Excitability In Dentate Gyrus Research Articles

Increased Dentate Gyrus Excitability in the Intrahippocampal Kainic Acid Mouse Model for Temporal Lobe Epilepsy.

The intrahippocampal kainic acid (IHKA) mouse model is an extensively used in vivo model to investigate the pathophysiology of mesial temporal lobe epilepsy (mTLE) and to develop novel therapies for drug-resistant epilepsy. It is characterized by profound hippocampal sclerosis and spontaneously occurring seizures with a major role for the injected damaged hippocampus, but little is known about the excitability of specific subregions. The purpose of this study was to electrophysiologically characterize the excitability of hippocampal subregions in the chronic phase of the induced epilepsy in the IHKA mouse model. We recorded field postsynaptic potentials (fPSPs) after electrical stimulation in the CA1 region and in the dentate gyrus (DG) of hippocampal slices of IHKA and healthy mice using a multielectrode array (MEA). In the DG, a significantly steeper fPSP slope was found, reflecting higher synaptic strength. Population spikes were more prevalent with a larger spatial distribution in the IHKA group, reflecting a higher degree of granule cell output. Only minor differences were found in the CA1 region. These results point to increased neuronal excitability in the DG but not in the CA1 region of the hippocampus of IHKA mice. This method, in which the excitability of hippocampal slices from IHKA mice is investigated using a MEA, can now be further explored as a potential new model to screen for new interventions that can restore DG function and potentially lead to novel therapies for mTLE.

ApoE variant associated with cognitive resilience alters AD associated hyperexcitability in dentate granule neurons

AbstractBackgroundCognitive decline in Alzheimer’s disease (AD) differs based on background genetics even with similar pathology. Using genetic linkage analysis, we identified a coding variant in the receptor binding domain of ApoE that leads to changes in cognitive performance across a genetically diverse population harboring familial (FAD) mutations known as the AD‐BXDs (Neuner et al., 2019). Using CRISPR‐based gene editing, we developed a C57BL/6J (B6) mouse carrying the ApoE allele from the DBA/2J (D2) strain (ApoEE163D) and determined that ApoEE163D mice with 5XFAD transgene (ApoEE163D‐5XFAD) are susceptible to cognitive decline compared to B6‐5XFAD mice (Kaczorowski, et al., 2022).Analysis of hippocampal RNA sequencing profiles from the hippocampus indicates robust transcriptomic changes in dentate gyrus (DG) granule cells associated with cognitive resilience to FAD mutations in the presence of the B6 ApoE genotype. Here we aim to evaluate the functional implications.MethodWe adapted the Patch‐Seq method (Cadwell et al., 2017) to investigate transcriptional and electrophysiological changes within the DG associated with both FAD mutations and ApoE genotype. Whole‐cell patch clamp was used to evaluate intrinsic excitability of granule cells from 14month old B6 mice carrying FAD mutations and ApoEE163D, compared to age matched controls. The cellular contents, including the nucleus, were collected after each recording to characterize the transcriptome, and the cells were filled and stained for downstream analysis of neuronal morphology.ResultWe observed a significant interaction of the 5XFAD and ApoE genotypes on DG granule cell excitability. Specifically, cells from ApoEE163D‐5XFAD required less current stimulus to both elicit a single action potential, and to fire in response to a current ramp (rheobase). Although input resistance was comparable across all 4 groups, the sag ratio of ApoEE163D‐5XFAD was also reduced.ConclusionEnhancement of DG excitability of ApoEE163D‐5XFAD mice may underlie increased seizure susceptibility that has been reported previously in FAD animal models on D2 genetic background and associated with increased risk of seizures in AD patients. Ongoing work will integrate DG excitability with single‐cell RNAseq, morphology, and behavior to dissect mechanisms underlying the modifier effect of ApoE genotype on susceptibility and resilience to cognitive deficits in FAD mutation carriers.

Neuroprotective Effects of Ferrostatin and Necrostatin Against Entorhinal Amyloidopathy-Induced Electrophysiological Alterations Mediated by voltage-gated Ca2+ Channels in the Dentate Gyrus Granular Cells.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the main form of dementia. Abnormal deposition of amyloid-beta (Aβ) peptides in neurons and synapses cause neuronal loss and cognitive deficits. We have previously reported that ferroptosis and necroptosis were implicated in Aβ25-35 neurotoxicity, and their specific inhibitors had attenuating effects on cognitive impairment induced by Aβ25-35 neurotoxicity. Here, we aimed to examine the impact of ferroptosis and necroptosis inhibition following the Aβ25-35 neurotoxicity on the neuronal excitability of dentate gyrus (DG) and the possible involvement of voltage-gated Ca2+ channels in their effects. After inducing Aβ25-35 neurotoxicity, electrophysiological alterations in the intrinsic properties and excitability were recorded by the whole-cell patch-clamp under current-clamp condition. Voltage-clamp recordings were also performed to shed light on the involvement of calcium channel currents. Aβ25-35 neurotoxicity induced a considerable reduction in input resistance (Rin), accompanied by a profoundly decreased excitability and a reduction in the amplitude of voltage-gated calcium channel currents in the DG granule cells. However, three days of administration of either ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Necrostatin-1 (Nec-1), a necroptosis inhibitor, in the entorhinal cortex could almost preserve the normal excitability and the Ca2+ currents. In conclusion, these findings suggest that ferroptosis and necroptosis involvement in EC amyloidopathy could be a potential candidate to prevent the suppressive effect of Aβ on the Ca2+ channel current and neuronal function, which might take place in neurons during the development of AD.

Silencing of dentate gyrus inhibits mossy fiber sprouting and prevents epileptogenesis through NDR2 kinase in pentylenetetrazole kindling rat model of TLE.

Epileptogenesis is a potential process. Mossy fiber sprouting (MFS) contributes to epileptogenesis. Silencing of the dentate gyrus (DG) suppressed spontaneous seizures model of epilepsy and hyperactivity of granule cells resulted in MFS in vitro. However, the role of DG's excitability in epileptogenesis have not yet been well explored, and underlying mechanisms has not been elucidated. Using chemical genetics, we studied whether MFS and epileptogenesis could be modulated by silencing of DG in the PTZ kindling rat model of epilepsy. MFS and protein expression was measured by Timm staining, Western blotting, and Immunofluorescence. Previous studies demonstrated that MFS and epileptogenesis could be modulated by a regulator of axonal growth (e.g. RGMa, PTEN). NDR2 kinase regulate neuronal polarity and prevents the formation of supernumerary axons in the hippocampus. We experimentally confirmed chemogenetic inhibition in DG resulted in decreased MFS and NDR2 expression, and alleviated epileptogenesis. Furthermore, our results showed that injection of AVV vector expressing NDR2 into DG induced upregulation of NDR2 in the hippocampus, and over expression of NDR2 in the hippocampus promote MFS and block protective effect of chemogenetic silencing of DG on epileptogenesis. Overall, we concluded that silencing of DG inhibits MFS and prevents epileptogenesis through NDR2 in the hippocampus in the PTZ kindling rat model of TLE, thereby providing a possible strategy to prevent epileptogenesis.

Circadian regulation of dentate gyrus excitability mediated by G-protein signaling.

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven by molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery, but whether these molecular programs generate oscillations of membrane properties is unclear. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-h oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium currents that reduce excitability during the Light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the Light phase by removing G-protein regulation. These results reveal that circadian transcriptional machinery regulates intrinsic excitability by coordinated regulation of ion channels by G-protein signaling, highlighting a potential novel mechanism of cell-autonomous oscillations.

Serotonin receptor 4 in the hippocampus modulates mood and anxiety

Serotonin receptor 4 (5-HT4R) plays an important role in regulating mood, anxiety, and cognition, and drugs that activate this receptor have fast-acting antidepressant (AD)-like effects in preclinical models. However, 5-HT4R is widely expressed throughout the central nervous system (CNS) and periphery, making it difficult to pinpoint the cell types and circuits underlying its effects. Therefore, we generated a Cre-dependent 5-HT4R knockout mouse line to dissect the function of 5-HT4R in specific brain regions and cell types. We show that the loss of functional 5-HT4R specifically from excitatory neurons of hippocampus led to robust AD-like behavioral responses and an elevation in baseline anxiety. 5-HT4R was necessary to maintain the proper excitability of dentate gyrus (DG) granule cells and cell type-specific molecular profiling revealed a dysregulation of genes necessary for normal neural function and plasticity in cells lacking 5-HT4R. These adaptations were accompanied by an increase in the number of immature neurons in ventral, but not dorsal, dentate gyrus, indicating a broad impact of 5-HT4R loss on the local cellular environment. This study is the first to use conditional genetic targeting to demonstrate a direct role for hippocampal 5-HT4R signaling in modulating mood and anxiety. Our findings also underscore the need for cell type-based approaches to elucidate the complex action of neuromodulatory systems on distinct neural circuits.

Chronic ghrelin administration restores hippocampal long-term potentiation and ameliorates memory impairment in rat model of Alzheimer's disease.

Alzheimer's disease (AD), as a common age-related dementia, is a progressive manifestation of cognitive decline following synaptic failure resulted majorly by senile plaques composed of deposits of amyloid beta (Aβ). Ghrelin is a multifunctional peptide hormone with receptors present in various brain tissues including hippocampus and has been associated with neuroprotection, neuromodulation, and memory processing. Here, we investigated the neuroprotective and therapeutic effects of intracerebroventricular (icv) ghrelin infusion for 2 weeks on passive avoidance learning (PAL), memory retention, and synaptic plasticity in the hippocampal dentate gyrus (DG) and CA1 of both normal rats and Aβ1-42-induced neurotoxicity in AD model. Male Wistar rats were evaluated for their passive memory performance using a shuttle box while some groups had already received Aβ1-42 and/or chronic ghrelin. Using field potential recording, the induction of short- and long-term potentiation (STP and LTP) was studied in DG granule cells along with the LTP changes in CA1 pyramidal neurons through stimulation of the medial perforant path (mPP) and Schaffer collaterals (SCs), respectively. Our results demonstrated that chronic ghrelin treatment not only improved memory processing and retrieval in normal rats during the PAL task, but also promoted memory retention and alleviated memory loss by amelioration of Aβ1-42-induced synaptic plasticity impairment in AD subjects through augmentation of field excitatory postsynaptic potential (fEPSP) slope that led to LTP restitution in both the mPP-DG and the CA3-CA1 synapses. Meanwhile, STP was not significantly changed, meaning that although ghrelin enhanced postsynaptic excitability in DG, it did not change presynaptic transmitter release significantly. This suggests the involvement of postsynaptic mechanisms in long-term ghrelin-enhanced memory. In conclusion, it can be inferred that chronic ghrelin administration has an auspicious therapeutic value for impaired cognitive performance and memory deficits in AD-like neuropathology.

Issue Cover (January 2017)

Front cover: Confocal microphotography of a triple inmunolabeling of the dentate gyrus against makers of adult-born (Bromodeoxyuridine, blue), mature (NeuN, green), and immature (Doublecortin, red) dentate gyrus granule cells. In mice chronically treated with Pregabalin the maturation of adult-born dentate gyrus granule cells is accelerated. In the population of Bromodeoxyurudine positive cells, that effect is evidenced as an increase in the fraction of NeuN positive cells concomitant with a reduction in the fraction of Doublecortin positive cells. Read the full article ‘Chronic pregabalin treatment decreases excitability of dentate gyrus and accelerates maturation of adult-born granule cells’ by A. A. Lempel, L. Coll, A. F. Schinder, O. D. Uchitel and J. Piriz (J. Neurochem. 2017, vol. 140 (2), pp. 257–267) on doi: 10.1111/jnc.13740

Chronic pregabalin treatment decreases excitability of dentate gyrus and accelerates maturation of adult-born granule cells.

Pregabalin (PGB) is extensively prescribed to treat neurological and neuropsychiatrical conditions such as neuropathic pain, anxiety disorders, and epilepsy. Although PGB is known to bind selectively to the α2δ subunit of voltage-gated calcium channels, there is little understanding about how it exerts its therapeutic effects. In this article, we analyzed the effects of an invivo chronic treatment with PGB over the physiology of dentate gyrus granule cells (DGGCs) using exvivo electrophysiological and morphological analysis in adult mice. We found that PGB decreases neuronal excitability of DGGCs. In addition, PGB accelerates maturation of adult-born DGGCs, an effect that would modify dentate gyrus plasticity. Together, these findings suggest that PGB reduces activity in the dentate gyrus and modulates overall network plasticity, which might contribute to its therapeutic effects. Cover Image for this issue: doi: 10.1111/jnc.13783.

Perturbed Hippocampal Synaptic Inhibition and γ-Oscillations in a Neuroligin-4 Knockout Mouse Model of Autism.

SummaryLoss-of-function mutations in the synaptic adhesion protein Neuroligin-4 are among the most common genetic abnormalities associated with autism spectrum disorders, but little is known about the function of Neuroligin-4 and the consequences of its loss. We assessed synaptic and network characteristics in Neuroligin-4 knockout mice, focusing on the hippocampus as a model brain region with a critical role in cognition and memory, and found that Neuroligin-4 deletion causes subtle defects of the protein composition and function of GABAergic synapses in the hippocampal CA3 region. Interestingly, these subtle synaptic changes are accompanied by pronounced perturbations of γ-oscillatory network activity, which has been implicated in cognitive function and is altered in multiple psychiatric and neurodevelopmental disorders. Our data provide important insights into the mechanisms by which Neuroligin-4-dependent GABAergic synapses may contribute to autism phenotypes and indicate new strategies for therapeutic approaches.

Experience-Dependent Regulation of Dentate Gyrus Excitability by Adult-Born Granule Cells.

Adult-born neurons in the hippocampal dentate gyrus are important for flexibly using memories, but the mechanism is controversial. Using tests of hippocampus-dependent place avoidance learning and dentate electrophysiology in mice with normal or ablated neurogenesis, we find that maturing adult-born neurons are crucial only when memory must be used flexibly, and that these neurons regulate dentate gyrus synaptic and spiking responses to neocortical input rather than directly storing information, as has been proposed. A day after learning to avoid the initial or changed locations of shock, the dentate synaptic responses are enhanced or suppressed, respectively, unlike mice lacking adult neurogenesis, which did not change. The contribution of adult neurogenesis to memory is indirect, by regulating dentate excitation-inhibition coupling.

Inhibitory Neuron and Hippocampal Circuit Dysfunction in an Aged Mouse Model of Alzheimer's Disease

In Alzheimer's disease (AD), a decline in explicit memory is one of the earliest signs of disease and is associated with hippocampal dysfunction. Amyloid protein exerts a disruptive impact on neuronal function, but the specific effects on hippocampal network activity are not well known. In this study, fast voltage-sensitive dye imaging and extracellular and whole-cell electrophysiology were used on entorhinal cortical-hippocampal slice preparations to characterize hippocampal network activity in 12–16 month old female APPswe/PSEN1DeltaE9 (APdE9 mice) mice. Aged APdE9 mice exhibited profound disruptions in dentate gyrus circuit activation. High frequency stimulation of the perforant pathway in the dentate gyrus (DG) area of APdE9 mouse tissue evoked abnormally large field potential responses corresponding to the wider neural activation maps. Whole-cell patch clamp recordings of the identified inhibitory interneurons in the molecular layer of DG revealed that they fail to reliably fire action potentials. Taken together, abnormal DG excitability and an inhibitory neuron failure to generate action potentials are suggested to be important contributors to the underlying cellular mechanisms of early-stage Alzheimer's disease pathophysiology.

Adult neurogenesis modifies excitability of the dentate gyrus

Adult-born dentate granule neurons contribute to memory encoding functions of the dentate gyrus (DG) such as pattern separation. However, local circuit-mechanisms by which adult-born neurons partake in this process are poorly understood. Computational, neuroanatomical and electrophysiological studies suggest that sparseness of activation in the granule cell layer (GCL) is conducive for pattern separation. A sparse coding scheme is thought to facilitate the distribution of similar entorhinal inputs across the GCL to decorrelate overlapping representations and minimize interference. Here we used fast voltage-sensitive dye (VSD) imaging combined with laser photostimulation and electrical stimulation to examine how selectively increasing adult DG neurogenesis influences local circuit activity and excitability. We show that DG of mice with more adult-born neurons exhibits decreased strength of neuronal activation and more restricted excitation spread in GCL while maintaining effective output to CA3c. Conversely, blockade of adult hippocampal neurogenesis changed excitability of the DG in the opposite direction. Analysis of GABAergic inhibition onto mature dentate granule neurons in the DG of mice with more adult-born neurons shows a modest readjustment of perisomatic inhibitory synaptic gain without changes in overall inhibitory tone, presynaptic properties or GABAergic innervation pattern. Retroviral labeling of connectivity in mice with more adult-born neurons showed increased number of excitatory synaptic contacts of adult-born neurons onto hilar interneurons. Together, these studies demonstrate that adult hippocampal neurogenesis modifies excitability of mature dentate granule neurons and that this non-cell autonomous effect may be mediated by local circuit mechanisms such as excitatory drive onto hilar interneurons. Modulation of DG excitability by adult-born dentate granule neurons may enhance sparse coding in the GCL to influence pattern separation.

Loss of survivin in neural precursor cells results in impaired long-term potentiation in the dentate gyrus and CA1-region

In adult mammals, newborn neural precursor cells (NPCs) derived from either the subventricular zone (SVZ) or the subgranular zone (SGZ) migrate into the olfactory bulb and the dentate gyrus (DG), respectively, where some of them mature into excitatory and inhibitory neurons. There is increasing evidence that this neurogenesis process is important for some types of learning and synaptic plasticity and vice versa. Survivin, a member of the inhibitor-of-apoptosis protein (IAP) family, has been suggested to have a central role in the regulation of neurogenesis. The protein is abundantly expressed in nervous tissue during embryonic development while being restricted postnatally to proliferating and migrating NPCs in SVZ and SGZ. Here we examined adult SurvivinCamcre mice with a conditional deletion of the survivin gene in embryonic neurogenic regions. Although the deletion of survivin had no effect on basic excitability in DG and CA1-region, there was a marked impairment of long-term potentiation (LTP) in these areas. Our data support a function of survivin in hippocampal synaptic plasticity and learning and underline the importance of adult brain neurogenesis for proper operation of the hippocampal tri-synaptic circuit and the physiological functions that depend on it.

Circadian dentate gyrus excitability in a rat model of temporal lobe epilepsy

In human mesial temporal lobe epilepsy (mTLE), seizure occurrence peaks in the late afternoon and early evening. This temporal binding of seizures has been replicated in animal models of mTLE following electrically-induced status epilepticus (SE). We hypothesized that in chronic epilepsy, alterations of circadian excitatory and inhibitory functions of the dentate gyrus (DG), which is believed to regulate the generation of limbic seizures, pathophysiologically contribute to the temporal binding of ictogenesis. We performed electrophysiological single and paired pulse measurements hourly over 24h in the DG of epileptic rats (n=8) 8weeks after electrically induced SE. Results were compared to individual data obtained before induction of SE and to those of control animals (n=3). Pre and post SE data were analyzed in two distinct phases of the day, i.e. a high-seizure phase between 2p.m. and 10p.m. and a low-seizure phase between 10p.m. and 2p.m. In chronic epileptic animals, latency of evoked potentials was significantly reduced in the high-seizure phase (p=0.027) but not in the low-seizure phase. Compared to baseline values, paired pulse inhibition was significantly increased during the low-seizure phase (interpulse interval (IPI) 25ms, p=0.003; IPI 30ms; p<0.001) but not in the high-seizure phase. Similarly, when compared to controls, inhibition at IPI 20ms was diminished only in the high-seizure phase (p=0.027). Thus, in chronic epileptic animals, DG excitability is increased in the afternoon and early evening possibly contributing to the time of day-dependency of spontaneous seizures in this model system of mTLE. Alterations of circadian DG excitability in epileptic animals may be influenced by changes in hypothalamus-regulated superordinate functions such as excretion of endocrine hormones but further studies are needed.

Increased Dentate Gyrus Excitability in Neuroligin-2-Deficient Mice in Vivo

The postsynaptic adhesion protein neuroligin-2 (NL2) is selectively localized at inhibitory synapses. Here, we studied network activity in the dentate gyrus of NL2-deficient mice following perforant path (PP) stimulation in vivo. We found a strong increase in granule cell (GC) excitability. Furthermore, paired-pulse inhibition (PPI) of the population spike, a measure for γ-aminobutyric acid (GABA)ergic network inhibition, was severely impaired and associated with reduced GABA(A) receptor (GABA(A)R)-mediated miniature inhibitory postsynaptic currents recorded from NL2-deficient GCs. In agreement with these functional data, the number of gephyrin and GABA(A)R clusters was significantly reduced in the absence of NL2, indicating a loss of synaptic GABA(A)Rs from the somata of GCs. Computer simulations of the dentate network showed that impairment of perisomatic inhibition is able to explain the electrophysiological changes observed in the dentate circuitry of NL2 knockout animals. Collectively, our data demonstrate for the first time that deletion of NL2 increases excitability of cortical neurons in the hippocampus of intact animals, most likely through impaired GABA(A)R clustering.

Mossy fiber sprouting interacts with sodium channel mutations to increase dentate gyrus excitability

Idiopathic epilepsy is caused by the complex interaction of genetic and environmental factors. The purpose of this study was to use computational approaches to explore the interaction between changes in sodium channel availability caused by mutations and mossy fiber sprouting. We used a previously published biophysically realistic computer model of dentate gyrus neurons and networks. A sensitivity analysis probed the effects of typical mutation-like changes in either single- or multiple-gating parameters. Isolated neuron models were stimulated with current injections, and networks were stimulated with perforant path synaptic input. The gene-environment interaction was studied by including mossy fiber sprouting into these networks. Single neuron responses to current injections were complex, with increased sodium channel availability paradoxically reducing firing rates. In the absence of mossy fiber sprouting, control networks showed strong accommodation supporting the role of the dentate gyrus as a gate. Availability changes alone were not able to drive the networks into ictal states, even though they reduced the effectiveness of the dentate gyrus gate. Interestingly, the presence of electrophysiologic changes substantially increased the ability of mossy fiber sprouting to induce ictal activity. (1) Increased sodium channel availability does not necessarily lead to increased firing rates, (2) network excitability is most sensitive to changes in steady state activation of sodium channels, (3) mutation-induced changes in availability reduce the effectiveness of the dentate gyrus gate, and (4) mutations interact strongly with structural network changes to allow ictal-like activity in the dentate gyrus.

‘Leaky’ neurons in the epileptic hippocampus: should we get excited?

‘Leaky’ neurons in the epileptic hippocampus: should we get excited?

Long-Term Plasticity Is Proportional to Theta-Activity

BackgroundTheta rhythm in the hippocampal formation is a main feature of exploratory behaviour and is believed to enable the encoding of new spatial information and the modification of synaptic weights. Cyclic changes of dentate gyrus excitability during theta rhythm are related to its function, but whether theta epochs per se are able to alter network properties of dentate gyrus for long time-periods is still poorly understood.Methodology/Principal FindingsWe used low-frequency stimulation protocols that amplify the power of endogenous theta oscillations, in order to estimate the plasticity effect of endogenous theta oscillations on a population level. We found that stimulation-induced augmentation of the theta rhythm is linked to a subsequent increase of neuronal excitability and decrease of the synaptic response. This EPSP-to-Spike uncoupling is related to an increased postsynaptic spiking on the positive phases of theta frequency oscillations. Parallel increase of the field EPSP slope and the population spike occurs only after concurrent pre- and postsynaptic activation. Furthermore, we observed that long-term potentiation (>24 h) occurs in the dentate gyrus of freely behaving adult rats after phasic activity of entorhinal afferents in the theta-frequency range. This plasticity is proportional to the field bursting activity of granule cells during the stimulation, and may comprise a key step in spatial information transfer. Long-term potentiation of the synaptic component occurs only when the afferent stimulus precedes the evoked population burst, and is input-specific.Conclusions/SignificanceOur data confirm the role of the dentate gyrus in filtering information to the subsequent network during the activated state of the hippocampus.

Reduced excitability in the dentate gyrus network of βIV‐spectrin mutant mice in vivo

The submembrane cytoskeletal meshwork of the axon contains the scaffolding protein betaIV-spectrin. It provides mechanical support for the axon and anchors membrane proteins. Quivering (qv(3j)) mice lack functional betaIV-spectrin and have reduced voltage-gated sodium channel (VGSC) immunoreactivity at the axon initial segment and nodes of Ranvier. Because VGSCs are critically involved in action potential generation and conduction, we hypothesized that qv(3j) mice should also show functional deficits at the network level. To test this hypothesis, we investigated granule cell function in the dentate gyrus of anesthetized qv(3j) mice after electrical stimulation of the perforant path in vivo. This revealed an impaired input-output relationship between stimulus intensity and granule cell population spikes and an enhanced paired-pulse inhibition of population spikes, indicating a reduced ability of granule cells to generate action potentials and decreased network excitability. In contrast, the input-output curve for evoked field excitatory postsynaptic potentials (fEPSPs) and paired-pulse facilitation of fEPSPs were unchanged, suggesting normal excitatory synaptic transmission at perforant path-granule cell synapses in qv(3j) mutants. To corroborate our findings, we analyzed the influence of VGSC density reduction on dentate network activity using an established computational model of the dentate gyrus network. This in silico approach confirmed that the loss of VGSCs is sufficient to explain the electrophysiological changes observed in qv(3j) mice. Taken together, our findings demonstrate that betaIV-spectrin is required for normal granule cell firing and for physiological levels of network excitability in the mouse dentate gyrus in vivo.