Chronic reduction in inhibition reduces receptive field size in mouse auditory cortex

Abstract

Inhibitory interneurons regulate the responses of cortical circuits. In auditory cortical areas, inhibition from these neurons narrows spectral tuning and shapes response dynamics. Acute disruptions of inhibition expand spectral receptive fields. However, the effects of long-term perturbations of inhibitory circuitry on auditory cortical responses are unknown. We ablated ~30% of dendrite-targeting cortical inhibitory interneurons after the critical period by studying mice with a conditional deletion of Dlx1. Following the loss of interneurons, baseline firing rates rose and tone-evoked responses became less sparse in auditory cortex. However, contrary to acute blockades of inhibition, the sizes of spectral receptive fields were reduced, demonstrating both higher thresholds and narrower bandwidths. Furthermore, long-latency responses at the edge of the receptive field were absent. On the basis of changes in response dynamics, the mechanism for the reduction in receptive field size appears to be a compensatory loss of cortico-cortically (CC) driven responses. Our findings suggest chronic conditions that feature changes in inhibitory circuitry are not likely to be well modeled by acute network manipulations, and compensation may be a critical component of chronic neuronal conditions.

Fig. 1.

Dendrite-targeting interneurons are reduced in cKO mutants. (A) Sections of auditory cortex from control and cKO mice labeled for various interneuron markers (from left to right, top to bottom: parvalbumin, somatostatin, neuropeptide Y, calretinin, vasoactive intestinal peptide). (B) Cell count in control and cKO mice: PV⁺ (P > 0.05, n = 3 animals), SOM⁺, NPY⁺, CR⁺, and VIP⁺ interneurons (P < 0.05, n = 3 animals for each).

Fig. 2.

Cortical spectral tuning area is reduced in cKO mutants. (A and B) the population mean FRAs aligned by CF for auditory cortical units. (C) Difference, cKO − control. (D) Difference with units aligned by threshold. (E–G) Size of responsive area of cortical units (P < 0.01, P < 0.001, and P < 0.05; n = 54 CT and 58 cKO). (H) Size of responsive area of thalamic units (P > 0.05; n = 30 CT and 61 cKO).

Fig. 3.

Long latency responses are absent near threshold in cKO mice. (A and B) Population mean PSTH near CF at various intensities for auditory cortical units. (C) Difference, cKO − control. (D) Baseline firing rates (50 ms preceding the stimulus; medians: CT 1.11 and cKO 2.38, P < 0.005). (E and F) Population mean PSTH at high (60–80 dB) and low intensities (threshold ±10 dB) near CF (±0.2 octaves, dotted lines are ± SEM). Black brackets, area with five or more consecutive samples with rank sum P < 0.05. Gray bar, stimulus. (G) Onset latency per unit at high and low intensities (*P < 0.05, **P < 0.01, all Bonferonni corrected, n = 54 control and 58 cKO).

Fig. 4.

Early and late responses are similar in cKO but not in control mice. (A and B) Onset FRA (A) and termination FRA (B) from a control unit (correlation = −0.37). White lines, size of the entire response FRA. (C) PSTH of the unit in A and B. Light gray bars, early and late response windows, respectively. Dark gray bar, stimulus. (D) Correlations of early and late responses (medians: CT = −0.05 and cKO = 0.05, P < 0.005, n = 54 and 58).

Fig. 5.

Cortical responses of cKO mice are less sparse. (A) Mean RLFs for single cortical units (dotted lines, ±SEM). (B) Response magnitude of single units for 80-dB stimuli (P = 0.37, n = 54 control and 58 cKO). (C) Mean RLFs for cortical multiunits (dotted lines, ±SEM). (D) Response magnitude of multiunits for 80-dB stimuli (P < 0.001, n = 88 control and 96 cKO).