GABAA receptor-mediated activity enhanced the generation of slow CA1 oscillations. In vitro, slow oscillations (0.5-1.5 Hz) were generated in CA1 neurons, and they consisted primarily of excitatory rather than inhibitory membrane-potential changes. These oscillations were greatly reduced by blocking GABAA receptor-mediated activity with bicuculline and were enhanced by increasing such activity with midazolam, suggesting that interneurons are required for oscillation generation. Consistently, CA1 fast-spiking interneurons were found to generate action potentials usually preceding those in CA1 pyramidal cells. These findings indicate a GABAA receptor-based mechanism for the generation of the slow CA1 oscillation in the hippocampus.