Gene therapy in epilepsy.

Gene therapy may constitute a promising alternative to conventional pharmacological tools and surgeries for epilepsy. For primary epilepsy, a single variant leading to a significant effect is relatively rare, while other forms are considered complex in inheritances with multiple susceptible mutations and impacts from the environment. Gene therapy in preclinical models of epilepsy has attempted to perform antiepileptogenic, anticonvulsant, or disease-modifying effects during epileptogenesis or after establishing the disease. Creating gene vectors tailored for different situations is the key to expanding gene therapy, and choosing the appropriate therapeutic target remains another fundamental problem. A variety of treatment strategies, from overexpressing inhibitory neuropeptides to modulating the expression of neurotransmitters or ion channels, have been tested in animal models. Additionally, emerging new approaches of optogenetics and chemogenetics, as well as genome-editing tools will further boost the prosperity of gene therapy. This review summarizes the experience obtained to date and discusses the challenges and opportunities in clinical translations.

Loss of the conserved PKA sites of SIK1 and SIK2 increases sleep need.

Although sleep is one of the most conserved behaviors, the intracellular mechanism regulating sleep/wakefulness remains unknown. We recently identified a protein kinase, SIK3, as a sleep-regulating molecule. Mice that lack a well-conserved protein kinase A (PKA) phosphorylation site, S551, showed longer non-rapid eye movement (NREM) sleep and increased NREMS delta density. S551 of SIK3 is conserved in other members of the SIK family, such as SIK1 (S577) and SIK2 (S587). Here, we examined whether the PKA phosphorylation sites of SIK1 and SIK2 are involved in sleep regulation by generating Sik1S577A and Sik2S587A mice. The homozygous Sik1S577A mice showed a shorter wake time, longer NREMS time, and higher NREMS delta density than the wild-type mice. The heterozygous and homozygous Sik2S587A mice showed increased NREMS delta density. Both the Sik1S577A and Sik2S587A mice exhibited proper homeostatic regulation of sleep need after sleep deprivation. Despite abundant expression of Sik1 in the suprachiasmatic nucleus, the Sik1S577A mice showed normal circadian behavior. Although Sik2 is highly expressed in brown adipose tissue, the male and female Sik2S587A mice that were fed either a chow or high-fat diet showed similar weight gain as the wild-type littermates. These results suggest that PKA-SIK signaling is involved in the regulation of sleep need.

Polygenic impact of morningness on the overnight dynamics of sleep spindle amplitude.

Sleep spindles are thalamocortical oscillations that contribute to sleep maintenance and sleep-related brain plasticity. The current study is an explorative study of the circadian dynamics of sleep spindles in relation to a polygenic score (PGS) for circadian preference towards morningness. The participants represent the 17-year follow-up of a birth cohort having both genome-wide data and an ambulatory sleep electroencephalography measurement available ( N = 154, Mean age = 16.9, SD = 0.1 years, 57% girls). Based on a recent genome-wide association study, we calculated a PGS for circadian preference towards morningness across the whole genome, including 354 single-nucleotide polymorphisms. Stage 2 slow (9-12.5 Hz, N = 186 739) and fast (12.5-16 Hz, N = 135 504) sleep spindles were detected using an automated algorithm with individual time tags and amplitudes for each spindle. There was a significant interaction of PGS for morningness and timing of sleep spindles across the night. These growth curve models showed a curvilinear trajectory of spindle amplitudes: those with a higher PGS for morningness showed higher slow spindle amplitudes in frontal derivations, and a faster dissipation of spindle amplitude in central derivations. Overall, the findings provide new evidence on how individual sleep spindle trajectories are influenced by genetic factors associated with circadian type. The finding may lead to new hypotheses on the associations previously observed between circadian types, psychiatric problems and spindle activity.

The heritability of the human K-complex: a twin study.

Sleep electroencephalogram (EEG) has a trait-like nature. Several findings highlighted the heritability of spectral power in specific frequency ranges and sleep spindles during nonrapid eye movement (NREM) sleep. However, a genetic influence on the K-complex (KC), one of the electrophysiological hallmarks of NREM sleep, has never been assessed. Here, we investigated the heritability of the KC detected during NREM stage 2 comparing 10 monozygotic (MZ) and 10 dizygotic (DZ) twin pairs. Genetic variance analysis (GVA) and intraclass correlation coefficients (ICCs) were performed to assess the genetic effect and within-pair similarity for KC density, amplitude, and for the area under the curve (AUC) of the KC average waveform at Fz, Cz, and Pz scalp locations. Moreover, cluster analysis was performed on the KC average waveform profile. We observed a significant genetic effect on KC AUC at Cz and Pz, and on amplitude at Pz. Within-pair similarity (ICCs) was always significant for MZ twins except for KC density at Fz, whereas DZ twins always exhibited ICCs below the significance threshold, with the exception of density at Pz. The largest differences in within-pair similarity between MZ and DZ groups were observed again for AUC at Cz and Pz. MZ pairs accurately clustered for the KC average waveform with a higher frequency (successful clustering rate for MZ pairs: Fz = 60%; Cz = 80%; Pz = 90%) compared with DZ pairs (successful clustering rate for DZ pairs: Fz = 10%; Cz = 10%; Pz = none). Our results suggest the existence of a genetic influence on the human KC, particularly related to its morphology and maximally observable in central and parietal locations.

Deficiency of urokinase-type plasminogen activator and its receptor affects social behavior and increases seizure susceptibility.

Extracellular proteolysis initiated by the binding of urokinase-type plasminogen activator (uPA) to its receptor (uPAR) regulates the development of inhibitory neuronal circuits in the cerebral cortex and tissue remodeling after epileptogenic brain injury. To study the function of different components of the uPA-uPAR system on behavior and epileptogenesis, and to complement our previous studies on naïve and injured mice deficient in the uPA-encoding gene Plau or the uPAR-encoding gene Plaur, we analyzed the behavioral phenotype, seizure susceptibility, and perineuronal nets surrounding parvalbumin-positive inhibitory interneurons in Plau and Plaur (double knockout dKO) mice. In a climbing test, dKO mice showed reduced interest towards the environment as compared with Wt mice (p < 0.01). In a social approach test, however, dKO mice spent more time than Wt mice exploring the compartment containing a stranger mouse than the empty compartment (p < 0.05). Moreover, in a social interaction test, dKO mice exhibited increased contact time (p < 0.01). Compared with Wt mice, the dKO mice also had a longer single contact duration (p < 0.001) with the stranger mouse. In the elevated plus-maze, grooming, and marble burying tests, the anxiety level of dKO mice did not differ from that of Wt mice. Rearing time in an exploratory activity test, and spatial learning and memory in the Morris swim navigation task were also comparable between dKO and Wt mice. In the pentylenetetrazol (PTZ) seizure-susceptibility test, dKO mice had a shorter latency to the first epileptiform spike (p = 0.0001) and a greater total number of spikes (p < 0.001) than Wt mice. The dKO genotype did not affect the number of cortical perineuronal nets. Our findings indicate that Plau/Plaur-deficiency leads to a more social phenotype toward other mice with diminished interest in the surrounding environment, and increased seizure susceptibility.

Somatic Depdc5 deletion recapitulates electroclinical features of human focal cortical dysplasia type IIA.

Epileptogenic mechanisms in focal cortical dysplasia (FCD) remain elusive, as no animal models faithfully recapitulate FCD seizures, which have distinct electrographic features and a wide range of semiologies. Given that DEPDC5 plays significant roles in focal epilepsies with FCD, we used in utero electroporation with clustered regularly interspaced short palindromic repeats gene deletion to create focal somatic Depdc5 deletion in the rat embryonic brain. Animals developed spontaneous seizures with focal pathological and electroclinical features highly clinically relevant to FCD IIA, paving the way toward understanding its pathogenesis and developing mechanistic-based therapies. Ann Neurol 2018;83:140-146.

Transient microstructural brain anomalies and epileptiform discharges in mice defective for epilepsy and language-related NMDA receptor subunit gene Grin2a.

OBJECTIVE: The epilepsy-aphasia spectrum (EAS) is a heterogeneous group of age-dependent childhood disorders characterized by sleep-activated discharges associated with infrequent seizures and language, cognitive, and behavioral deficits. Defects in the GRIN2A gene, encoding a subunit of glutamate-gated N-methyl-d-aspartate (NMDA) receptors, represent the most important cause of EAS identified so far. Neocortical or thalamic lesions were detected in a subset of severe EAS disorders, and more subtle anomalies were reported in patients with so-called "benign" phenotypes. However, whether brain structural alterations exist in the context of GRIN2A defects is unknown. METHODS: Magnetic resonance diffusion tensor imaging (MR-DTI) was used to perform longitudinal analysis of the brain at 3 developmental timepoints in living mice genetically knocked out (KO) for Grin2a. In addition, electroencephalography (EEG) was recorded using multisite extracellular electrodes to characterize the neocortical activity in vivo. RESULTS: Microstructural alterations were detected in the neocortex, the corpus callosum, the hippocampus, and the thalamus of Grin2a KO mice. Most MR-DTI alterations were detected at a specific developmental stage when mice were aged 30 days, but not at earlier (15 days) or later (2 months) ages. EEG analysis detected epileptiform discharges in Grin2a KO mice in the third postnatal week. SIGNIFICANCE: Grin2a KO mice replicated several anomalies found in patients with EAS disorders. Transient structural alterations detected by MR-DTI recalled the age-dependent course of EAS disorders, which in humans start during childhood and show variable outcome at the onset of adolescence. Together with the epileptiform discharges detected in young Grin2a KO mice, our data suggested the existence of early anomalies in the maturation of the neocortical and thalamocortical systems. Whereas the possible relationship of those anomalies with sleep warrants further investigations, our data suggest that Grin2a KO mice may serve as an animal model to study the neuronal mechanisms of EAS disorders and to design new therapeutic strategies.

Sleep and EEG Power Spectral Analysis in Three Transgenic Mouse Models of Alzheimer's Disease: APP/PS1, 3xTgAD, and Tg2576.

BACKGROUND: Sleep disturbances have long been associated with Alzheimer's disease (AD), and there is a growing interest in how these disturbances might impact AD pathophysiology. Despite this growing interest, surprisingly little is known about how sleep architecture and the broader neuronal network are affected in widely used transgenic mouse models of AD. OBJECTIVE: We analyzed sleep and electroencephalography (EEG) power in three transgenic mouse models of AD, using identical and commercially available hardware and analytical software. The goal was to assess the suitability of these mouse lines to model sleep and the broader neuronal network dysfunction measured by EEG in AD. METHODS: Tg2576, APP/PS1, and 3xTgAD transgenic AD mice were studied using in vivo EEG recordings for sleep/wake time and power spectral analysis. RESULTS: Both the APP/PS1 model at 8- 10 months and the Tg2576 model at 12 months of age exhibited stage-dependent decreases in theta and delta power, and shifts in the power spectra toward higher frequencies. Stage-dependent power spectral analyses showed no changes in the 3xTgAD model at 18 months of age. The percentage of time spent awake, in non-rapid eye movement sleep (NREM), or in rapid-eye-movement sleep (REM) was not different between genotypes in any of the transgenic lines. CONCLUSION: Our findings are consistent with data from several other transgenic AD models as well as certain studies in patients with mild cognitive impairment. Further studies will be needed to better understand the correlation between EEG spectra and AD pathophysiology, both in AD models and the human condition.

Dendritic Cell Factor 1-Knockout Results in Visual Deficit Through the GABA System in Mouse Primary Visual Cortex.

The visual system plays an important role in our daily life. In this study, we found that loss of dendritic cell factor 1 (DCF1) in the primary visual cortex (V1) caused a sight deficit in mice and induced an abnormal increase in glutamic acid decarboxylase 67, an enzyme that catalyzes the decarboxylation of glutamate to gamma aminobutyric acid and CO2, particularly in layer 5. In vivo electrophysiological recordings confirmed a decrease in delta, theta, and beta oscillation power in DCF1-knockout mice. This study presents a previously unknown function of DCF1 in V1, suggests an unknown contact between DCF1 and GABA systems, and provides insight into the mechanism and treatment of visual deficits.

A relatively mild phenotype associated with mutation of SCN8A.

Mutations in SCN8A gene have been described in relation to infantile onset epilepsy with movement disorders and developmental delay. Recently various authors have reported patients carrying autosomal dominant heterozygous SCN8A mutations and a milder phenotype expression. We discuss the case of a 6-year-old girl with a positive family history for epilepsy, early benign focal epilepsy, well controlled by Carbamazepine, upper limb tremor since birth, ataxia, slight motor delay and normal cognitive development. Neuroradiological study is normal, waking EEGs are normal, while epileptiform abnormalities on the vertex appear during sleep. The girl carries a de novo mutation of the SCN8A gene with nucleotide substitution of c.3943G > A (p.Val 1315 Met), located in the domain III S4/S5 intracellular linker. In literature two other cases with the same mutation have been reported, both patients have an epileptic encephalopathy. Our patient's milder phenotype could be caused by a modifier effect, possibly a mutation in another gene or a mosaicism. The detailed description of our case should contribute to enlarging the description of the clinical features of SCN8A mutations and to recommending the deepening of genetic investigations to.

Ongoing Electroencephalographic Activity Associated with Cortical Arousal in Transgenic PDAPP Mice (hAPP V717F).

BACKGROUND: It has been shown that theta (6-10 Hz) and delta (1-6 Hz) ongoing electroencephalographic (EEG) rhythms revealed variations in the cortical arousal in C57 Wild Type (WT) mice during cage exploration (active condition) compared to awake quiet behavior (passive condition; IMI PharmaCog project, www.pharmacog.eu). OBJECTIVE: The objective was to test if these EEG rhythms might be abnormal in old PDAPP mice modeling Alzheimer's disease (AD) with a hAPP Indiana V717F mutation (They show abnormal neural transmission, cognitive deficits, and brain accumulation of Aß1-42). METHODS: Ongoing EEG rhythms were recorded by a frontoparietal bipolar channel in 15 PDAPP and 23 WT C57 male mice (mean age of 22.8 months ±0.4 and 0.3 standard error, respectively). EEG absolute power (density) was calculated. Frequency and amplitude of individual delta and theta frequency (IDF and ITF) peaks were considered during passive and active states in the wakefulness. RESULTS: Compared with the WT group, the PDAPP group showed higher frequency of the IDF during the passive condition and lower frequency of the ITF during the active state. Furthermore, the WT but not PDAPP group showed significant changes in the frontoparietal EEG power (IDF, ITF) during active over passive state. CONCLUSION: PDAPP mice were characterized by less changes in the brain arousal during an active state as revealed by frontoparietal EEG rhythms. Future studies will have to cross-validate the present results on large animal groups, clarify the neurophysiological underpinning of the effect, and test if the disease modifying drugs against AD amyloidosis normalize those candiate EEG biomarkers in PDAPP mice.

Human Genomic Signatures of Brain Oscillations During Memory Encoding.

Memory encoding is an essential step for all learning. However, the genetic and molecular mechanisms underlying human memory encoding remain poorly understood, and how this molecular framework permits the emergence of specific patterns of brain oscillations observed during mnemonic processing is unknown. Here, we directly compare intracranial electroencephalography recordings from the neocortex in individuals performing an episodic memory task with human gene expression from the same areas. We identify genes correlated with oscillatory memory effects across 6 frequency bands. These genes are enriched for autism-related genes and have preferential expression in neurons, in particular genes encoding synaptic proteins and ion channels, supporting the idea that the genes regulating voltage gradients are involved in the modulation of oscillatory patterns during successful memory encoding across brain areas. Memory-related genes are distinct from those correlated with other forms of cognitive processing and resting state fMRI. These data are the first to identify correlations between gene expression and active human brain states as well as provide a molecular window into memory encoding oscillations in the human brain.

Genetic resistance to kindling associated with alterations in circuit function.

How a seizure spreads from a focal onset zone to other regions of the brain is not well understood, and animal studies suggest that there is a genetic influence. To understand how genetic factors may influence seizure spread, we examined whether the kindling resistance of WAG/Rij rats, which are slow to develop kindled motor seizures, is independent of the site of seizure induction and thus a global phenomenon, or whether it is circuit specific. We compared the kindling rates (number of stimulations to induce kindled motor seizures) of WAG/Rij rats to the rates of kindling in Sprague Dawley rats. Both groups underwent a standard hippocampal kindling protocol and a separate group was kindled from the medial dorsal nucleus of the thalamus, a site that has been previously demonstrated to result in the very rapid development of motor seizures. To examine whether there were differences in the interaction in a circuit involved with the motor seizures, evoked responses were obtained from the prefrontal cortex following stimulation of the subiculum or medial dorsal thalamic nucleus. The WAG/Rij rats once again demonstrated resistance to kindling in the hippocampus, but both strains kindled rapidly from the medial dorsal nucleus. In the WAG/Rij rats there was also a reduction in the duration of the afterdischarge in the frontal cortex during hippocampal stimulation, but there was no reduction during thalamic kindling. The prefrontal cortex evoked responses were reduced following stimulation of the subiculum in the WAG/Rij rats, but the evoked responses to thalamic stimulation were the same in both strains. These findings suggest that there are genetic influences in the strength of the input from the subiculum to the prefrontal cortex in WAG/Rij rats that could explain the resistance to limbic kindling because of reduced excitatory drive onto a key target region.

Precuneus Failures in Subjects of the PSEN1 E280A Family at Risk of Developing Alzheimer's Disease Detected Using Quantitative Electroencephalography.

BACKGROUND: Presenilin-1 (PSEN1) mutations are the most common cause of familial early onset Alzheimer's disease (AD). The PSEN1 E280A (E280A) mutation has an autosomal dominant inheritance and is involved in the production of amyloid-ß. The largest family group of carriers with E280A mutation is found in Antioquia, Colombia. The study of mutation carriers provides a unique opportunity to identify brain changes in stages previous to AD. Electroencephalography (EEG) is a low cost and minimally invasiveness technique that enables the following of brain changes in AD. OBJECTIVE: To examine how previous reported differences in EEG for Theta and Alpha-2 rhythms in E280A subjects are related to specific regions in cortex and could be tracked across different ages. METHODS: EEG signals were acquired during resting state from non-carriers and carriers, asymptomatic and symptomatic subjects from E280A kindred from Antioquia, Colombia. Independent component analysis (ICA) and inverse solution methods were used to locate brain regions related to differences in Theta and Alpha-2 bands. RESULTS: ICA identified two components, mainly related to the Precuneus, where the differences in Theta and Alpha-2 exist simultaneously at asymptomatic and symptomatic stages. When the ratio between Theta and Alpha-2 is used, significant correlations exist with age and a composite cognitive scale. CONCLUSION: Theta and Alpha-2 rhythms are altered in E280A subjects. The alterations are possible to track at Precuneus regions using EEG, ICA, and inverse solution methods.

A novel device for continuous long-term electroencephalogram recording and drug administration in mice with a nice, powerful and sophisticated wired system.

BACKGROUND: To elucidate mechanisms of epileptogenesis and epileptic maturation, and to develop new AEDs, it is indispensable to administer various drugs and to examine their effects on EEG over a long period of observation. NEW METHOD: We constructed a device for the continuous measurement of electroencephalography (EEG) and the infusion of anti-epileptic drugs over a prolonged period of time in moving mice. The system includes a slip ring and a swivel to prevent twisting of the recording cable and infusion tube, respectively. We introduced three arms, ball bearing, and stabilizing frame to rotate the slip ring and swivel with only a small applied force, and to facilitate the start of rotation of the slip ring and the swivel. RESULTS: Continuous EEG recording was successfully performed for up to 63 days in 99 mice, for a total of 1872 days of EEG data. Continuous drug infusion with continuous EEG recording was successfully performed for up to 22 days. COMPARISON WITH EXISTING METHOD(S): Our system is superior to current system in continuous drug delivery during long-term EEG recording in moving mouse. CONCLUSIONS: Our device will be quite useful for long-term EEG recording and drug application in moving mice.

A Deletion Variant of the α2b-Adrenoceptor Modulates the Stress-Induced Shift from "Cognitive" to "Habit" Memory.

Stress induces a shift from hippocampus-based "cognitive" toward dorsal striatum-based "habitual" learning and memory. This shift is thought to have important implications for stress-related psychopathologies, including post-traumatic stress disorder (PTSD). However, there is large individual variability in the stress-induced bias toward habit memory, and the factors underlying this variability are completely unknown. Here we hypothesized that a functional deletion variant of the gene encoding the α2b-adrenoceptor (ADRA2B), which has been linked to emotional memory processes and increased PTSD risk, modulates the stress-induced shift from cognitive toward habit memory. In two independent experimental studies, healthy humans were genotyped for the ADRA2B deletion variant. After a stress or control manipulation, participants completed a dual-solution learning task while electroencephalographic (Study I) or fMRI measurements (Study II) were taken. Carriers compared with noncarriers of the ADRA2B deletion variant exhibited a significantly reduced bias toward habit memory after stress. fMRI results indicated that, whereas noncarriers of the ADRA2B deletion variant showed increased functional connectivity between amygdala and putamen after stress, this increase in connectivity was absent in carriers of the deletion variant, who instead showed overall enhanced connectivity between amygdala and entorhinal cortex. Our results indicate that a common genetic variation of the noradrenergic system modulates the impact of stress on the balance between cognitive and habitual memory systems, most likely via altered amygdala orchestration of these systems.SIGNIFICANCE STATEMENT Stressful events have a powerful effect on human learning and memory. Specifically, accumulating evidence suggests that stress favors more rigid dorsal striatum-dependent habit memory, at the expense of flexible hippocampus-dependent cognitive memory. Although this shift may have important implications for understanding mental disorders, such as post-traumatic stress disorder, little is known about the source of individual differences in the sensitivity for the stress-induced bias toward habit memory. We report here that a common genetic variation of the noradrenergic system, a known risk factor for post-traumatic stress disorder, modulates the stress-induced shift from cognitive to habit memory, most likely through altered crosstalk between the hippocampus and dorsal striatum with the amygdala, a key structure in emotional memory.

Fast sleep spindle reduction in schizophrenia and healthy first-degree relatives: association with impaired cognitive function and potential intermediate phenotype.

Several studies in patients with schizophrenia reported a marked reduction in sleep spindle activity. To investigate whether the reduction may be linked to genetic risk of the illness, we analysed sleep spindle activity in healthy volunteers, patients with schizophrenia and first-degree relatives, who share an enriched set of schizophrenia susceptibility genes. We further investigated the correlation of spindle activity with cognitive function in first-degree relatives and whether spindle abnormalities affect both fast (12-15 Hz) and slow (9-12 Hz) sleep spindles. We investigated fast and slow sleep spindle activity during non-rapid eye movement sleep in a total of 47 subjects comprising 17 patients with schizophrenia, 13 healthy first-degree relatives and 17 healthy volunteers. Groups were balanced for age, gender, years of education and estimated verbal IQ. A subsample of relatives received additional testing for memory performance. Compared to healthy volunteers, fast spindle density was reduced in patients with schizophrenia and healthy first-degree relatives following a pattern consistent with an assumed genetic load for schizophrenia. The deficit in spindle density was specific to fast spindles and was associated with decreased memory performance. Our findings indicate familial occurrence of this phenotype and thus support the hypothesis that deficient spindle activity relates to genetic liability for schizophrenia. Furthermore, spindle reductions predict impaired cognitive function and are specific to fast spindles. This physiological marker should be further investigated as an intermediate phenotype of schizophrenia. It could also constitute a target for drug development, especially with regard to cognitive dysfunction.

Development and genetics of brain temporal stability related to attention problems in adolescent twins.

The brain continuously develops and reorganizes to support an expanding repertoire of behaviors and increasingly complex cognition. These processes may, however, also result in the appearance or disappearance of specific neurodevelopmental disorders such as attention problems. To investigate whether brain activity changed during adolescence, how genetics shape this change, and how these changes were related to attention problems, we measured EEG activity in 759 twins and siblings, assessed longitudinally in four waves (12, 14, 16, and 18years of age). Attention problems were assessed with the SWAN at waves 12, 14, and 16. To characterize functional brain development, we used a measure of temporal stability (TS) of brain oscillations over the recording time of 5min reflecting the tendency of a brain to maintain the same oscillatory state for longer or shorter periods. Increased TS may reflect the brain's tendency to maintain stability, achieve focused attention, and thus reduce "mind wandering" and attention problems. The results indicate that brain TS is increased across the scalp from 12 to 18. TS showed large individual differences that were heritable. Change in TS (alpha oscillations) was heritable between 12 and 14 and between 14 and 16 for the frontal brain areas. Absolute levels of brain TS at each wave were positively correlated with attention problems but not significantly. High and low attention problems subjects showed different developmental trajectories in TS, which was significant in a cluster of frontal leads. These results indicate that trajectories in brain TS development are a biomarker for the developing brain. TS in brain oscillations is highly heritable, and age-related change in TS is also heritable in selected brain areas. These results suggest that high and low attention problems subjects are at different stages of brain development.

Variation at NRG1 genotype related to modulation of small-world properties of the functional cortical network.

Functional brain networks possess significant small-world (SW) properties. Genetic variation relevant to both inhibitory and excitatory transmission may contribute to modulate these properties. In healthy controls, genotypic variation in Neuregulin 1 (NRG1) related to the risk of psychosis (risk alleles) would contribute to functional SW modulation of the cortical network. Electroencephalographic activity during an odd-ball task was recorded in 144 healthy controls. Then, small-worldness (SWn) was calculated in five frequency bands (i.e., theta, alpha, beta1, beta2 and gamma) for baseline (from -300 to the stimulus onset) and response (150-450 ms post-target stimulus) windows. The SWn modulation was defined as the difference in SWn between both windows. Association between SWn modulation and carrying the risk allele for three single nucleotide polymorphisms (SNP) of NRG1 (i.e., rs6468119, rs6994992 and rs7005606) was assessed. A significant association between three SNPs of NRG1 and the SWn modulation was found, specifically: NRG1 rs6468119 in alpha and beta1 bands; NRG1 rs6994992 in theta band; and NRG1 rs7005606 in theta and beta1 bands. Genetic variation at NRG1 may influence functional brain connectivity through the modulation of SWn properties of the cortical network.