Somatostatin Interneurons Control a Key Component of Mismatch Negativity in Mouse Visual Cortex

Abstract

Summary Patients with schizophrenia have deficient sensory processing, undermining how they perceive and relate to a changing environment. This impairment can be captured by the reduced “mismatch negativity” index (MMN), an electroencephalographic biomarker of psychosis. The biological factors contributing to MMN are unclear, though mouse research, where genetic and optical methods could be applied, has given some insight. Using fast two-photon calcium imaging and multielectrode recordings in awake mice, we find that visual cortical circuits display i) adapted (decreased) responses to repeated stimuli and ii) amplified responses to a deviant stimulus, the key component of human MMN. Moreover, pharmacogenetic silencing of somatostatin-containing interneurons specifically eliminated this amplification along with its associated theta/alpha band response, leaving stimulus specific adaption and related gamma-band modulations intact. Our results validate a mouse model of MMN and suggest that abnormalities in somatostatin-containing interneurons cause sensory deficits underlying MMN and schizophrenia.

Altered Cortical Ensembles in Mouse Models of Schizophrenia

“…We focused on oscillatory activity at baseline and during the presentation of full field grating stimuli. Frequency and time-frequency spectra were first segregated with principal components analysis into 5 bins (Hamm and Yuste, 2016; Hamm et al, 2014) which conformed well to established neocortical frequency bands (Buzsaki, 2009): low/theta/alpha (1–14Hz), Beta (15–35Hz) Gamma1 (36–58Hz), Gamma2 (62–110Hz), and High (>111Hz).…”

“…Moreover, visual processing abnormalities in particular are robustly reported in patients (Spencer et al, 2004; Uhlhaas and Singer, 2010) and visual perceptual disturbances are actually more common than auditory sequelae in first episode patients and prodromal individuals (Javitt, 2009). Given recent progress in understanding functional properties (Niell and Stryker, 2008) and SZ biomarkers in mouse visual cortex (Hamm and Yuste, 2016), we reasoned this cortical area, which can be rigorously studied given its sensory accessibility, could provide potent translational inroads to understanding local cortical circuit dysfunction.…”

Stimulus-specific adaptation in a recurrent network model of primary auditory cortex

“…in the way spatial adaptation in V1 appears to arise from integration of LGN responses [65] and motion adaptation in MT can be explained by broadly-tuned adaptation of their input V1 neurons [66,67]. Recently, true deviance sensitivity has been demonstrated in visual cortex using both extracellular recordings and calcium imaging, but the difference between deviant and many-standards responses occurs late [68]. This difference may challenge the purely feedforward explanation of adaptation in visual cortex, even if only indicating a late top-down modulation.…”

Somatostatin-Positive Gamma-Aminobutyric Acid Interneuron Deficits in Depression: Cortical Microcircuit and Therapeutic Perspectives

“…In contrast to these findings, L4 SST interneuron silencing decreased local PN activity due to SST-PV connections (68), suggesting that regulation of neuronal output may be layer-dependent. Increased PN burst firing from SST interneuron silencing was also demonstrated in hippocampal CA1 (110) and cortical V1 (111). …”