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

Abstract

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 (MMN) index, an electroencephalographic biomarker of psychosis. The biological factors contributing to MMN are unclear, though mouse research, in which 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 adapted (decreased) responses to repeated stimuli and 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.

Figure 1. Circuit-level components of Mismatch Negativity are present in visual cortices of awake mice

(a) Head-fixed mice viewed square-wave gratings while running on a treadmill during (b) oddball and many-standards control of stimulus frequency. (c) 16-channel multielectrode recordings in left visual cortex reveal (d) a significant “deviant” vs “redundant” effect in the peak LFP channel with a similar timecourse to human MMN. (e) Current source density profiles with an initial large current sink occurring in putative granular layer evinced stimulus-specific adaptation (SSA) and deviance detection (DD) across all depths (averaged over orientations). (e,f) significant SSA occurred early (40-80ms) while DD occurred later (120-240ms; plots in c-f are cross animal averages. Bars reflect area under the curve (A.U.C.) for these time ranges averaged across all depths). (g, h) two-photon calcium imaging of GCaMP6 expressing cells demonstrate (h,i,j) SSA and DD in the 19% neurons significantly activated by stimuli (only response to preferred stimulus plotted/analyzed for each cell; i, averaged across 159 neurons, 0-1 sec A.U.C.). **p<.01. All error bars S.E.M.

Figure 2. Suppression of somatostatin interneurons diminishes deviance processing in LFP and CSD measurements

Grand-averaged (a) LFP and (b) CSD waveforms (across mice and 40-60 trials) in the CNO-control condition before and after CNO injection confirm the stability of (c) mismatch negativity-like potentials (deviant minus redundant, 120-240ms post-stim), (d) SSA (control-minus deviant; 40-80ms), and (e) deviance detection (deviant minus control; 120-240ms; n=4 mice; all p>.30). hM4Di mediated suppression of SOMs (f,g) disrupted LFP-MMN difference potentials. (h) In the CSD, (i) SSA was not affected, but (j) deviance detection was abolished (n=5 mice; F(4)=7.51, *p<.05; bars reflect area under the curve, averaged across all depths)). All error bars S.E.M.

Figure 3. Suppression of somatostatin interneurons reduces MMN in two-photon calcium imaging measurements

Compared to the CNO-control (above), (a,b) SOM-suppression reduced early and late deviance detection responses in individual neurons. (c,d) The proportion off all visually responsive neurons showing deviance detection, but not SSA, was reduced across thresholds. (e) This pattern held also when focusing on the top 10% of pre-treatment neurons showing the largest average responses (normalized to pre-CNO control stimulus response).

Figure 4. Somatostatin interneurons influence salience processing in low but not high frequency bands

LFP data converted to time/freq domain. (a) Log-scaled time-frequency spectra averaged across trials (<50) and 5 mice for each condition, and (b) averaged across post-stim time-points (30-450ms) show that deviant stimuli augment low-frequency induced power (relative to control) while low-gamma power is suppressed to redundant stimuli. (c-d) The former effect is absent after SOM-suppression, while the latter is not. Note that the magnitudes of control and redundant oscillatory power are nominally unchanged by SOM-suppression (scales are constant across all plots). (e-f) Low-pass filtered (4-14Hz) single trial traces show that deviant elicited low-freq enhancement lasts 1-2 cycles, is not phase locked, and is suppressed after SOM suppression (from 1 representative mouse). **p<.01. All error bars S.E.M.