Surviving mossy cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy

Zhang, Wei; Thamattoor, Ajoy K.; Leroy, C.; Buckmaster, Paul S.

doi:10.1002/hipo.22396

Cited by 19 publications

(27 citation statements)

References 85 publications

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“…In epileptic mice, the hilus appeared to contain fewer large GluR2‐positive neurons (Figure a), as reported previously (Tang et al, ; Zhang, Thamattoor, LeRoy, & Buckmaster, ). More small GluR2‐positive neurons (<12 μm soma diameter) were evident, but they were likely to be ectopic granule cells (Jiao & Nadler, ).…”

Section: Resultssupporting

confidence: 87%

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

Buckmaster

Abrams

Wen

2017

J of Comparative Neurology

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Epilepsy occurs in one of 26 people. Temporal lobe epilepsy is common and can be difficult to treat effectively. It can develop after brain injuries that damage the hippocampus. Multiple pathophysiological mechanisms involving the hippocampal dentate gyrus have been proposed. This study evaluated a mouse model of temporal lobe epilepsy to test which pathological changes in the dentate gyrus correlate with seizure frequency and help prioritize potential mechanisms for further study. FVB mice (n = 127) that had experienced status epilepticus after systemic treatment with pilocarpine 31–61 days earlier were video-monitored for spontaneous, convulsive seizures 9 hr/day every day for 24–36 days. Over 4,060 seizures were observed. Seizure frequency ranged from an average of one every 3.6 days to one every 2.1 hr. Hippocampal sections were processed for Nissl stain, Prox1-immunocytochemistry, GluR2-immunocytochemistry, Timm stain, glial fibrillary acidic protein-immunocytochemistry, glutamic acid decarboxylase in situ hybridization, and parvalbumin-immunocytochemistry. Stereological methods were used to measure hilar ectopic granule cells, mossy cells, mossy fiber sprouting, astrogliosis, and GABAergic interneurons. Seizure frequency was not significantly correlated with the generation of hilar ectopic granule cells, the number of mossy cells, the extent of mossy fiber sprouting, the extent of astrogliosis, or the number of GABAergic interneurons in the molecular layer or hilus. Seizure frequency significantly correlated with the loss of GABAergic interneurons in or adjacent to the granule cell layer, but not with the loss of parvalbumin-positive interneurons. These findings prioritize the loss of granule cell layer interneurons for further testing as a potential cause of temporal lobe epilepsy.

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Section: Resultssupporting

confidence: 87%

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

Buckmaster

Abrams

Wen

2017

J of Comparative Neurology

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“…However, research on the mossy cells themselves has found enhanced action potential discharges in response to perforant path stimulation after rodent FPI, as researchers have hypothesized that mossy cells may be vulnerable to injury as a result of presynaptic mechanisms [5,40]. In a mouse model of temporal lobe epilepsy, Zhang et al observed a reduction of input resistance to mossy cells, as well as a frequency increase of miniature postsynaptic currents in epileptic mice, indicating an overall increase in excitatory synaptic input to mossy cells [33]. Interestingly, Jinde et al used a transgenic mouse line to ablate mossy cells, which resulted in granule cell excitability but no detection of epileptiform activity [41].…”

Section: Discussionmentioning

confidence: 99%

“…As there were significant changes in the mossy cell area, we postulated that local synaptic circuitry may have been remodeled after mild TBI [33]. Therefore, to histologically assess synaptic changes, we looked at the synaptic inputs to the mossy cells themselves.…”

Section: Synapsin-positive Staining Increased At 7 Days After Mild Tbimentioning

confidence: 99%

Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs

Grovola

Paleologos

Wofford

et al. 2020

J Neuroinflammation

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Background: Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial activation after TBI may play a role in hippocampal circuit and/or synaptic remodeling; however, the potential effects of chronic microglial changes are currently unknown. The objective of the current study was to assess neuropathological and neuroinflammatory changes in subregions of the dentate gyrus at acute to chronic time points following mild TBI using an established model of closed-head rotational acceleration induced TBI in pigs.Methods: This study utilized archival tissue of pigs which were subjected to sham conditions or rapid head rotation in the coronal plane to generate mild TBI. A quantitative assessment of neuropathological changes in the hippocampus was performed via immunohistochemical labeling of whole coronal tissue sections at 3 days postinjury (DPI), 7 DPI, 30 DPI, and 1 year post-injury (YPI), with a focus on mossy cell atrophy and synaptic reorganization, in context with microglial alterations (e.g., density, proximity to mossy cells) in the dentate gyrus.Results: There were no changes in mossy cell density between sham and injured animals, indicating no frank loss of mossy cells at the mild injury level evaluated. However, we found significant mossy cell hypertrophy at 7 DPI and 30 DPI in anterior (> 16% increase in mean cell area at each time; p = < 0.001 each) and 30 DPI in posterior (8.3% increase; p = < 0.0001) hippocampus. We also found dramatic increases in synapsin staining around mossy cells at 7 DPI in both anterior (74.7% increase in synapsin labeling; p = < 0.0001) and posterior (82.7% increase; p = < 0.0001) hippocampus. Interestingly, these morphological and synaptic alterations correlated with a significant change in microglia in proximity to mossy cells at 7 DPI in anterior and at 30 DPI in the posterior hippocampus. For broader context, while we found that there were significant increases in microglia density in the granule cell layer at 30 DPI (anterior and posterior) and 1 YPI (posterior only) and in the molecular layer at 1 YPI (anterior only), we found no significant changes in overall microglial density in the hilus at any of the time points evaluated postinjury.

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“…Studies of ectopic granule cells in status epilepticus models of epilepsy demonstrate that these neurons are hyperexcitable and prone to burst firing (Cameron et al, 2011; Scharfman et al, 2000; Zhan and Nadler, 2009), which might lead to additional tertiary and quaternary spikes. Hilar mossy cells - which directly excite granule cells in addition to mediating feedback inhibition through granule cells - might also provoke abnormal activity (Scharfman et al, 2001; Zhang et al, 2015). …”

Section: Discussionmentioning

confidence: 99%

Disrupted hippocampal network physiology following PTEN deletion from newborn dentate granule cells

LaSarge

Pun

Muntifering

et al. 2016

Neurobiology of Disease

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Abnormal hippocampal granule cells are present in patients with temporal lobe epilepsy, and are a prominent feature of most animal models of the disease. These abnormal cells are hypothesized to contribute to epileptogenesis. Isolating the specific effects of abnormal granule cells on hippocampal physiology, however, has been difficult in traditional temporal lobe epilepsy models. While epilepsy induction in these models consistently produces abnormal granule cells, the causative insults also induce widespread cell death among hippocampal, cortical and subcortical structures. Recently, we demonstrated that introducing morphologically abnormal granule cells into an otherwise normal mouse brain – by selectively deleting the mTOR pathway inhibitor PTEN from postnatally-generated granule cells – produced hippocampal and cortical seizures. Here, we conducted acute slice field potential recordings to assess the impact of these cells on hippocampal function. PTEN deletion from a subset of granule cells reproduced aberrant responses present in traditional epilepsy models, including enhanced excitatory post-synaptic potentials (fEPSPs) and multiple, rather than single, population spikes in response to perforant path stimulation. These findings provide new evidence that abnormal granule cells initiate a process of epileptogenesis – in the absence of widespread cell death – which culminates in an abnormal dentate network similar to other models of temporal lobe epilepsy. Findings are consistent with the hypothesis that accumulation of abnormal granule cells is a common mechanism of temporal lobe epileptogenesis.

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Surviving mossy cells enlarge and receive more excitatory synaptic input in a mouse model of temporal lobe epilepsy

Cited by 19 publications

References 85 publications

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

Seizure frequency correlates with loss of dentate gyrus GABAergic neurons in a mouse model of temporal lobe epilepsy

Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs

Disrupted hippocampal network physiology following PTEN deletion from newborn dentate granule cells

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