IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus

Kim, Dong-Wook; Jung, Hyeji; Shirai, Yoshinori; Kim, Hyeonho; Kim, Jinhu; Lim, Dongseok; Mori, Tomohisa; Lee, Hyojeong; Park, Dongseok; Kim, Hee Young; Qi, Guo; Pang, Bo; Qiu, Wen; Cao, Xueshan; Kouyama-Suzuki, Emi; Uemura, Takeshi; Kasem, Enas; Fu, Yu; Kim, Seungjoon; Tokunaga, Akinori; Yoshizawa, Takahiro; Suzuki, Tatsuo; Sakagami, Hiroyuki; Lee, Kea Joo; Ko, Jaewon; Tabuchi, Katsuhiko; Um, Ji Won

doi:10.1016/j.biopsych.2021.12.016

Cited by 7 publications

(5 citation statements)

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“…In particular, altered E-I balance induced by a reduction in GABAergic synapses in the hippocampus was shown to result in cognitive and memory deficits in mice. Mice with a deletion of IQSEC3 or collybistin, key GABAergic synaptic components, exhibit deficits in hippocampus-dependent spatial learning or fear memory formation, respectively 27 , 48 . Moreover, impairment in APP-mediated GABAergic synapse signaling by the negative regulator MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) in hippocampal CA1 regions also impairs novel object-recognition memory in mice 25 .…”

Section: Discussionmentioning

confidence: 99%

“…The following commercially available antibodies were used: rabbit polyclonal anti-Iba-1 (Fujifilm Wako, Cat# 016-20,001; RRID: AB_839506), rat monoclonal anti-CD68 (clone FA-11; Bio-Rad, Cat# MCA1957GA; RRID: AB_324217), rabbit polyclonal anti-GFAP (ABFrontier, Cat# AR09-PA0002; RRID: AB_2755016), rabbit polyclonal anti-VGAT (Synaptic Systems, Cat# 131 003; RRID: AB_887869), rabbit polyclonal anti-GABA A Rγ2 (Synaptic Systems, Cat# 224 003; RRID: AB_2263066), mouse monoclonal anti-gephyrin (Synaptic Systems, Cat# 147 111; RRID: AB_887719), mouse monoclonal anti-GAD67 (Millipore, Cat# MAB5406; RRID:AB_2278725), mouse monoclonal anti-PV (Swant, Cat# 235; RRID: AB_10000343), rat monoclonal anti-SST (Millipore, Cat# MAB354; RRID: AB_2255365), mouse monoclonal anti-β-actin (Santa Cruz, Cat# sc-47778; RRID: AB_626632), mouse monoclonal anti-VGAT (Synaptic Systems, Cat# 131 011; RRID: AB_887872), and guinea pig polyclonal anti-VGLUT1 (Millipore, Cat# AB5905; RRID: AB_2301751). The following antibodies have been previously described: anti-PSD-95 (JK016; RRID: AB_2722693) and anti-VGLUT1 (JK111; RRID: AB_2810945) 27 .…”

Section: Methodsmentioning

confidence: 99%

“…A P2 (crude synaptosome) subcellular fraction was prepared as previously described 27 . Protein concentration was measured by using the Bradford assay, and samples were immunoblotted with the antibodies indicated in each figure legends.…”

Section: Methodsmentioning

confidence: 99%

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LPS induces microglial activation and GABAergic synaptic deficits in the hippocampus accompanied by prolonged cognitive impairment

Jung

Lee

You

et al. 2023

Sci Rep

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Neuroinflammation impacts the brain and cognitive behavior through microglial activation. In this study, we determined the temporal sequence from microglial activation to synaptic dysfunction and cognitive behavior induced by neuroinflammation in mice. We found that LPS injection activated microglia within a short period, followed by impairments in GABAergic synapses, and that these events led to long-term cognitive impairment. We demonstrated that, 3 days after LPS injection, microglia in the hippocampus were significantly activated due to the LPS-induced inflammation in association with alterations in cellular morphology, microglial density, and expression of phagocytic markers. GABAergic synaptic impairments were detected at 4–6 days after LPS treatment, a time when microglia activity had returned to normal. Consequently, memory impairment persisted for 6 days after injection of LPS. Our results suggest that neuroinflammation induces microglia activation, GABAergic synaptic deficits and prolonged memory impairment over a defined temporal sequence. Our observations provide insight into the temporal sequence of neuroinflammation-associated brain pathologies. Moreover, the specific loss of inhibitory synapses accompanying the impaired inhibitory synaptic transmission provides mechanistic insight that may explain the prolonged cognitive deficit observed in patients with neuroinflammation. Thus, this study provides essential clues regarding early intervention strategies against brain pathologies accompanying neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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LPS induces microglial activation and GABAergic synaptic deficits in the hippocampus accompanied by prolonged cognitive impairment

Jung

Lee

You

et al. 2023

Sci Rep

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“…Histological analysis was followed by the previous procedures [ 43 , 44 , 45 ]. Briefly, under deep anesthesia, the mice were perfused transcardially with ice-cold phosphate-buffered saline (PBS, pH 7.4), followed by 4% paraformaldehyde in PBS.…”

Section: Methodsmentioning

confidence: 99%

An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice

Pang

Mori

Badawi

et al. 2022

IJMS

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Six mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing and found an increase in excitatory synaptic transmission and enhancement of neural excitability in neocortical neurons in SIK1-MT mice. NMDA was injected into SIK1-MT males to induce epileptic seizures in the mice. The severity of the NMDA-induced seizures was estimated by the latency and the number of tail flickering and hyperflexion. Activated brain regions were evaluated by immunohistochemistry against c-fos, Iba1, and GFAP. As another epilepsy model, pentylenetetrazol was injected into the adult SIK1 mutant mice. Seizure susceptibility induced by both NMDA and PTZ was enhanced in SIK1-MT mice. Brain regions including the thalamus and hypothalamus were strongly activated in NMDA-induced seizures. The epilepsy-associated mutation of SIK1 canceled the pharmacological effects of the ACTH treatment on NMDA-induced seizures. These results suggest that SIK1 may be involved in the neuropathological mechanisms of NMDA-induced spasms and the pharmacological mechanism of ACTH treatment.

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“…Long-term memory (LTM) consolidation and persistence involves synaptic remodeling as a consequence of long-lasting changes in gene expression ( Josselyn et al, 2001 ; Dudai, 2002 ) and protein synthesis ( Schafe and LeDoux, 2000 ; Kim et al, 2022 ). Glucose consumption increases contextual fear memory and results from a hippocampal-dependent associative learning mechanisms ( Glenn et al, 2014 ), which may be mediated by phosphorylation (activation) of the cAMP response-element protein (CREB) ( Impey et al, 1998 ).…”

Section: Molecular Mechanisms Underlying Epinephrine Effect In Contex...mentioning

confidence: 99%

Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder

Azevedo,

Martinho,

Oliveira

et al. 2024

Front. Mol. Neurosci.

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The sympathoadrenal medullary system and the hypothalamic-pituitary-adrenal axis are both activated upon stressful events. The release of catecholamines, such as dopamine, norepinephrine (NE), and epinephrine (EPI), from sympathetic autonomic nerves participate in the adaptive responses to acute stress. Most theories suggest that activation of peripheral β-adrenoceptors (β-ARs) mediates catecholamines-induced memory enhancement. These include direct activation of β-ARs in the vagus nerve, as well as indirect responses to catecholamine-induced glucose changes in the brain. Excessive sympathetic activity is deeply associated with memories experienced during strong emotional stressful conditions, with catecholamines playing relevant roles in fear and traumatic memories consolidation. Recent findings suggest that EPI is implicated in fear and traumatic contextual memories associated with post-traumatic stress disorder (PTSD) by increasing hippocampal gene transcription (e.g., Nr4a) downstream to cAMP response-element protein activation (CREB). Herein, we reviewed the literature focusing on the molecular mechanisms underlying the pathophysiology of memories associated with fear and traumatic experiences to pave new avenues for the treatment of stress and anxiety conditions, such as PTSD.

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IQSEC3 Deletion Impairs Fear Memory Through Upregulation of Ribosomal S6K1 Signaling in the Hippocampus

Cited by 7 publications

References 53 publications

LPS induces microglial activation and GABAergic synaptic deficits in the hippocampus accompanied by prolonged cognitive impairment

LPS induces microglial activation and GABAergic synaptic deficits in the hippocampus accompanied by prolonged cognitive impairment

An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice

Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder

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