GABAergic neuron deficit as an idiopathic generalized epilepsy mechanism: the role of BRD2 haploinsufficiency in juvenile myoclonic epilepsy

Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/- mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/- males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/- female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/- vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/- mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/- mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.     

Atp1a3‐deficient heterozygous mice show lower rank in the hierarchy and altered social behavior

Atp1a3 is the Na‐pump alpha3 subunit gene expressed mainly in neurons of the brain. Atp1a3‐deficient heterozygous mice (Atp1a3^+/?) show altered neurotransmission and deficits of motor function after stress loading. To understand the function of Atp1a3 in a social hierarchy, we evaluated social behaviors (social interaction, aggression, social approach and social dominance) of Atp1a3^+/? and compared the rank and hierarchy structure between Atp1a3^+/? and wild‐type mice within a housing cage using the round‐robin tube test and barbering observations. Formation of a hierarchy decreases social conflict and promote social stability within the group. The hierarchical rank is a reflection of social dominance within a cage, which is heritable and can be regulated by specific genes in mice. Here we report: (1) The degree of social interaction but not aggression was lower in Atp1a3^+/? than wild‐type mice, and Atp1a3^+/? approached Atp1a3^+/? mice more frequently than wild type. (2) The frequency of barbering was lower in the Atp1a3^+/? group than in the wild‐type group, while no difference was observed in the mixed‐genotype housing condition. (3) Hierarchy formation was not different between Atp1a3^+/? and wild type. (4) Atp1a3^+/? showed a lower rank in the mixed‐genotype housing condition than that in the wild type, indicating that Atp1a3 regulates social dominance. In sum, Atp1a3^+/? showed unique social behavior characteristics of lower social interaction and preference to approach the same genotype mice and a lower ranking in the hierarchy.     

Mice lacking Asic3 show reduced anxiety‐like behavior on the elevated plus maze and reduced aggression

Sensing external stimulation is crucial for central processing in the brain and subsequent behavioral expression. Although sensory alteration or deprivation may result in behavioral changes, most studies related to the control of behavior have focused on central mechanisms. Here we created a sensory deficit model of mice lacking acid‐sensing ion channel 3 (Asic3^?/?) to probe behavioral alterations. ASIC3 is predominately distributed in the peripheral nervous system. RT‐PCR and immunohistochemistry used to examine the expression of Asic3 in the mouse brain showed near‐background mRNA and protein levels of ASIC3 throughout the whole brain, except for the sensory mesencephalic trigeminal nucleus. Consistent with the expression results, Asic3 knockout had no effect on synaptic plasticity of the hippocampus and the behavioral tasks of motor function, learning and memory. In anxiety behavior tasks, Asic3^?/? mice spent more time in the open arms of an elevated plus maze than did their wild‐type littermates. Asic3^?/? mice also displayed less aggressiveness toward intruders but more stereotypic repetitive behaviors during resident–intruder testing than did wild‐type littermates. Therefore, loss of ASIC3 produced behavioral changes in anxiety and aggression in mice, which suggests that ASIC3‐dependent sensory activities might relate to the central process of emotion modulation.     

The role of BRD7 in embryo development and glucose metabolism

Bromodomain‐containing protein 7 (BRD7) is a member of bromodomain‐containing protein family and its function has been implicated in several diseases. We have previously shown that BRD7 plays a role in metabolic processes. However, the effect of BRD7 deficiency in glucose metabolism and its role in in vivo have not been fully revealed. Here, we report the essential role of BRD7 during embryo development. Mice homozygous for BRD7 led to embryonic lethality at mid‐gestation. Homozygous BRD7 knockout (KO) mice showed retardation in development, and eventually all BRD7 KO embryos died in utero prior to E16.5. Partial knockdown of Brd7 gene displayed mild changes in glucose metabolism.     

Haploinsufficiency of glutamine synthetase increases susceptibility to experimental febrile seizures

Glutamine synthetase (GS) is a pivotal glial enzyme in the glutamate–glutamine cycle. GS is important in maintaining low extracellular glutamate concentrations and is downregulated in the hippocampus of temporal lobe epilepsy patients with mesial–temporal sclerosis, an epilepsy syndrome that is frequently associated with early life febrile seizures (FS). Human congenital loss of GS activity has been shown to result in brain malformations, seizures and death within days after birth. Recently, we showed that GS knockout mice die during embryonic development and that haploinsufficient GS mice have no obvious abnormalities or behavioral seizures. In the present study, we investigated whether reduced expression/activity of GS in haploinsufficient GS mice increased the susceptibility to experimentally induced FS. FS were elicited by warm-air-induced hyperthermia in 14-day-old mice and resulted in seizures in most animals. FS susceptibility was measured as latencies to four behavioral FS characteristics. Our phenotypic data show that haploinsufficient mice are more susceptible to experimentally induced FS ( P  < 0.005) than littermate controls. Haploinsufficient animals did not differ from controls in hippocampal amino acid content, structure (Nissl and calbindin), glial properties ( glial fibrillary acidic protein and vimentin) or expression of other components of the glutamate–glutamine cycle (excitatory amino acid transporter-2 and vesicular glutamate transporter-1). Thus, we identified GS as a FS susceptibility gene. GS activity-disrupting mutations have been described in the human population, but heterozygote mutations were not clearly associated with seizures or epilepsy. Our results indicate that individuals with reduced GS activity may have reduced FS seizure thresholds. Genetic association studies will be required to test this hypothesis.     

Scn1a dysfunction alters behavior but not the effect of stress on seizure response

Mutations in the voltage‐gated sodium channel gene SCN1A are responsible for a number of epilepsy disorders, including genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. In addition, dysfunction in SCN1A is increasingly being linked to neuropsychiatric abnormalities, social deficits and cognitive disabilities. We have previously reported that mice heterozygous for the SCN1A R1648H mutation identified in a GEFS+ family have infrequent spontaneous seizures, increased susceptibility to chemically and hyperthermia‐induced generalized seizures and sleep abnormalities. In this study, we characterized the behavior of heterozygous mice expressing the SCN1A R1648H mutation (Scn1a^RH/+) and the effect of stress on spontaneous and induced seizures. We also examined the effect of the R1648H mutation on the hypothalamic–pituitary–adrenal (HPA) axis response. We confirmed our previous finding that Scn1a^RH/+ mutants are hyperactive, and also identified deficits in social behavior, spatial memory, cued fear conditioning, pre‐pulse inhibition and risk assessment. Furthermore, while exposure to a stressor did increase seizure susceptibility, the effect seen in the Scn1a^RH/+ mutants was similar to that seen in wild‐type littermates. In addition, Scn1a dysfunction does not appear to alter HPA axis function in adult animals. Our results suggest that the behavioral abnormalities associated with Scn1a dysfunction encompass a wider range of phenotypes than previously reported and factors such as stress exposure may alter disease severity in patients with SCN1A mutations.     

Heterozygous loss of epilepsy gene KCNQ2 alters social,repetitive and exploratory behaviors

KCNQ/K_v7 channels conduct voltage‐dependent outward potassium currents that potently decrease neuronal excitability. Heterozygous inherited mutations in their principle subunits K_v7.2/KCNQ2 and K_v7.3/KCNQ3 cause benign familial neonatal epilepsy whereas patients with de novo heterozygous K_v7.2 mutations are associated with early‐onset epileptic encephalopathy and neurodevelopmental disorders characterized by intellectual disability, developmental delay and autism. However, the role of K_v7.2‐containing K_v7 channels in behaviors especially autism‐associated behaviors has not been described. Because pathogenic K_v7.2 mutations in patients are typically heterozygous loss‐of‐function mutations, we investigated the contributions of K_v7.2 to exploratory, social, repetitive and compulsive‐like behaviors by behavioral phenotyping of both male and female KCNQ2^+/? mice that were heterozygous null for the KCNQ2 gene. Compared with their wild‐type littermates, male and female KCNQ2^+/? mice displayed increased locomotor activity in their home cage during the light phase but not the dark phase and showed no difference in motor coordination, suggesting hyperactivity during the inactive light phase. In the dark phase, KCNQ2^+/? group showed enhanced exploratory behaviors, and repetitive grooming but decreased sociability with sex differences in the degree of these behaviors. While male KCNQ2^+/? mice displayed enhanced compulsive‐like behavior and social dominance, female KCNQ2^+/? mice did not. In addition to elevated seizure susceptibility, our findings together indicate that heterozygous loss of K_v7.2 induces behavioral abnormalities including autism‐associated behaviors such as reduced sociability and enhanced repetitive behaviors. Therefore, our study is the first to provide a tangible link between loss‐of‐function K_v7.2 mutations and the behavioral comorbidities of K_v7.2‐associated epilepsy.     

Hyperactive and anxiolytic‐like behaviors result from loss of COUP‐TFI/Nr2f1 in the mouse cortex

The nuclear receptor COUP TFI (also known as Nr2f1) plays major roles in specifying distinct neuronal subtypes during patterning of the neocortical motor and somatosensory cortex, as well as in regulating the longitudinal growth of the hippocampus during development. In humans, mutations in the NR2F1 gene lead to a global developmental delay and intellectual disabilities. While more than 30% of patients show behavioral features of autism spectrum disorder, 16% of haploinsufficient children show signs of hyperactivity and impulsivity. Loss of COUP‐TFI in the cortical mouse primordium results in altered area organization and serotonin distribution, abnormal coordination of voluntary movements and learning and memory deficits. Here, we asked whether absence of COUP‐TFI affects locomotor activity, anxiety, as well as depression. Mice mutant for COUP‐TFI have normal motor coordination, but significant traits of hyperactivity, which does not seem to respond to N‐Methyl‐D‐aspartate (NMDA) antagonists. However, no changes in anxiety, despite increased locomotor performances, were observed in the open field task. On the contrary, elevated plus maze and dark‐light test explorations indicate a decreased anxiety‐like behavior in COUP‐TFI mutant mice. Finally, significantly reduced immobility in the forced swim test and no changes in anhedonia in the sucrose preference task suggest no particular depressive behaviors in mutant mice. Taken together, our study shows that loss of COUP‐TFI leads to increased locomotor activity but less anxiety and contributes in further deciphering the pathophysiology of patients haploinsufficient for NR2F1.     

Magel2 knockout mice manifest altered social phenotypes and a deficit in preference for social novelty

MAGEL2 is one of five protein‐coding, maternally imprinted, paternally expressed genes in the Prader–Willi syndrome (PWS)‐critical domain on chromosome 15q11‐q13. Truncating pathogenic variants of MAGEL2 cause Schaaf‐Yang syndrome (SHFYNG) (OMIM #615547), a neurodevelopmental disorder related to PWS. Affected individuals manifest a spectrum of neurocognitive and behavioral phenotypes, including intellectual disability and autism spectrum disorder (ASD). Magel2 knockout mice carrying a maternally inherited, imprinted wild‐type (WT) allele and a paternally inherited Magel2‐lacZ knock‐in allele, which abolishes endogenous Magel2 gene function, exhibit several features reminiscent of the human Prader–Willi phenotypes, including neonatal growth retardation, excessive weight gain after weaning and increased adiposity in adulthood. They were shown to have altered circadian rhythm, reduced motor activity and reduced fertility. An extensive assessment for autism‐like behaviors in this mouse model was warranted, because of the high prevalence of ASD in human patients. The behavior of Magel2 knockout mice and their WT littermates were assayed via open field, elevated plus maze, tube, three‐chamber and partition tests. Our studies confirm decreased horizontal activity of male and female mice and increased vertical activity of females, in the open field. Both sexes spent more time in the open arm of the elevated plus maze, suggestive of reductions in anxiety. Both sexes displayed a lack of preference for social novelty, via a lack of discrimination between known and novel partners in the partition test. The in‐depth investigation of behavioral profiles caused by Magel2 loss‐of‐function helps to elucidate the etiology of behavioral phenotypes both for SHFYNG and PWS in general.     

Not all water mazes are created equal: cyclin D2 knockout mice with constitutively suppressed adult hippocampal neurogenesis do show specific spatial learning deficits

Studies using the Morris water maze to assess hippocampal function in animals, in which adult hippocampal neurogenesis had been suppressed, have yielded seemingly contradictory results. Cyclin D2 knockout (Ccnd2^?/?) mice, for example, have constitutively suppressed adult hippocampal neurogenesis but had no overt phenotype in the water maze. In other paradigms, however, ablation of adult neurogenesis was associated with specific deficits in the water maze. Therefore, we hypothesized that the neurogenesis‐related phenotype might also become detectable in Ccnd2^?/? mice, if we used the exact setup and protocol that in our previous study had revealed deficits in mice with suppressed adult neurogenesis. Ccnd2^?/? mice indeed learned the task and developed a normal preference for the goal quadrant, but were significantly less precise for the exact goal position and were slower in acquiring efficient and spatially more precise search strategies. Upon goal reversal (when the hidden platform was moved to a new position) Ccnd2^?/? mice showed increased perseverance at the former platform location, implying that they were less flexible in updating the previously learned information. Both with respect to adult neurogenesis and behavioral performance, Ccnd2^+/? mice ranged between wild types and knockouts. Importantly, hippocampus‐dependent learning was not generally impaired by the mutation, but specifically functional aspects relying on precise and flexible encoding were affected. Whether ablation of adult neurogenesis causes a specific behavioral phenotype thus also depends on the actual task demands. The test parameters appear to be important variables influencing whether a task can pick up a contribution of adult neurogenesis to test performance.     

COMT Val158Met moderates the link between rank and aggression in a non‐human primate

The COMT Val¹⁵⁸Met polymorphism is one of the most widely studied genetic polymorphisms in humans implicated in aggression and the moderation of stressful life event effects. We screened a wild primate population for polymorphisms at the COMT Val¹⁵⁸Met site and phenotyped them for aggression to test whether the human polymorphism exists and is associated with variation in aggressive behavior. Subjects were all adults from 4 study groups (37 males, 40 females) of Assamese macaques (Macaca assamensis) in their natural habitat (Phu Khieo Wildlife Sanctuary, Thailand). We collected focal animal behavioral data (27 males, 36 females, 5964 focal hours) and fecal samples for non‐invasive DNA analysis. We identified the human COMT Val¹⁵⁸Met polymorphism (14 Met/Met, 41 Val/Met and 22 Val/Val). Preliminary results suggest that COMT genotype and dominance rank interact to influence aggression rates. Aggression rates increased with rank in Val/Val, but decreased in Met/Met and Val/Met individuals, with no significant main effect of COMT genotype on aggression. Further support for the interaction effect comes from time series analyses revealing that when changing from lower to higher rank position Val/Val individuals decreased, whereas Met/Met individuals increased their aggression rate. Contradicting the interpretation of earlier studies, we show that the widely studied Val¹⁵⁸Met polymorphism in COMT is not unique to humans and yields similar behavioral phenotypes in a non‐human primate. This study represents an important step towards understanding individual variation in aggression in a wild primate population and may inform human behavioral geneticists about the evolutionary roots of inter‐individual variation in aggression.     

Reduced levels of Cacna1c attenuate mesolimbic dopamine system function

Genetic variation in CACNA1C, which codes for the L‐type calcium channel (LTCC) Ca_v1.2, is associated with clinical diagnoses of bipolar disorder, depression and schizophrenia. Dysregulation of the mesolimbic‐dopamine (ML‐DA) system is linked to these syndromes and LTCCs are required for normal DAergic neurotransmission between the ventral tegmental area (VTA) and nucleus accumbens (NAc). It is unclear, however, how variations in CACNA1C genotype, and potential subsequent changes in expression levels in these regions, modify risk. Using constitutive and conditional knockout mice, and treatment with the LTCC antagonist nimodipine, we examined the role of Cacna1c in DA‐mediated behaviors elicited by psychomotor stimulants. Using fast‐scan cyclic voltammetry, DA release and reuptake in the NAc were measured. We find that subsecond DA release in Cacna1c haploinsufficient mice lacks normal sensitivity to inhibition of the DA transporter (DAT). Constitutive haploinsufficiency of Cacna1c led to attenuation of hyperlocomotion following acute administration of stimulants specific to DAT, and locomotor sensitization of these mice to the DAT antagonist GBR12909 did not reach the same level as wild‐type mice. The maintenance of sensitization to GBR12909 was attenuated by administration of nimodipine. Sensitization to GBR12909 was attenuated in mice with reduced Cacna1c selectively in the VTA but not in the NAc. Our findings show that Cacna1c is crucial for normal behavioral responses to DA stimulants and that its activity in the VTA is required for behavioral sensitization. Cacna1c likely exerts these effects through modifications to presynaptic ML‐DA system function.     

Detailed analysis of paternal knockout Grb10 mice suggests effects on stability of social behavior,rather than social dominance

Imprinted genes are highly expressed in monoaminergic regions of the midbrain and their functions in this area are thought to have an impact on mammalian social behaviors. One such imprinted gene is Grb10, of which the paternal allele is generally recognized as mediating social dominance behavior. However, there has been no detailed study of social dominance in Grb10 ^+/p mice. Moreover, the original study examined tube‐test behavior in isolated mice 10 months of age. Isolation testing favors more territorial and aggressive behaviors, and does not address social dominance strategies employed in group housing contexts. Furthermore, isolation stress impacts midbrain function and dominance related behavior, often through alterations in monoaminergic signaling. Thus, we undertook a systematic study of Grb10 ^+/p social rank and dominance behavior within the cage group, using a number of convergent behavioral tests. We examined both male and female mice to account for sex differences and tested cohorts aged 2, 6 and 10 months to examine any developments related to age. We found group‐housed Grb10 ^+/p mice do not show evidence of enhanced social dominance, but cages containing Grb10 ^+/p and wild‐type mice lacked the normal correlation between three different measures of social rank. Moreover, a separate study indicated isolation stress induced inconsistent changes in tube test behavior. Taken together, these data suggest future research on Grb10 ^+/p mice should focus on the stability of social behaviors, rather than dominance per se.     

Early postnatal behavioral changes in the Mecp2‐308 truncation mouse model of Rett syndrome

In a mouse model of Rett syndrome (RTT) which expresses a truncated form of methyl‐CpG‐binding protein 2 (Mecp2) gene (Mecp2‐308), we performed a neurobehavioral evaluation across the life span, starting from soon after birth till adulthood. A focus was made on those developmental phases and behavioral domains which have not been previously investigated. The results evidenced subtle anomalies on postnatal days (pnds) 3 to 9 (so‐called presymptomatic phase) in spontaneous movements by hemizygous neonatal male mice. Specifically as early as pnd 3, mutant pups exhibited more intense curling and more side responses and on pnd 9 more pivoting and head rising behaviors than wild type (wt) littermates. A significant decrease in ultrasonic vocalization rate, also emerged in Mecp2‐308 pups. The same mice were also characterized by increased anxiety‐like behaviors (open‐field and zero‐maze tests) during the early symptomatic phase, in the absence of changes in cognitive passive‐avoidance task and rotarod performances. Upon the clearly symptomatic stage, 5‐month‐old Mecp2‐308 mice were also associated with reduced spontaneous home‐cage motor activity, motor coordination impairments (rotarod and dowel tests), and a more marked profile of d ‐amphetamine (10 mg/kg) released stereotyped behavioral syndrome than wt mice. Present results provide an interesting timeline of the progression of symptoms in the Mecp2‐308 model and emphasize the need for increased attention to the presymptomatic phase which may be especially informative in mouse models of human neurodevelopmental disorders. This analysis has provided evidence of precocious behavioral markers of RTT and has identified an early developmental window of opportunities on which potential therapies could be investigated.     

Loss of EphA4 impairs short‐term spatial recognition memory performance and locomotor habituation

EphA4 receptor (EphA4) tyrosine kinase is an important regulator of central nervous system development and synaptic plasticity in the mature brain, but its relevance to the control of normal behavior remains largely unexplored. This study is the first attempt to obtain a behavioral profile of constitutive homozygous and heterozygous EphA4 knockout mice. A deficit in locomotor habituation in the open field, impairment in spatial recognition in the Y‐maze and reduced probability of spatial spontaneous alternation in the T‐maze were identified in homozygous EphA4^?/? mice, while heterozygo us EphA4^+/? mice appeared normal on these tests in comparison with wild‐type (WT) controls. The multiple phenotypes observed in EphA4^?/? mice might stem from an underlying deficit in habituation learning, reflecting an elementary form of nonassociative learning that is in contrast to Pavlovian associative learning, which appeared unaffected by EphA4 disruption. A deficit in motor coordination on the accelerating rotarod was also demonstrated only in EphA4^?/? mice – a finding in keeping with the presence of abnormal gait in EphA4^?/? mice – although they were able to improve performance over training. There was no evidence for substantial changes in major neurochemical markers in various brain regions rich in EphA4 as shown by post‐mortem analysis. This excludes the possibility of major neurochemical compensation in the brain of EphA4^?/? mice. In summary, we have demonstrated for the first time the behavioral significance of EphA4 disruption, supporting further investigation of EphA4 as a possible target for behavioral interventions where habituation deficits are prominent.     

The relative biological effectiveness of densely ionizing heavy-ion radiation for inducing ocular cataracts in wild type versus mice heterozygous for the ATM gene

The accelerated appearance of ocular cataracts at younger ages has been recorded in both astronauts and airline pilots, and is usually attributed to high-energy heavy ions in galactic cosmic ray radiation. We have previously shown that high-LET 1-GeV/nucleon ⁵⁶Fe ions are significantly more effective than X-rays in producing cataracts in mice. We have also shown that mice haploinsufficient for ATM develop cataracts earlier than wild-type animals, when exposed to either low-LET X-rays or high-LET ⁵⁶Fe ions. In this paper we derive quantitative estimates for the relative biological effectiveness (RBE) of high energy ⁵⁶Fe ions compared with X-rays, both for wild type and for mice haploinsufficient for ATM. There is a clear trend toward higher RBE’s in haploinsufficient animals, both for low- and high-grade cataracts. Haploinsufficiency for ATM results in an enhanced sensitivity to X-rays compared with the wild type, and this enhancement appears even larger after exposure to high-LET heavy ions.Dedicated to the memory of Professor Basil V. Worgul, who passed away in January 2006, much missed by all his colleagues.     

Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease

Deficient energy metabolism and network hyperactivity are the early symptoms of Alzheimer's disease (AD). In this study, we show that administration of exogenous oxidative energy substrates (OES) corrects neuronal energy supply deficiency that reduces the amyloid‐beta‐induced abnormal neuronal activity in vitro and the epileptic phenotype in AD model in vivo. In vitro, acute application of protofibrillar amyloid‐β_1–42 (Aβ_1–42) induced aberrant network activity in wild‐type hippocampal slices that was underlain by depolarization of both the neuronal resting membrane potential and GABA‐mediated current reversal potential. Aβ_1–42 also impaired synaptic function and long‐term potentiation. These changes were paralleled by clear indications of impaired energy metabolism, as indicated by abnormal NAD(P)H signaling induced by network activity. However, when glucose was supplemented with OES pyruvate and 3‐beta‐hydroxybutyrate, Aβ_1–42 failed to induce detrimental changes in any of the above parameters. We administered the same OES as chronic supplementation to a standard diet to APPswe/PS1dE9 transgenic mice displaying AD‐related epilepsy phenotype. In the ex‐vivo slices, we found neuronal subpopulations with significantly depolarized resting and GABA‐mediated current reversal potentials, mirroring abnormalities we observed under acute Aβ_1‐42 application. Ex‐vivo cortex of transgenic mice fed with standard diet displayed signs of impaired energy metabolism, such as abnormal NAD(P)H signaling and strongly reduced tolerance to hypoglycemia. Transgenic mice also possessed brain glycogen levels twofold lower than those of wild‐type mice. However, none of the above neuronal and metabolic dysfunctions were observed in transgenic mice fed with the OES‐enriched diet. In vivo, dietary OES supplementation abated neuronal hyperexcitability, as the frequency of both epileptiform discharges and spikes was strongly decreased in the APPswe/PS1dE9 mice placed on the diet. Altogether, our results suggest that early AD‐related neuronal malfunctions underlying hyperexcitability and energy metabolism deficiency can be prevented by dietary supplementation with native energy substrates.