Auditory evoked gamma synchrony: Validating translational biomarkers for schizophrenia and autism
Schizophrenia and autism are highly disabling neurodevelopmental, neuropsychiatric illnesses with a combined population prevalence of 2-4%. Diagnosis is made according to a constellation of behavioral symptoms, without the aid of validated biological markers, despite the fact that genetics contribute strongly to the etiology of both disorders. Current therapeutic options are limited and lack efficacy for the most disabling symptoms. Across both disorders, treatment-refractory symptoms include impairments in reciprocal social interactions, deficits in social communication, and cognitive dysfunction. ^ A major obstacle for the development of interventions that target core symptoms is the difficulty assessing such complex human behavioral phenotypes (e.g., language) in preclinical settings. An emerging strategy has been to identify intermediate “endophenotypes”, quantitative neural measures reflecting disease heritability that are likely more closely related to underlying brain abnormalities than behavioral symptoms alone. For example, recent work has demonstrated significant deficits in the neural correlates of auditory processing in subjects with schizophrenia and autism as well as in their first-degree unaffected relatives, to a lesser degree. In particular, both diseases are characterized by abnormalities in the generation of gamma-frequency (30-80 Hz) brain oscillations in response to auditory tones, neural synchrony that is integral for cortical information processing and sensory perception. Although not considered diagnostic features of either disorder, such abnormalities are thought to contribute to (or reflect) higher-order behavioral deficits and, importantly, can be directly investigated in preclinical settings. ^ This work sought to validate auditory-evoked potential (AEP) abnormalities as translational biomarkers of autism and schizophrenia. AEP endophenotypes were investigated in mice exposed in utero to valproic acid (VPA), an established teratogenic model of autism, and in mice with constitutive downregulation of the NR1 subunit of the NMDA-receptor, an established transgenic model of schizophrenia. Both models demonstrated gamma-band abnormalities reflective of the clinical population. Such neural abnormalities were predictive of behavior deficits and were modulated by drugs that normalize the balance of excitatory and inhibitory signaling. Such findings provide a novel framework for preclinical pathophysiological investigation and therapeutic development for autism and schizophrenia.^
Biology, Neuroscience|Engineering, Biomedical
Michael Jeffrey Gandal,
"Auditory evoked gamma synchrony: Validating translational biomarkers for schizophrenia and autism"
(January 1, 2011).
Dissertations available from ProQuest.