Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus

Kelly, T.; Beck, Hanno

doi:10.1111/epi.13605

Cited by 24 publications

(19 citation statements)

References 45 publications

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“…Recent work suggests that axons which originate from a basal dendrite, rather than the soma, convey distinct properties to the parent cell (Thome et al, 2014; Kelly and Beck, 2017). We queried, therefore, the extent to which KO cells exhibit basal dendrite-originating axons.…”

Section: Resultsmentioning

confidence: 99%

PTEN deletion increases hippocampal granule cell excitability in male and female mice

Santos

Pun

Arafa

et al. 2017

Neurobiology of Disease

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Deletion of the mTOR pathway inhibitor PTEN from postnatally-generated hippocampal dentate granule cells causes epilepsy. Here, we conducted field potential, whole cell recording and single cell morphology studies to begin to elucidate the mechanisms by which granule cell-specific PTEN-loss produces disease. Cells from both male and female mice were recorded to identify sex-specific effects. PTEN knockout granule cells showed altered intrinsic excitability, evident as a tendency to fire in bursts. PTEN knockout granule cells also exhibited increased frequency of spontaneous excitatory synaptic currents (sEPSCs) and decreased frequency of inhibitory currents (sIPSCs), further indicative of a shift towards hyperexcitability. Morphological studies of PTEN knockout granule cells revealed larger dendritic trees, more dendritic branches and an impairment of dendrite self-avoidance. Finally, cells from both female control and female knockout mice received more sEPSCs and more sIPSCs than corresponding male cells. Despite the difference, the net effect produced statistically equivalent EPSC/IPSC ratios. Consistent with this latter observation, extracellularly evoked responses in hippocampal slices were similar between male and female knockouts. Both groups of knockouts were abnormal relative to controls. Together, these studies reveal a host of physiological and morphological changes among PTEN knockout cells likely to underlie epileptogenic activity.

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Section: Resultsmentioning

confidence: 99%

PTEN deletion increases hippocampal granule cell excitability in male and female mice

Santos

Pun

Arafa

et al. 2017

Neurobiology of Disease

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“…As explained above, our results suggest deficits in inhibition, but other anatomical or biophysical changes could be in play. For example, in individual mice with TLE, some GCs display pathological hilar basal dendrites that have been associated with increased intrinsic excitability that might allow them to fire bursts more easily (Kelly and Beck, 2017). It is also possible that there exist heterogeneity in GC mossy fiber sprouting, with some GCs receiving recurrent excitatory connections and some not.…”

Section: Discussionmentioning

confidence: 99%

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

Madar

Pfammatter

Bordenave

et al. 2020

Preprint

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8Health 9 Acknowledgement: We thank Lin Lin who helped start behavioral tests in mice in the Jones lab 10 and Drs. C.E.L Stark and M.A. Yassa for allowing us to use software and materials they 11 developed.12 Abstract: 24 In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the 25 hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help 26 discriminate between similar memories by performing pattern separation, but whether epilepsy 27 leads to a breakdown in this neural computation, and thus to mnemonic discrimination 28 impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by 29 behavioral deficits in mnemonic discrimination tasks, in both humans and mice. Using a recently 30 developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the 31 dentate gyrus to perform certain forms of pattern separation. This is due to a subset of granule 32 cells with abnormal bursting that can develop independently of early EEG abnormalities. 33Overall, our results linking physiology, computation and cognition in the same mice, advance 34 our understanding of episodic memory mechanisms and their dysfunction in epilepsy. 35 36 Keywords: 37 Patch-clamp, low-dose systemic kainate model, kainic acid, interictal spikes, novelty 38 recognition, firing rate, spiking patterns, similarity metrics, input-output, entorhinal cortex, 39 perforant path, EPSC, excitation/inhibition ratio, dentate gate, Hebb-Marr theory 40 41 Introduction: 42 Temporal lobe epilepsy (TLE) represents about 60% of all epilepsy cases, a third of 43 which are refractory to medication (Tellez-Zenteno and Hernandez-Ronquillo, 2012). TLE is 44DG neural pattern separation and 2) that such a failure causes mnemonic discrimination 87 impairments remain experimentally untested. 88Here we tested, in humans and mice, whether TLE is characterized by deficits in 89 mnemonic discrimination and then recorded, in brain slices from the same mice, the spiking 90 patterns of single GCs in response to parametrically varied afferent stimulation in order to gauge 91 neuronal pattern separation. 92 93 Materials and Methods: 94 Human Behavior. A mnemonic similarity task (Stark et al., 2019), also known as a 95 behavioral pattern separation (BPS) task (Stark et al., 2013), was administered to 15 patients in 96 the University of Wisconsin-Madison Epilepsy Monitoring Unit. Under an approved Institutional 97 Review Board protocol and after obtaining informed consent, the task was administered in 98 conjunction with a standard neuropsychiatric evaluation and during electroencephalographic 99 (EEG) recording, both of which are part of standard practice for diagnosing the patients' seizures. 100 Patients were 18-65 years old, male and female. Only patients with a preliminary diagnosis of 101 TLE were included in our analysis. As controls, 20 subjects without epilepsy, recruited to match 102 the patients' age and sex distributions (family members of ...

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“…Burst firing in the dentate gyrus has often been associated with pathological conditions such as epilepsy ( Shao and Dudek 2011 ; Dengler and Coulter 2016 ; Kelly and Beck 2017 ). However, recent in vivo recordings have shown that mature granule cells preferentially fire in bursts while animals are exploring a new environment ( Pernía-Andrade and Jonas 2014 ).…”

Section: Discussionmentioning

confidence: 99%

The Low-Threshold Calcium Channel Cav3.2 Mediates Burst Firing of Mature Dentate Granule Cells

et al. 2018

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Mature granule cells are poorly excitable neurons that were recently shown to fire action potentials, preferentially in bursts. It is believed that the particularly pronounced short-term facilitation of mossy fiber synapses makes granule cell bursting a very effective means of properly transferring information to CA3. However, the mechanism underlying the unique bursting behavior of mature granule cells is currently unknown. Here, we show that Cav3.2 T-type channels at the axon initial segment are responsible for burst firing of mature granule cells in rats and mice. Accordingly, Cav3.2 knockout mice fire tonic spikes and exhibit impaired bursting, synaptic plasticity and dentate-to-CA3 communication. The data show that Cav3.2 channels are strong modulators of bursting and can be considered a critical molecular switch that enables effective information transfer from mature granule cells to the CA3 pyramids.

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Functional properties of granule cells with hilar basal dendrites in the epileptic dentate gyrus

Cited by 24 publications

References 45 publications

PTEN deletion increases hippocampal granule cell excitability in male and female mice

PTEN deletion increases hippocampal granule cell excitability in male and female mice

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

The Low-Threshold Calcium Channel Cav3.2 Mediates Burst Firing of Mature Dentate Granule Cells

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