A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex

Abstract

Early sensory experience instructs the maturation of neural circuitry in the cortex. This has been studied extensively in the primary visual cortex, in which loss of vision to one eye permanently degrades cortical responsiveness to that eye, a phenomenon known as ocular dominance plasticity (ODP). Cortical inhibition mediates this process, but the precise role of specific classes of inhibitory neurons in ODP is controversial. Here we report that evoked firing rates of binocular excitatory neurons in the primary visual cortex immediately drop by half when vision is restricted to one eye, but gradually return to normal over the following twenty-four hours, despite the fact that vision remains restricted to one eye. This restoration of binocular-like excitatory firing rates after monocular deprivation results from a rapid, although transient, reduction in the firing rates of fast-spiking, parvalbumin-positive (PV) interneurons, which in turn can be attributed to a decrease in local excitatory circuit input onto PV interneurons. This reduction in PV-cell-evoked responses after monocular lid suture is restricted to the critical period for ODP and appears to be necessary for subsequent shifts in excitatory ODP. Pharmacologically enhancing inhibition at the time of sight deprivation blocks ODP and, conversely, pharmacogenetic reduction of PV cell firing rates can extend the critical period for ODP. These findings define the microcircuit changes initiating competitive plasticity during critical periods of cortical development. Moreover, they show that the restoration of evoked firing rates of layer 2/3 pyramidal neurons by PV-specific disinhibition is a key step in the progression of ODP.

Figure 1. L2/3 pyramidal neuron responsiveness and local circuit organization is unchanged 1d after MD

a-c, Responses of pyramidal (PYR) neurons to drifting gratings in alert mice. a, Cartoon of head-fixed configuration. b, Example loose-cell attached recordings from controls (black) and after 1d MD (red) in response to visual stimulation (gray shading). Scale: 1mV, 500 ms. c, Mean firing rate at optimal orientation (Bi 10 mice, n= 30 cells; Ipsi control 7 mice, n= 22 cells; Ipsi MD 6 mice, n= 33 cells; Contra control 3 mice, n= 9 cells; Contra MD 3 mice, n= 10 cells). d, PYR neuron recorded in binocular V1 in an acute slice; overlaid are 16 ×16 LSPS stimulation locations spanning pia to white matter. e, In vitro LSPS aggregate excitatory input maps pooled across PYR neurons, triangles indicate soma location (Control 4 mice, n= 9 cells; MD 4 mice, n= 9 cells). Scale: 200 μm. f, Mean LSPS-evoked EPSC amplitude, same cells as e. *P<0.05.

Figure 2. L2/3 PV responsiveness to visual stimuli is reduced after 1d MD

a, Cartoon of targeted recording in alert mice (left). Two-photon excitation (red beam) is used to visualize PV cells expressing tdTomato and recording pipette filled with Alexa dye (inset, 6 red PV cells, the pipette, green, is loose cell-attached to the PV cell in the center of the image; scale: 20 μm). Spike waveform is used to verify targeting of fast-spiking PV cells (black trace; gray trace is a PYR neuron waveform for comparison, scale: 0.5 mV, 1 ms). Bottom, example PV response to visual stimulation (gray shading, scale: 1mV, 500 ms). b, Example PV responses evoked by stimulation through either eye in control (black) and 1d MD (blue) anesthetized mice. Scale bar: 1mV, 500 ms. c, Mean firing rate at optimal orientation (Ipsi control 14 mice, n= 26 cells; Ipsi MD 5 mice, n= 18 cells; Contra control 14 mice, n= 26 cells; Contra MD 5 mice, n= 18 cells). ** P<0.005

Figure 3. L2/3 PV local circuit organization is altered after 1d MD

a, In vitro LSPS aggregate excitatory input maps pooled across PV cells, circles indicate soma location (Control 4 mice, n= 7 cells; MD 4 mice, n= 7 cells). Scale: 200 μm. b, Mean laminar LSPS-evoked EPSC amplitude, same cells as a. **P<0.007. c, Example sEPSCs, scale: 20 pA, 100 ms. d, Mean sEPSC frequencies, same cells as a. *P<0.05 e, Mean sEPSC amplitude, same cells as a.

Figure 4. Reducing PV-specific inhibition restores ocular dominance plasticity after the closure of the critical period

a, In vivo image of GCaMP6 expression, cells outlined in yellow, scale: 20μm. Right, individual cell images (1-4) of the average evoked fluorescence in response to visual stimuli presented independently to the contralateral and ipsilateral eye, before (Pre) and 3 days after MD in a mouse expressing the hM4D DREADD receptor specifically in PV cells, treated with CNO; scale: 5 μm. b, Relative change in fluorescence before and after 3d MD + CNO for cells 1-4 in panel a in response to visual stimulation (gray shading; 5s duration). c, Log-log scatter plot of visually evoked fluorescence response for each cell (saline n= 242 cells; CNO n= 327 cells). Note the significant leftward shift after 3d MD in mice treated with CNO, but not those treated with saline, indicating a reduced response to contralateral eye stimulation after 3d MD. d, Longitudinal ‘optical field potential’ response (average value of all pixels in the entire imaging field, inclusive of neuropil) for the region in panel a. Note the decrease in response to contralateral eye stimulation after MD + CNO that is not seen for the ipsilateral eye. e, Mean ‘optical field potential’ response (Saline n= 4 mice; CNO n=4 mice). * P<0.05.