Topiramate alters the gut microbiome to aid in its anti-seizure effect.

Introduction: There is a growing interest in the role of the gut microbiota in epilepsy, however, it is unclear if anti-seizure medications (ASMs) play a role in the gut-brain axis. To test this, we investigated the impact of the ASM topiramate on the gut microbiome of mice. Methods: C57BL/6J mice were administered topiramate in their drinking water for 5 weeks. 16S ribosomal RNA gene sequencing was performed on fecal samples collected at 5 weeks. Analysis of alpha diversity, beta diversity, and differential abundance were performed. Cecal contents were analyzed for short-chain fatty acids (SCFAs) composition. Pentylenetetrazol (PTZ)-kindling was performed in saline, topiramate, Lactobacillus johnsonii, and topiramate and Lactobacillus johnsonii treated mice. Mice received PTZ injection every other day for a total of twelve injections, seizure activity was video monitored for 30 minutes and scored. Results and discussion: Our study revealed that topiramate ingestion significantly increased Lactobacillus johnsonii in the gut microbiome of naïve mice. Treatment with topiramate and Lactobacillus johnsonii together, but not alone, reduced susceptibility to PTZ-induced seizures. Co-treatment also significantly increased the percent of butyrate and the abundance of butyrate-producing family Lachnospiraceae in the gut, and elevated the GABA/glutamate ratio in the cortex. Our results demonstrate that an ASM can alter the gut microbiome to aid in their anti-seizure effect in vivo and suggest the potential of the probiotic Lactobacillus johnsonii as an adjunct therapy with topiramate in reducing seizure susceptibility.

Perineuronal nets support astrocytic ion and glutamate homeostasis at tripartite synapses.

Perineuronal nets (PNNs) are dense, negatively charged extracellular matrices that cover the cell body of fast-spiking inhibitory neurons. Synapses can be embedded and stabilized by PNNs believed to prevent synaptic plasticity. We find that in cortical fast-spiking interneurons synaptic terminals localize to perforations in the PNNs, 95% of which contain either excitatory or inhibitory synapses or both. The majority of terminals also colocalize with astrocytic processes expressing Kir4.1 as well as glutamate (Glu) and GABA transporters, hence can be considered tripartite synapses. In the adult brain, degradation of PNNs does not alter axonal terminals but causes expansion of astrocytic coverage of the neuronal somata. However, loss of PNNs impairs astrocytic transmitter and K+ uptake and causes spillage of synaptic Glu into the extrasynaptic space. This data suggests a hitherto unrecognized role of PNNs, to synergize with astrocytes to contain synaptically released signals.

KCa-Related Neurological Disorders: Phenotypic Spectrum and Therapeutic Indications.

Although potassium channelopathies have been linked to a wide range of neurological conditions, the underlying pathogenic mechanism is not always clear, and a systematic summary of clinical manifestation is absent. Several neurological disorders have been associated with alterations of calcium-activated potassium channels (KCa channels), such as loss- or gain-of-function mutations, post-transcriptional modification, etc. Here, we outlined the current understanding of the molecular and cellular properties of three subtypes of KCa channels, including big conductance KCa channels (BK), small conductance KCa channels (SK), and the intermediate conductance KCa channels (IK). Next, we comprehensively reviewed the loss- or gain-of-function mutations of each KCa channel and described the corresponding mutation sites in specific diseases to broaden the phenotypic-genotypic spectrum of KCa-related neurological disorders. Moreover, we reviewed the current pharmaceutical strategies targeting KCa channels in KCa-related neurological disorders to provide new directions for drug discovery in anti-seizure medication.

Na+/HCO3- Co-transporters Inhibitor S0859 Attenuates Global Cerebral Ischemia-reperfusion Injury of the CA1 Neurons in the Gerbil's Hippocampus.

BACKGROUND: Metabolic acidosis plays a key role in transient global cerebral ischemiareperfusion (I/R) induced delayed neuronal death (DND) of the hippocampal CA1 region of gerbils. Na+ coupled HCO3 - transporters (NBCs) mediated Na+/HCO3- - co-transportation can be activated by the pH gradient of intracellular and extracellular environments induced by acidosis. However, whether NBCs are activated and involved in I/R-induced neuronal injury is unknown. OBJECTIVE: In this work, we studied neuronal apoptosis, astrocyte activation, and hippocampusdependent memory task using a well-established transient global cerebral I/R model of gerbils and investigated whether the specific NBCs inhibitor S0859 could reverse this injury. METHODS: To explore the role of S0859 in I/R-induced DND, we established a transient global cerebral I/R model of Mongolian gerbils and studied neuronal apoptosis by using Nissl stain and TUNEL assay. The excitability and NBCs current were analyzed by whole-cell patch-clamp, while the cognitive function was evaluated by Barnes maze. RESULTS: We found that I/R increased the NBCs current, inhibited the excitability of CA1 neurons, and led to apoptosis in CA1 neurons. Selective NBCs inhibitor S0859 protected CA1 neurons from I/R induced neuronal cell death, astrocyte accumulation, and spatial memory impairment. CONCLUSION: These findings indicate that NBCs mediate transient global cerebral I/R induced DND of CA1 neurons, and NBCs inhibitors could be a promising target to protect neuronal functions after I/R.

Intentional and unintentional benefits of minority writing accountability groups.

A faculty position can be a balancing act. Many new faculty, particularly minorities, struggle due to a lack of mentorship. Writing accountability groups (WAGs) offer new faculty an opportunity to glean advice from mentors and improve their writing skills and enhance their career development in science, technology, engineering, and mathematics (STEM).

Na+/H+ Exchanger 1, a Potential Therapeutic Drug Target for Cardiac Hypertrophy and Heart Failure.

Cardiac hypertrophy is defined as increased heart mass in response to increased hemodynamic requirements. Long-term cardiac hypertrophy, if not counteracted, will ultimately lead to heart failure. The incidence of heart failure is related to myocardial infarction, which could be salvaged by reperfusion and ultimately invites unfavorable myocardial ischemia-reperfusion injury. The Na+/H+ exchangers (NHEs) are membrane transporters that exchange one intracellular proton for one extracellular Na+. The first discovered NHE isoform, NHE1, is expressed almost ubiquitously in all tissues, especially in the myocardium. During myocardial ischemia-reperfusion, NHE1 catalyzes increased uptake of intracellular Na+, which in turn leads to Ca2+ overload and subsequently myocardial injury. Numerous preclinical research has shown that NHE1 is involved in cardiac hypertrophy and heart failure, but the exact molecular mechanisms remain elusive. The objective of this review is to demonstrate the potential role of NHE1 in cardiac hypertrophy and heart failure and investigate the underlying mechanisms.

Sulfasalazine decreases astrogliosis-mediated seizure burden.

OBJECTIVE: Previously, we reported that inhibition of the astrocytic cystine/glutamate antiporter system xc- (SXC), using sulfasalazine (SAS), decreased evoked excitatory signaling in three distinct hyperexcitability models ex vivo. The current study expands on this work by evaluating the in vivo efficacy of SAS in decreasing astrogliosis-mediated seizure burden seen in the beta-1 integrin knockout (B1KO) model. METHODS: Video-EEG (electroencephalography) monitoring (24/7) was obtained using Biopac EEG acquisition hardware and software. EEG spectral analysis was performed using MATLAB. SAS was used at an equivalence of doses taken by Crohn's disease patients. Whole-cell patch-clamp recordings were made from cortical layer 2/3 pyramidal neurons. RESULTS: We report that 100% of B1KO mice that underwent 24/7 video-EEG monitoring developed spontaneous recurrent seizures and that intraperitoneal administration of SAS significantly reduced seizure frequency in B1KOs compared to B1KOs receiving sham saline. Spectral analysis found an acute reduction in EEG power following SAS treatment in B1KOs; however, this effect was not observed in nonepileptic control mice receiving SAS. Finally, whole-cell recordings from SXC knockout mice had hyperpolarized neurons and SXC-B1 double knockouts fired significantly less action potentials in response to current injection compared to B1KOs with SXC. SIGNIFICANCE: To devise effective strategies in finding relief for one-in-three patients with epilepsy who experience drug-resistant epilepsy we must continue to explore the mechanisms regulating glutamate homeostasis. This study explored the efficacy of targeting an astrocytic glutamate antiporter, SXC, as a novel antiepileptic drug (AED) target and further characterized a unique mouse model in which chronic astrogliosis is sufficient to induce spontaneous seizures and epilepsy. These findings may serve as a foundation to further assess the potential for SAS or inform the development of more potent and specific compounds that target SXC as a novel treatment for epilepsy.

Gut metabolite S-equol ameliorates hyperexcitability in entorhinal cortex neurons following Theiler murine encephalomyelitis virus-induced acute seizures.

OBJECTIVE: A growing body of evidence indicates a potential role for the gut-brain axis as a novel therapeutic target in treating seizures. The present study sought to characterize the gut microbiome in Theiler murine encephalomyelitis virus (TMEV)-induced seizures, and to evaluate the effect of microbial metabolite S-equol on neuronal physiology as well as TMEV-induced neuronal hyperexcitability ex vivo. METHODS: We infected C57BL/6J mice with TMEV and monitored the development of acute behavioral seizures 0-7 days postinfection (dpi). Fecal samples were collected at 5-7 dpi and processed for 16S sequencing, and bioinformatics were performed with QIIME2. Finally, we conducted whole-cell patch-clamp recordings in cortical neurons to investigate the effect of exogenous S-equol on cell intrinsic properties and neuronal hyperexcitability. RESULTS: We demonstrated that gut microbiota diversity is significantly altered in TMEV-infected mice at 5-7 dpi, exhibiting separation in beta diversity in TMEV-infected mice dependent on seizure phenotype, and lower abundance of genus Allobaculum in TMEV-infected mice regardless of seizure phenotype. In contrast, we identified specific loss of S-equol-producing genus Adlercreutzia as a microbial hallmark of seizure phenotype following TMEV infection. Electrophysiological recordings indicated that exogenous S-equol alters cortical neuronal physiology. We found that entorhinal cortex neurons are hyperexcitable in TMEV-infected mice, and exogenous application of microbial-derived S-equol ameliorated this TMEV-induced hyperexcitability. SIGNIFICANCE: Our study presents the first evidence of microbial-derived metabolite S-equol as a potential mechanism for alteration of TMEV-induced neuronal excitability. These findings provide new insight for the novel role of S-equol and the gut-brain axis in epilepsy treatment.

Glioma-induced peritumoral hyperexcitability in a pediatric glioma model.

Epileptic seizures are among the most common presenting symptom in patients with glioma. The etiology of glioma-related seizures is complex and not completely understood. Studies using adult glioma patient tissue and adult glioma mouse models, show that neurons adjacent to the tumor mass, peritumoral neurons, are hyperexcitable and contribute to seizures. Although it is established that there are phenotypic and genotypic distinctions in gliomas from adult and pediatric patients, it is unknown whether these established differences in pediatric glioma biology and the microenvironment in which these glioma cells harbor, the developing brain, differentially impacts surrounding neurons. In the present study, we examine the effect of patient-derived pediatric glioma cells on the function of peritumoral neurons using two pediatric glioma models. Pediatric glioma cells were intracranially injected into the cerebrum of postnatal days 2 and 3 (p2/3) mouse pups for 7 days. Electrophysiological recordings showed that cortical layer 2/3 peritumoral neurons exhibited significant differences in their intrinsic properties compared to those of sham control neurons. Peritumoral neurons fired significantly more action potentials in response to smaller current injection and exhibited a depolarization block in response to higher current injection. The threshold for eliciting an action potential and pharmacologically induced epileptiform activity was lower in peritumoral neurons compared to sham. Our findings suggest that pediatric glioma cells increase excitability in the developing peritumoral neurons by exhibiting early onset of depolarization block, which was not previously observed in adult glioma peritumoral neurons.

Sulfasalazine decreases mouse cortical hyperexcitability.

OBJECTIVE: Currently prescribed antiepileptic drugs (AEDs) are ineffective in treating approximately 30% of epilepsy patients. Sulfasalazine (SAS) is an US Food and Drug Administration (FDA)-approved drug for the treatment of Crohn disease that has been shown to inhibit the cystine/glutamate antiporter system xc- (SXC) and decrease tumor-associated seizures. This study evaluates the effect of SAS on distinct pharmacologically induced network excitability and determines whether it can further decrease hyperexcitability when administered with currently prescribed AEDs. METHODS: Using in vitro cortical mouse brain slices, whole-cell patch-clamp recordings were made from layer 2/3 pyramidal neurons. Epileptiform activity was induced with bicuculline (bic), 4-aminopyridine (4-AP) and magnesium-free (Mg2+ -free) solution to determine the effect of SAS on epileptiform events. In addition, voltage-sensitive dye (VSD) recordings were performed to characterize the effect of SAS on the spatiotemporal spread of hyperexcitable network activity and compared to currently prescribed AEDs. RESULTS: SAS decreased evoked excitatory postsynaptic currents (eEPSCs) and increased the decay kinetics of evoked inhibitory postsynaptic currents (eIPSCs) in layer 2/3 pyramidal neurons. Although application of SAS to bic and Mg2+ -free-induced epileptiform activity caused a decrease in the duration of epileptiform events, SAS completely blocked 4-AP-induced epileptiform events. In VSD recordings, SAS decreased VSD optical signals induced by 4-AP. Co-application of SAS with the AED topiramate (TPM) caused a significantly further decrease in the spatiotemporal spread of VSD optical signals. SIGNIFICANCE: Taken together this study provides evidence that inhibition of SXC by SAS can decrease network hyperexcitability induced by three distinct pharmacologic agents in the superficial layers of the cortex. Furthermore, SAS provided additional suppression of 4-AP-induced network activity when administered with the currently prescribed AED TPM. These findings may serve as a foundation to assess the potential for SAS or other compounds that selectively target SXC as an adjuvant treatment for epilepsy.

Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy.

Brain tumor patients commonly present with epileptic seizures. We show that tumor-associated seizures are the consequence of impaired GABAergic inhibition due to an overall loss of peritumoral fast spiking interneurons (FSNs) concomitant with a significantly reduced firing rate of those that remain. The reduced firing is due to the degradation of perineuronal nets (PNNs) that surround FSNs. We show that PNNs decrease specific membrane capacitance of FSNs permitting them to fire action potentials at supra-physiological frequencies. Tumor-released proteolytic enzymes degrade PNNs, resulting in increased membrane capacitance, reduced firing, and hence decreased GABA release. These studies uncovered a hitherto unknown role of PNNs as an electrostatic insulator that reduces specific membrane capacitance, functionally akin to myelin sheaths around axons, thereby permitting FSNs to exceed physiological firing rates. Disruption of PNNs may similarly account for excitation-inhibition imbalances in other forms of epilepsy and PNN protection through proteolytic inhibition may provide therapeutic benefits.

Altered phosphorylation, electrophysiology, and behavior on attenuation of PDE4B action in hippocampus.

BACKGROUND: PDE4 cyclic nucleotide phosphodiesterases regulate 3', 5' cAMP abundance in the CNS and thereby regulate PKA activity and phosphorylation of CREB, which has been implicated in learning and memory, depression and other functions. The PDE4 isoform PDE4B1 also interacts with the DISC1 protein, implicated in neural development and behavioral disorders. The cellular functions of PDE4B1 have been investigated extensively, but its function(s) in the intact organism remained unexplored. RESULTS: To specifically disrupt PDE4B1, we developed mice that express a PDE4B1-D564A transgene in the hippocampus and forebrain. The transgenic mice showed enhanced phosphorylation of CREB and ERK1/2 in hippocampus. Hippocampal neurogenesis was increased in the transgenic mice. Hippocampal electrophysiological studies showed increased baseline synaptic transmission and enhanced LTP in male transgenic mice. Behaviorally, male transgenic mice showed increased activity in prolonged open field testing, but neither male nor female transgenic mice showed detectable anxiety-like behavior or antidepressant effects in the elevated plus-maze, tail-suspension or forced-swim tests. Neither sex showed any significant differences in associative fear conditioning or showed any demonstrable abnormalities in pre-pulse inhibition. CONCLUSIONS: These data support the use of an isoform-selective approach to the study of PDE4B1 function in the CNS and suggest a probable role of PDE4B1 in synaptic plasticity and behavior. They also provide additional rationale and a refined approach to the development of small-molecule PDE4B1-selective inhibitors, which have potential functions in disorders of cognition, memory, mood and affect.

SLC7A11 expression is associated with seizures and predicts poor survival in patients with malignant glioma.

Glioma is the most common malignant primary brain tumor. Its rapid growth is aided by tumor-mediated glutamate release, creating peritumoral excitotoxic cell death and vacating space for tumor expansion. Glioma glutamate release may also be responsible for seizures, which complicate the clinical course for many patients and are often the presenting symptom. A hypothesized glutamate release pathway is the cystine/glutamate transporter System xc (-) (SXC), responsible for the cellular synthesis of glutathione (GSH). However, the relationship of SXC-mediated glutamate release, seizures, and tumor growth remains unclear. Probing expression of SLC7A11/xCT, the catalytic subunit of SXC, in patient and mouse-propagated tissues, we found that ~50% of patient tumors have elevated SLC7A11 expression. Compared with tumors lacking this transporter, in vivo propagated and intracranially implanted SLC7A11-expressing tumors grew faster, produced pronounced peritumoral glutamate excitotoxicity, induced seizures, and shortened overall survival. In agreement with animal data, increased SLC7A11 expression predicted shorter patient survival according to genomic data in the REMBRANDT (National Institutes of Health Repository for Molecular Brain Neoplasia Data) database. In a clinical pilot study, we used magnetic resonance spectroscopy to determine SXC-mediated glutamate release by measuring acute changes in glutamate after administration of the U.S. Food and Drug Administration-approved SXC inhibitor, sulfasalazine (SAS). In nine glioma patients with biopsy-confirmed SXC expression, we found that expression positively correlates with glutamate release, which is acutely inhibited with oral SAS. These data suggest that SXC is the major pathway for glutamate release from gliomas and that SLC7A11 expression predicts accelerated growth and tumor-associated seizures.

Behavioral and electrophysiological characterization of Dyt1 heterozygous knockout mice.

DYT1 dystonia is an inherited movement disorder caused by mutations in DYT1 (TOR1A), which codes for torsinA. Most of the patients have a trinucleotide deletion (ΔGAG) corresponding to a glutamic acid in the C-terminal region (torsinA(ΔE)). Dyt1 ΔGAG heterozygous knock-in (KI) mice, which mimic ΔGAG mutation in the endogenous gene, exhibit motor deficits and deceased frequency of spontaneous excitatory post-synaptic currents (sEPSCs) and normal theta-burst-induced long-term potentiation (LTP) in the hippocampal CA1 region. Although Dyt1 KI mice show decreased hippocampal torsinA levels, it is not clear whether the decreased torsinA level itself affects the synaptic plasticity or torsinA(ΔE) does it. To analyze the effect of partial torsinA loss on motor behaviors and synaptic transmission, Dyt1 heterozygous knock-out (KO) mice were examined as a model of a frame-shift DYT1 mutation in patients. Consistent with Dyt1 KI mice, Dyt1 heterozygous KO mice showed motor deficits in the beam-walking test. Dyt1 heterozygous KO mice showed decreased hippocampal torsinA levels lower than those in Dyt1 KI mice. Reduced sEPSCs and normal miniature excitatory post-synaptic currents (mEPSCs) were also observed in the acute hippocampal brain slices from Dyt1 heterozygous KO mice, suggesting that the partial loss of torsinA function in Dyt1 KI mice causes action potential-dependent neurotransmitter release deficits. On the other hand, Dyt1 heterozygous KO mice showed enhanced hippocampal LTP, normal input-output relations and paired pulse ratios in the extracellular field recordings. The results suggest that maintaining an appropriate torsinA level is important to sustain normal motor performance, synaptic transmission and plasticity. Developing therapeutics to restore a normal torsinA level may help to prevent and treat the symptoms in DYT1 dystonia.

Reactive astrogliosis causes the development of spontaneous seizures.

Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause or a consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of ß1-integrin (Itgß1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted ß1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch-clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl(-) gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.

GABAergic disinhibition and impaired KCC2 cotransporter activity underlie tumor-associated epilepsy.

Seizures frequently accompany gliomas and often escalate to peritumoral epilepsy. Previous work revealed the importance of tumor-derived excitatory glutamate (Glu) release mediated by the cystine-glutamate transporter (SXC) in epileptogenesis. We now show a novel contribution of GABAergic disinhibition to disease pathophysiology. In a validated mouse glioma model, we found that peritumoral parvalbumin-positive GABAergic inhibitory interneurons are significantly reduced, corresponding with deficits in spontaneous and evoked inhibitory neurotransmission. Most remaining peritumoral neurons exhibit elevated intracellular Cl(-) concentration ([Cl(-) ]i ) and consequently depolarizing, excitatory gamma-aminobutyric acid (GABA) responses. In these neurons, the plasmalemmal expression of KCC2, which establishes the low [Cl(-) ]i required for GABAA R-mediated inhibition, is significantly decreased. Interestingly, reductions in inhibition are independent of Glu release, but the presence of both decreased inhibition and decreased SXC expression is required for epileptogenesis. We suggest GABAergic disinhibition renders peritumoral neuronal networks hyper-excitable and susceptible to seizures triggered by excitatory stimuli, and propose KCC2 as a therapeutic target.

Functional changes in glutamate transporters and astrocyte biophysical properties in a rodent model of focal cortical dysplasia.

Cortical dysplasia is associated with intractable epilepsy and developmental delay in young children. Recent work with the rat freeze-induced focal cortical dysplasia (FCD) model has demonstrated that hyperexcitability in the dysplastic cortex is due in part to higher levels of extracellular glutamate. Astrocyte glutamate transporters play a pivotal role in cortical maintaining extracellular glutamate concentrations. Here we examined the function of astrocytic glutamate transporters in a FCD model in rats. Neocortical freeze lesions were made in postnatal day (PN) 1 rat pups and whole cell electrophysiological recordings and biochemical studies were performed at PN 21-28. Synaptically evoked glutamate transporter currents in astrocytes showed a near 10-fold reduction in amplitude compared to sham operated controls. Astrocyte glutamate transporter currents from lesioned animals were also significantly reduced when challenged exogenously applied glutamate. Reduced astrocytic glutamate transport clearance contributed to increased NMDA receptor-mediated current decay kinetics in lesioned animals. The electrophysiological profile of astrocytes in the lesion group was also markedly changed compared to sham operated animals. Control astrocytes demonstrate large-amplitude linear leak currents in response to voltage-steps whereas astrocytes in lesioned animals demonstrated significantly smaller voltage-activated inward and outward currents. Significant decreases in astrocyte resting membrane potential and increases in input resistance were observed in lesioned animals. However, Western blotting, immunohistochemistry and quantitative PCR demonstrated no differences in the expression of the astrocytic glutamate transporter GLT-1 in lesioned animals relative to controls. These data suggest that, in the absence of changes in protein or mRNA expression levels, functional changes in astrocytic glutamate transporters contribute to neuronal hyperexcitability in the FCD model.

Pre-synaptic release deficits in a DYT1 dystonia mouse model.

DYT1 early-onset generalized torsion dystonia (DYT1 dystonia) is an inherited movement disorder caused by mutations in one allele of DYT1 (TOR1A), coding for torsinA. The most common mutation is a trinucleotide deletion (ΔGAG), which causes a deletion of a glutamic acid residue (ΔE) in the C-terminal region of torsinA. Although recent studies using cultured cells suggest that torsinA contributes to protein processing in the secretory pathway, endocytosis, and the stability of synaptic proteins, the nature of how this mutation affects synaptic transmission remains unclear. We previously reported that theta-burst-induced long-term potentiation (LTP) in the CA1 region of the hippocampal slice is not altered in Dyt1 ΔGAG heterozygous knock-in (KI) mice. Here, we examined short-term synaptic plasticity and synaptic transmission in the hippocampal slices. Field recordings in the hippocampal Schaffer collaterals (SC) pathway revealed significantly enhanced paired pulse ratios (PPRs) in Dyt1 ΔGAG heterozygous KI mice, suggesting an impaired synaptic vesicle release. Whole-cell recordings from the CA1 neurons showed that Dyt1 ΔGAG heterozygous KI mice exhibited normal miniature excitatory post-synaptic currents (mEPSC), suggesting that action-potential independent spontaneous pre-synaptic release was normal. On the other hand, there was a significant decrease in the frequency, but not amplitude or kinetics, of spontaneous excitatory post-synaptic currents (sEPSC) in Dyt1 ΔGAG heterozygous KI mice, suggesting that the action-potential dependent pre-synaptic release was impaired. Moreover, hippocampal torsinA was significantly reduced in Dyt1 ΔGAG heterozygous KI mice. Although the hippocampal slice model may not represent the neurons directly associated with dystonic symptoms, impaired release of neurotransmitters caused by partial dysfunction of torsinA in other brain regions may contribute to the pathophysiology of DYT1 dystonia.