Familiarity with stimuli that bring neither reward nor punishment, manifested through behavioural habituation, enables organisms to detect novelty and devote cognition to important elements of the environment. Here we describe in mice a form of long-term behavioural habituation to visual grating stimuli that is selective for stimulus orientation. Orientation-selective habituation (OSH) can be observed both in exploratory behaviour in an open arena, and in a stereotyped motor response to visual stimuli in head-restrained mice. We show that the latter behavioural response, termed a vidget, requires V1. Parallel electrophysiological recordings in V1 reveal that plasticity, in the form of stimulus-selective response potentiation (SRP), occurs in layer 4 of V1 as OSH develops. Local manipulations of V1 that prevent and reverse electrophysiological modifications likewise prevent and reverse memory demonstrated behaviourally. These findings suggest that a form of long-term visual recognition memory is stored via synaptic plasticity in primary sensory cortex.

The roles played by cortical inhibitory neurons in experience-dependent plasticity are not well understood. Here we evaluate the participation of parvalbumin-expressing (PV+) GABAergic neurons in two forms of experience-dependent modification of primary visual cortex (V1) in adult mice: ocular dominance (OD) plasticity resulting from monocular deprivation and stimulus-selective response potentiation (SRP) resulting from enriched visual experience. These two forms of plasticity are triggered by different events but lead to a similar increase in visual cortical response. Both also require the NMDA class of glutamate receptor (NMDAR). However, we find that PV+ inhibitory neurons in V1 play a critical role in the expression of SRP and its behavioral correlate of familiarity recognition, but not in the expression of OD plasticity. Furthermore, NMDARs expressed within PV+ cells, reversibly inhibited by the psychotomimetic drug ketamine, play a critical role in SRP, but not in the induction or expression of adult OD plasticity.DOI: http://dx.doi.org/10.7554/eLife.11450.001

d-Serine is a co-agonist of NMDA receptors (NMDARs) whose activity is potentially regulated by Asc-1 (SLC7A10), a transporter that displays high affinity for d-serine and glycine. Asc-1 operates as a facilitative transporter and as an antiporter, though the preferred direction of d-serine transport is uncertain. We developed a selective Asc-1 blocker, Lu AE00527, that blocks d-serine release mediated by all the transport modes of Asc-1 in primary cultures and neocortical slices. Furthermore, d-serine release is reduced in slices from Asc-1 knockout (KO) mice, indicating that d-serine efflux is the preferred direction of Asc-1. The selectivity of Lu AE00527 is assured by the lack of effect on slices from Asc-1-KO mice, and the lack of interaction with the co-agonist site of NMDARs. Moreover, in vivo injection of Lu AE00527 in P-glycoprotein-deficient mice recapitulates a hyperekplexia-like phenotype similar to that in Asc-1-KO mice. In slices, Lu AE00527 decreases the long-term potentiation at the Schaffer collateral-CA1 synapses, but does not affect the long-term depression. Lu AE00527 blocks NMDAR synaptic potentials when typical Asc-1 extracellular substrates are present, but it does not affect AMPAR transmission. Our data demonstrate that Asc-1 mediates tonic co-agonist release, which is required for optimal NMDAR activation and synaptic plasticity.