Seong-Wook Kim

Phospholipase C β4 in the Medial Septum Controls Cholinergic Theta Oscillations and Anxiety Behaviors

Anxiety is among the most prevalent and costly diseases of the CNS, but its underlying mechanisms are not fully understood. Although attenuated theta rhythms have been observed in human subjects with increased anxiety, no study has been done on the possible physiological link between these two manifestations. We found that the mutant mouse for phospholipase C β4 (PLC-β4−/−) showed attenuated theta rhythm and increased anxiety, presenting the first animal model for the human condition. PLC-β4 is abundantly expressed in the medial septum, a region implicated in anxiety behavior. RNA interference-mediated PLC-β4 knockdown in the medial septum produced a phenotype similar to that of PLC-β4−/− mice. Furthermore, increasing cholinergic signaling by administering an acetylcholinesterase inhibitor cured the anomalies in both cholinergic theta rhythm and anxiety behavior observed in PLC-β4−/− mice. These findings suggest that (1) PLC-β4 in the medial septum is involved in controlling cholinergic theta oscillation and (2) cholinergic theta rhythm plays a critical role in suppressing anxiety. We propose that defining the cholinergic theta rhythm profile may provide guidance in subtyping anxiety disorders in humans for more effective diagnosis and treatments.

Deletion of phospholipase C β4 in thalamocortical relay nucleus leads to absence seizures

Absence seizures are characterized by cortical spike-wave discharges (SWDs) on electroencephalography, often accompanied by a shift in the firing pattern of thalamocortical (TC) neurons from tonic to burst firing driven by T-type Ca2+ currents. We recently demonstrated that the phospholipase C β4 (PLCβ4) pathway tunes the firing mode of TC neurons via the simultaneous regulation of T- and L-type Ca2+ currents, which prompted us to investigate the contribution of TC firing modes to absence seizures. PLCβ4-deficient TC neurons were readily shifted to the oscillatory burst firing mode after a slight hyperpolarization of membrane potential. TC-limited knockdown as well as whole-animal knockout of PLCβ4 induced spontaneous SWDs with simultaneous behavioral arrests and increased the susceptibility to drug-induced SWDs, indicating that the deletion of thalamic PLCβ4 leads to the genesis of absence seizures. The SWDs were effectively suppressed by thalamic infusion of a T-type, but not an L-type, Ca2+ channel blocker. These results reveal a primary role of TC neurons in the genesis of absence seizures and provide strong evidence that an alteration of the firing property of TC neurons is sufficient to generate absence seizures. Our study presents PLCβ4-deficient mice as a potential animal model for absence seizures.

Medial septal GABAergic projection neurons promote object exploration behavior and type 2 theta rhythm

Significance Two different kinds of exploratory behavior, object and place, have been proposed. Their distinction has been debated, however, because of the lack of solid experimental evidence to support their heterogeneity. In this report, we show neural evidence for the heterogeneity of exploratory behaviors. Thus, we demonstrate that T-type Ca2+ channels in the septo-hippocampal GABAergic pathway play a specific role in control of exploratory behavior of novel objects. In addition, we show that type 2 but not type 1 hippocampal theta rhythm is associated with object exploration. Exploratory drive is one of the most fundamental emotions, of all organisms, that are evoked by novelty stimulation. Exploratory behavior plays a fundamental role in motivation, learning, and well-being of organisms. Diverse exploratory behaviors have been described, although their heterogeneity is not certain because of the lack of solid experimental evidence for their distinction. Here we present results demonstrating that different neural mechanisms underlie different exploratory behaviors. Localized Cav3.1 knockdown in the medial septum (MS) selectively enhanced object exploration, whereas the null mutant (KO) mice showed enhanced-object exploration as well as open-field exploration. In MS knockdown mice, only type 2 hippocampal theta rhythm was enhanced, whereas both type 1 and type 2 theta rhythm were enhanced in KO mice. This selective effect was accompanied by markedly increased excitability of septo-hippocampal GABAergic projection neurons in the MS lacking T-type Ca2+ channels. Furthermore, optogenetic activation of the septo-hippocampal GABAergic pathway in WT mice also selectively enhanced object exploration behavior and type 2 theta rhythm, whereas inhibition of the same pathway decreased the behavior and the rhythm. These findings define object exploration distinguished from open-field exploration and reveal a critical role of T-type Ca2+ channels in the medial septal GABAergic projection neurons in this behavior.

Utility of quantitative 18F-fluorodeoxyglucose uptake measurement to identify occult tonsillar carcinoma in patients with cervical metastasis of unknown primary tumours: a retrospective case–control study

Due to relatively high 18F‐fluorodeoxyglucose accumulation in the tonsillar region, the detection of occult tonsillar cancers by 18F‐fluorodeoxyglucose positron emission tomography/computerised tomography remains controversial. Therefore, we assessed the usefulness of quantitative tonsil 18F‐fluorodeoxyglucose uptake in identifying occult tonsillar squamous cell carcinoma.

LARGE, an intellectual disability-associated protein, regulates AMPA-type glutamate receptor trafficking and memory

Significance In human patients, mutations in the LARGE gene cause congenital muscular dystrophy (CMD) type 1D, which, unlike other types of CMD, is accompanied by severe intellectual disability. Neurological phenotypes of LARGE knockout mice also suggest the possibility of impaired learning and memory. Our study using region-specific LARGE knockdown provides strong evidence that a deficit of LARGE in the hippocampus results in excitatory synapses being abnormally potentiated through the overloading of AMPA-type glutamate receptor, thereby impairing hippocampus-dependent memory. Our data reveal an intriguing role for LARGE in regulating the fine-tuning of synaptic strength in the hippocampus, which influences hippocampus-dependent memory. The results provide crucial insights for the therapeutic treatment of brain disorders associated with intellectual disability. Mutations in the human LARGE gene result in severe intellectual disability and muscular dystrophy. How LARGE mutation leads to intellectual disability, however, is unclear. In our proteomic study, LARGE was found to be a component of the AMPA-type glutamate receptor (AMPA-R) protein complex, a main player for learning and memory in the brain. Here, our functional study of LARGE showed that LARGE at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to down-regulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired contextual fear memory. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for hippocampus-dependent memory in the brain. Our study thus provides insights into the pathophysiology underlying cognitive deficits in brain disorders associated with intellectual disability.

LARGE, an AMPA receptor interactor, plays a large role in long-term memory formation by driving homeostatic scaling-down

Dynamic trafficking of AMPA-type glutamate receptor (AMPA-R) in neuronal cells is a key cellular mechanism for learning and memory in the brain, which is regulated by AMPA-R interacting proteins. LARGE, a protein associated with intellectual disability, was found to be a novel component of the AMPA-R protein complex in our proteomic study. Here, our functional study of LARGE showed that during homeostatic scaling-down, increased LARGE expression at the Golgi apparatus (Golgi) negatively controlled AMPA-R trafficking from the Golgi to the plasma membrane, leading to downregulated surface and synaptic AMPA-R targeting. In LARGE knockdown mice, long-term potentiation (LTP) was occluded by synaptic AMPA-R overloading, resulting in impaired long-term memory formation. These findings indicate that the fine-tuning of AMPA-R trafficking by LARGE at the Golgi is critical for memory stability in the brain. Our study thus provides novel insights into the pathophysiology of brain disorders associated with intellectual disability.