Excitation-inhibition imbalance in autistic auditory cortex and its effects on spectro-temporal sound integration
Recent studies on autistic patients have accumulated rich knowledge on these diseases at both genetic and behavioral levels. However, we still know little about the neuronal circuit mechanisms that connect the gene mutations to the behavioral deficits. Researchers will study how disturbed interplay between excitatory and inhibitory neurons leads to auditory processing deficits in autistic brains. The circuit-level knowledge obtained in this study will help identifying the novel therapeutic entry points for developing future treatments.
Hiroyuki Kato, Ph.D.
Need/Problem: In social species like humans, hearing is of particular importance for vocal communication among conspecifics. In this research, we aim to understand the neuronal circuit mechanisms that lead to disturbed auditory processing in autistic brains.
Grant Summary: Using autism mouse models, we will elucidate the interplay of excitation and inhibition during sound processing in living brains, and compare their actions between healthy and autistic animals.
Goals & Projected Outcomes: Our goal is to build a circuit model that explains how abnormal operation of inhibitory neurons leads to disrupted sound processing in the ASD brains. Findings in simple mouse models would give us the first step towards the ultimate understanding of the mechanisms underlying language comprehension deficits in autistic patients.
Grant Details: Disturbed language comprehension is one of the core symptoms in autism spectrum disorders (ASD). Consistent with this symptom, ASD patients have difficulty processing spectrally and temporally complex sounds. However, little is known regarding the circuit mechanisms underlying how autistic brains fail to extract complex sound features.
One fundamental deficit in neuronal circuits shared by many ASD genotypes is the imbalance of excitation and inhibition. Excitation and inhibition are inseparable events in neuronal circuits, and their imbalance may underlie many phenotypes in ASD, including epilepsy, disrupted plasticity, and abnormal EEG. Nevertheless, since previous measurements of excitation and inhibition were limited to brain slices, how their imbalance in ASD affects the sound processing in living brains has been completely unknown. Therefore, there is still a major gap in our understanding of the mechanisms underlying language comprehension deficits in ASD patients; we already have rich knowledge at the genetic and behavioral levels, but we need to bridge them with the circuit-level investigation of auditory processing.
Here we propose to elucidate the interplay of excitation and inhibition during auditory processing in awake brains, and compare their actions between wild type and ASD model mice. We will perform in vivo whole-cell recordings in awake, head-fixed mice to directly measure excitatory and inhibitory currents triggered by sound stimuli in the auditory cortex of wild type and ASD model mice. Once we find abnormal inhibition in ASD cortical neurons, we will further investigate the source of these deficits by conducting in vivo two-photon calcium imaging experiments to measure activity selectively from genetically identified inhibitory neuron populations. Through those experiments, we aim to build a circuit model that explains how abnormal operation of inhibitory neurons leads to the disrupted extraction of complex sounds in the ASD brains.
These experiments will greatly improve our understanding of auditory information processing circuits in both healthy and diseased brains and will lead to the identification of novel therapeutic entry points for developing future treatments for social communication deficits in ASD.