Validating γ Oscillations and Delayed Auditory Responses as Translational Biomarkers of Autism

Gandal, Michael J.; Edgar, J. Christopher; Ehrlichman, Richard S.; Mehta, Mili; Roberts, Timothy P.L.; Siegel, Steven J.

doi:10.1016/j.biopsych.2010.09.031

Cited by 282 publications

(356 citation statements)

References 63 publications

(77 reference statements)

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“…Rojas, Maharajh, Teale & Rogers, 2008) whereas other studies have found no difference in evoked (Gandal et al 2010;Wright et al 2012) or induced gamma power (Gandal et al 2010). Here, we found no significant difference in either evoked or induced peak gamma power between the participants with and without ASC.…”

Section: Differences (See Dickinson Et Al 2014 For a Full Discussion)contrasting

confidence: 87%

Superior orientation discrimination and increased peak gamma frequency in autism spectrum conditions.

Dickinson¹,

Bruyns‐Haylett²,

Smith³

et al. 2016

Journal of Abnormal Psychology

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While perception is recognised as being atypical in individuals with autism spectrum conditions (ASC), the underlying mechanisms for such atypicality are unclear. Here we test the hypothesis that individuals with ASC will show enhanced orientation discrimination compared to neurotypical observers. This prediction is based both on anecdotal report of superior discriminatory skills in ASC and also on evidence in the auditory domain that some individuals with ASC have superior pitch discrimination. In order to establish whether atypical perception might be mediated by an imbalance in the ratio of neural excitation and inhibition (E:I ratio) we also measured peak gamma frequency which provides an indication of neural inhibition levels. Using a rigorous thresholding method we found that orientation discrimination thresholds for obliquely oriented stimuli were significantly lower in participants with ASC. Using EEG to measure the visually induced gamma band response we also found that peak gamma frequency was higher in participants with ASC, relative to a well-matched control group. These novel results suggest that neural inhibition may be increased in the occipital cortex of individuals with ASC. Implications for existing theories of an imbalance in the E:I ratio of ASC are discussed.

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Section: Differences (See Dickinson Et Al 2014 For a Full Discussion)contrasting

confidence: 87%

Superior orientation discrimination and increased peak gamma frequency in autism spectrum conditions.

Dickinson¹,

Bruyns‐Haylett²,

Smith³

et al. 2016

Journal of Abnormal Psychology

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“…In particular, auditory-evoked high γ-activity correlated with both PPI and auditory S2/S1 ratio. Recent intracerebral recordings in humans have also associated hippocampal γ-activity with working memory capacity, and working memory is a behavior disrupted in the Dys1 −/− mouse (33,47,48,69). Thus, by extension, our findings suggest that γ-abnormalities may be associated with the working memory deficits found in the Dys1 −/− mouse.…”

Section: Role Of Disrupted Fast-phasic Inhibition In Reduced γ-Powersupporting

confidence: 73%

“…Abnormalities in auditory-evoked γ-oscillatory activity have been observed in schizophrenia as well as other neuropsychiatric disorders such as autism (3,7,10,(46)(47)(48). To test for disruptions in oscillatory activity during the evoked response in the Dys1 −/− mice, EEG trials were wavelet-transformed to extract instantaneous power and phase over all frequencies from θ to γ (4-100 Hz) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

Carlson

Talbot²,

Halene³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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DTNBP1 (dystrobrevin binding protein 1) is a leading candidate susceptibility gene in schizophrenia and is associated with working memory capacity in normal subjects. In schizophrenia, the encoded protein dystrobrevin-binding protein 1 (dysbindin-1) is often reduced in excitatory cortical limbic synapses. We found that reduced dysbindin-1 in mice yielded deficits in auditory-evoked response adaptation, prepulse inhibition of startle, and evoked γ-activity, similar to patterns in schizophrenia. In contrast to the role of dysbindin-1 in glutamatergic transmission, γ-band abnormalities in schizophrenia are most often attributed to disrupted inhibition and reductions in parvalbumin-positive interneuron (PV cell) activity. To determine the mechanism underlying electrophysiological deficits related to reduced dysbindin-1 and the potential role of PV cells, we examined PV cell immunoreactivity and measured changes in net circuit activity using voltage-sensitive dye imaging. The dominant circuit impact of reduced dysbindin-1 was impaired inhibition, and PV cell immunoreactivity was reduced. Thus, this model provides a link between a validated candidate gene and an auditory endophenotypes. Furthermore, these data implicate reduced fast-phasic inhibition as a common underlying mechanism of schizophrenia-associated intermediate phenotypes.GABAergic | γ-oscillation | hippocampus | evoked response spectral perturbation | Sandy mouse P atients with schizophrenia have reduced amplitude and gating of auditory event-related potentials (ERPs) (1, 2). Recent clinical studies also show abnormal γ-band oscillations (30-100 Hz) as an endophenotype of the illness that is associated with reduced cognitive function (3-7). Work in animal models shows a prominent role of cortical inhibitory networks in generating γ-oscillations (8, 9), which in turn, supports the role of aberrant GABAergic inhibition as an important potential component of schizophrenia (4,7,10,11). The GABA-producing enzyme glutamic acid decarboxylase is dysregulated in schizophrenia, and postsynaptic GABA A receptors are dysregulated as well (4). Risk alleles for GABA A receptor subunits are also associated with the disease (12, 13), although linkage is weaker than the linkage found with dysbindin-1 and other candidate genes such as DISC1 (14). At the anatomical level, there is a loss of immunoreactivity for parvalbumin (PV) in schizophrenia. PV is a calcium-binding protein marker for a class of fast-spiking GABAergic neurons. It is debated whether reduced PV in postmortem studies is caused by reduction in cell number or merely loss of protein expression. In either case, reduced PV immunoreactivity suggests disruption of an important source of local circuit inhibition (4, 15).Although clinical electrophysiological and postmortem anatomical findings support the role of GABA dysfunction in schizophrenia, a larger set of schizophrenia risk haplotypes are thought to confer reduced NMDA receptor-mediated function and changes in glutamatergic transmission [e.g., DISC1; Neuregu...

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“…Gogolla et al (2009) reported a loss of parvalbumin-staining neurons in parts of adult VPA mouse neocortex, with the deficiency confined to a single hemisphere. Gandal et al (2010), also using adult VPA mice, reported a reduction of phase locking in the ␥ band (30 -50 Hz) of the auditory evoked signal. Fast-spiking interneurons contain parvalbumin and are believed to be critical for the generation of ␥ oscillations (Cardin et al, 2009;Sohal et al, 2009).…”

Section: Valproate Teratogenicitymentioning

confidence: 89%

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

Walcott¹,

Higgins²,

Desai³

2011

J. Neurosci.

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Valproic acid (VPA) is among the most teratogenic of commonly prescribed anticonvulsants, increasing the risk in humans of major malformations and impaired cognitive development. Likewise, rats exposed prenatally to VPA exhibit a variety of neuroanatomical and behavioral abnormalities. Previous work has shown that pyramidal neuron physiology in young VPA-exposed animals is marked by two strong abnormalities: an impairment in intrinsic neuronal excitability and an increase in NMDA synaptic currents. In this study, we investigated these abnormalities across postnatal development using whole-cell patch recordings from layer 2/3 neurons of medial prefrontal cortex. We found that both abnormalities were at a peak soon after birth but were gradually corrected as animals matured, to the extent that normal excitability and NMDA currents had been restored by early adolescence. The manner in which this correction happened suggested coordination between the two processes. Using computational models fitted to the physiological data, we argue that the two abnormalities trade off against each other, with the effects on network activity of the one balancing the effects of the other. This may constitute part of the nervous system's homeostatic response to teratogenic insult: an attempt to maintain stability despite a strong challenge.

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Validating γ Oscillations and Delayed Auditory Responses as Translational Biomarkers of Autism

Cited by 282 publications

References 63 publications

Superior orientation discrimination and increased peak gamma frequency in autism spectrum conditions.

Superior orientation discrimination and increased peak gamma frequency in autism spectrum conditions.

Dysbindin-1 mutant mice implicate reduced fast-phasic inhibition as a final common disease mechanism in schizophrenia

Synaptic and Intrinsic Balancing during Postnatal Development in Rat Pups Exposed to Valproic Acidin Utero

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