Normal and epilepsy-associated pathologic function of the dentate gyrus

Dengler, Christopher G.; Coulter, Douglas A.

doi:10.1016/bs.pbr.2016.04.005

Cited by 65 publications

(69 citation statements)

References 118 publications

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“…Bursting does not seem to result from other changes in excitatory input-output coupling either ( Figure 7B5 ), which suggest that inhibition might be involved. GCs are indeed subjected to strong tonic, feedforward and feedback inhibition that controls the sparseness of their activity (Coulter and Carlson, 2007; Ewell and Jones, 2010; Pardi et al, 2015; Lee et al, 2016) and is altered in TLE (Alexander et al, 2016; Dengler and Coulter, 2016). We did not record evoked IPSCs directly but, in normal mice, partial block of inhibition elevates GC firing rates and causes bursts (Madar et al, 2019b) similar to what we observed here in KA mice.…”

Section: Resultsmentioning

confidence: 99%

“…Overlapping memory representations would in turn lead to interference during recall and thus cognitive confusion. To solve these problems, it was proposed that the dentate gyrus (DG) of the hippocampus acts as a) a gate and b) a pattern separator, so that similar cortical representations are transformed into sparse and dissimilar patterns before reaching CA3 (O’Reilly and McClelland, 1994; Hsu, 2007; Treves et al, 2008; Dengler and Coulter, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…The function of DG as a gate for cortical activity to prevent seizure generation fails in TLE (Hsu, 2007; Krook-Magnuson et al, 2015; Dengler and Coulter, 2016; Lu et al, 2016): granule cells (GCs), the output neurons of DG, lose their usual sparseness due to network reorganization (Artinian et al, 2011; Dengler and Coulter, 2016; Dengler et al, 2017) making cortical excitation easier to propagate to CA3 (Behr et al, 1998; Patrylo et al, 1999; Ouedraogo et al, 2016). Even in healthy animals, repeated excitation of GCs induces seizures (Krook-Magnuson et al, 2015) and prolonged stimulation of DG causes TLE (Sloviter, 1983).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

Madar

Pfammatter

Bordenave

et al. 2020

Preprint

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“…The DG is also considered to be important in many diseases, some of which surprisingly do not appear to be related to memory, such as temporal lobe epilepsy (TLE) (2). One explanation is based on the idea that the DG is an inhibitory filter or gate (3, 4), preventing too much information from corrupting memory formation as well as preventing seizures. However, it is unclear exactly how and when the DG limits the influence of afferent input to the hippocampus, and when the DG is permissive, because the DG has powerful excitatory and inhibitory characteristics.…”

mentioning

confidence: 99%

Controlling learning and epilepsy together

Scharfman

2018

Science

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“…The marked reduction in tonic inhibition in dentate granule cells in this model of FXS could have important functional effects as the granule cells control the massive input from the entorhinal cortex and can thus limit the information that reaches the hippocampus (Dengler and Coulter, 2016; Leutgeb et al, 2007). This filtering function of the dentate gyrus provides a critical early step in information processing within the hippocampal formation.…”

Section: Discussionmentioning

confidence: 96%

Decreased surface expression of the δ subunit of the GABA A receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome

Zhang

Peng

Tong

et al. 2017

Experimental Neurology

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While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABAA receptors (GABAARs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the δ subunit of the GABAAR, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two δ subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that δ subunit-containing GABAARs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in δ subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the δ subunit led to studies of surface expression of the δ subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total δ subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the δ subunit in these mice. No significant changes were observed in total or surface expression of the α4 subunit protein, a major partner of the δ subunit in the forebrain. Postembedding immunogold labeling for the δ subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with immunolabeling at perisynaptic locations in Fmr1 KO mice. While α4 immunogold particles were also reduced at perisynaptic locations in the Fmr1 KO mice, the labeling was increased at synaptic sites. Together these findings suggest that, in the dentate gyrus, altered surface expression of the δ subunit, rather than a decrease in δ subunit expression alone, could be limiting δ subunit-mediated tonic inhibition in this model of FXS. Finding ways to increase surface expression of the δ subunit of the GABAAR could be a novel approach to treatment of hyperexcitability-related alterations in FXS.

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Normal and epilepsy-associated pathologic function of the dentate gyrus

Cited by 65 publications

References 118 publications

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy

Controlling learning and epilepsy together

Decreased surface expression of the δ subunit of the GABA A receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome

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