Vulnerability of cholecystokinin-expressing GABAergic interneurons in the unilateral intrahippocampal kainate mouse model of temporal lobe epilepsy

Kang, Young-Jin; Clement, Ethan M.; Park, In‐Hyun; Greenfield, Lazar J.; Smith, Bret N.; Lee, Sang-Hun

doi:10.1016/j.expneurol.2021.113724

Cited by 14 publications

(17 citation statements)

References 72 publications

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“…The preservation of VIP/CR bipolar cells contrasts with the loss of approximately half of VIP+/CR– somata across the pyramidal and radiatum layers of CA1. VIP+/CR– cells include cholecystokinin-expressing interneurons ( Acsády et al, 1996a ; Somogyi et al, 2004 ; Luo et al, 2020 ) and the loss reported here is consistent with the degeneration of cholecystokinin basket cell boutons, and their reduced collective functional output, in CA1 of epileptic mice ( Wyeth et al, 2010 ; Kang et al, 2021 ). It is notable that the decrease in VIP+/CR– cell bodies was particularly apparent in temporal hippocampus, a region commonly identified as the seizure onset zone in the pilocarpine model ( Toyoda et al, 2013 ; Wyeth et al, 2020 ).…”

Section: Discussionsupporting

confidence: 88%

Lack of Hyperinhibition of Oriens Lacunosum-Moleculare Cells by Vasoactive Intestinal Peptide-Expressing Cells in a Model of Temporal Lobe Epilepsy

Wyeth

Buckmaster

2021

eNeuro

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Temporal lobe epilepsy remains a common disorder with no cure and inadequate treatments, potentially because of an incomplete understanding of how seizures start. CA1 pyramidal cells and many inhibitory interneurons increase their firing rate in the seconds-minutes before a spontaneous seizure in epileptic rats. However, some interneurons fail to do so, including those identified as putative interneurons with somata in oriens and axons targeting lacunosum-moleculare (OLM cells). Somatostatin-containing cells, including OLM cells, are the primary target of inhibitory vasoactive intestinal polypeptide and calretinin-expressing (VIP/CR) bipolar interneuron-selective interneurons, type 3 (ISI-3). The objective of this study was to test the hypothesis that in epilepsy inhibition of OLM cells by ISI-3 is abnormally increased, potentially explaining the failure of OLM recruitment when needed most during the ramp up of activity preceding a seizure. Stereological quantification of VIP/CR cells in a model of temporal lobe epilepsy demonstrated that they survive in epileptic mice, despite a reduction in their somatostatin-expressing (Som) cell targets. Paired recordings of unitary IPSCs (uIPSCs) from ISI-3 to OLM cells did not show increased connection probability or increased connection strength, and failure rate was unchanged. When miniature postsynaptic currents in ISI-3 were compared, only mIPSC frequency was increased in epileptic hippocampi. Nevertheless, spontaneous and miniature postsynaptic potentials were unchanged in OLM cells of epileptic mice. These results are not consistent with the hypothesis of hyperinhibition from VIP/CR bipolar cells impeding recruitment of OLM cells in advance of a seizure.

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Section: Discussionsupporting

confidence: 88%

Lack of Hyperinhibition of Oriens Lacunosum-Moleculare Cells by Vasoactive Intestinal Peptide-Expressing Cells in a Model of Temporal Lobe Epilepsy

Wyeth

Buckmaster

2021

eNeuro

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“…A selective loss of CCK+ interneurons is consistent with our recent findings that the inhibitory postsynaptic current (IPSC) in CA2 PNs from PILO-SE animals decays more rapidly than the IPSC in control cells (Whitebirch et al, 2022). Thus, the most parsimonious interpretation of our combined immunohistochemical and electrophysiological data is that there is a significant reduction in the contribution of CCK+ interneurons to the IPSP, possibly due to the degeneration of CCK+ interneurons, consistent with several recent investigations in chemoconvulsant-treated animals (Kang et al, 2021;Khan, Shekh-Ahmad, Khalil, Walker, & Ali, 2018;C. Sun et al, 2014;Wyeth et al, 2010).…”

Section: Cholecystokinin-expressing Interneurons Are Vulnerable In Ep...supporting

confidence: 92%

Reduced cholecystokinin-expressing interneuron input contributes to disinhibition of the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

Whitebirch

Barnett

Santoro

et al. 2022

Preprint

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A significant proportion of temporal lobe epilepsy (TLE) patients experience drug-resistant seizures associated with mesial temporal sclerosis, in which there is extensive cell loss in the hippocampal CA1 and CA3 subfields, with a relative sparing of dentate gyrus granule cells and the CA2 pyramidal neurons. A role for CA2 in seizure generation was suggested based on findings of a reduction in synaptic inhibition (Williamson & Spencer, 1994) and the presence of interictal-like spike activity in resected hippocampal tissue from TLE patients (Wittner et al., 2009). We recently found that in the pilocarpine-induced status epilepticus mouse model of TLE there was an increase in CA2 intrinsic excitability associated with a loss of CA2 synaptic inhibition. Furthermore, chemogenetic silencing of CA2 significantly reduced seizure frequency, consistent with a role of CA2 in promoting seizure generation and/or propagation (Whitebirch et al., 2022). In the present study we explored the basis of this inhibitory deficit using immunohistochemical and electrophysiological approaches. We report a widespread decrease in the density of pro-cholecystokinin-immunopositive interneurons and a functional impairment of cholecystokinin-expressing interneuron-mediated inhibition of CA2 pyramidal neurons. We also found a decrease in the density of CA2 parvalbumin-immunopositive interneurons and disruption to the pyramidal neuron-associated perisomatic perineuronal net in the CA2 subfield. These data reveal a set of pathological alterations that may disrupt inhibition of CA2 pyramidal neurons and their downstream targets in epileptic mice.

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“…After pentobarbital injection (200 mg/kg), mice (P21-P44) were perfused with ice-cold cutting solution consisting of the following (in mM): sucrose 228, NaHCO 3 26, glucose 11, KCl 2.5, NaH 2 PO 4 1, CaCl 2 0.5, MgSO 4 7. Brains were quickly removed, and horizontal hippocampal slices (300 mm) were prepared with a vibratome (Leica VT1200) (Kang et al, 2021). Slices were incubated in ACSF for 1 h at 33°C, then at room temperature (22°C-24°C) until use.…”

Section: Electrophysiologymentioning

confidence: 99%

Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8

et al. 2022

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Interferon regulatory factor 8 (IRF8) is a transcription factor necessary for the maturation of microglia, as well as other peripheral immune cells. It also regulates the transition of microglia and other immune cells to a pro-inflammatory phenotype. Irf8 is also a known risk gene for multiple sclerosis and lupus, and it has recently been shown to be downregulated in schizophrenia. While most studies have focused on IRF8-dependent regulation of immune cell function, little is known about how it impacts neural circuits. Here, we show by RNAseq from Irf8 2/2 male and female mouse brains that several genes involved in regulation of neural activity are dysregulated. We then show that these molecular changes are reflected in heightened neural excitability and a profound increase in susceptibility to lethal seizures in male and female Irf8 2/2 mice. Finally, we identify that TNF-a is elevated specifically in microglia in the CNS, and genetic or acute pharmacological blockade of TNF-a in the Irf8 2/2 CNS rescued the seizure phenotype. These results provide important insights into the consequences of IRF8 signaling and TNF-a on neural circuits. Our data further suggest that neuronal function is impacted by loss of IRF8, a factor involved in neuropsychiatric and neurodegenerative diseases.

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Vulnerability of cholecystokinin-expressing GABAergic interneurons in the unilateral intrahippocampal kainate mouse model of temporal lobe epilepsy

Cited by 14 publications

References 72 publications

Lack of Hyperinhibition of Oriens Lacunosum-Moleculare Cells by Vasoactive Intestinal Peptide-Expressing Cells in a Model of Temporal Lobe Epilepsy

Lack of Hyperinhibition of Oriens Lacunosum-Moleculare Cells by Vasoactive Intestinal Peptide-Expressing Cells in a Model of Temporal Lobe Epilepsy

Reduced cholecystokinin-expressing interneuron input contributes to disinhibition of the hippocampal CA2 region in a mouse model of temporal lobe epilepsy

Elevated TNF-α Leads to Neural Circuit Instability in the Absence of Interferon Regulatory Factor 8

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