Protocadherin 10 alters γ oscillations, amino acid levels, and their coupling; baclofen partially restores these oscillatory deficits.

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TitleProtocadherin 10 alters γ oscillations, amino acid levels, and their coupling; baclofen partially restores these oscillatory deficits.
Publication TypeJournal Article
Year of Publication2017
AuthorsPort, RG, Gajewski, C, Krizman, E, Dow, HC, Hirano, S, Brodkin, ES, Carlson, GC, Robinson, MB, Roberts, TPL, Siegel, SJ
JournalNeurobiol Dis
Date Published2017 Dec
KeywordsAcoustic Stimulation, Animals, Auditory Perception, Autism Spectrum Disorder, Baclofen, Cadherins, Chromatography, High Pressure Liquid, Electrocorticography, Electrodes, Implanted, Evoked Potentials, Female, GABA-B Receptor Agonists, Gamma Rhythm, gamma-Aminobutyric Acid, Glutamine, Male, Mice, Transgenic, Sex Characteristics, Theta Rhythm

Approximately one in 45 children have been diagnosed with Autism Spectrum Disorder (ASD), which is characterized by social/communication impairments. Recent studies have linked a subset of familial ASD to mutations in the Protocadherin 10 (Pcdh10) gene. Additionally, Pcdh10's expression pattern, as well as its known role within protein networks, implicates the gene in ASD. Subsequently, the neurobiology of mice heterozygous for Pcdh10 (Pcdh10) has been investigated as a proxy for ASD. Male Pcdh10 mice have demonstrated sex-specific deficits in social behavior, recapitulating the gender bias observed in ASD. Furthermore, in vitro slice preparations of these Pcdh10 mice demonstrate selective decreases to high frequency electrophysiological responses, mimicking clinical observations. The direct in vivo ramifications of such decreased in vitro high frequency responses are unclear. As such, Pcdh10 mice and their wild-type (WT) littermates underwent in vivo electrocorticography (ECoG), as well as ex vivo amino acid concentration quantification using High Performance Liquid Chromatography (HPLC). Similar to the previously observed reductions to in vitro high frequency electrophysiological responses in Pcdh10 mice, male Pcdh10 mice exhibited reduced gamma-band (30-80Hz), but not lower frequency (10 and 20Hz), auditory steady state responses (ASSR). In addition, male Pcdh10 mice exhibited decreased signal-to-noise-ratio (SNR) for high gamma-band (60-100Hz) activity. These gamma-band perturbations for both ASSR and SNR were not observed in females. Administration of a GABA agonist remediated these electrophysiological alterations among male Pcdh10mice. Pcdh10 mice demonstrated increased concentrations of GABA and glutamine. Of note, a correlation of auditory gamma-band responses with underlying GABA concentrations was observed in WT mice. This correlation was not present in Pcdh10 mice. This study demonstrates the role of Pcdh10 in the regulation of excitatory-inhibitory balance as a function of GABA in ASD.

Alternate JournalNeurobiol. Dis.
PubMed ID28844789
Grant ListU54 HD086984 / HD / NICHD NIH HHS / United States