Figure 7. Ketamine prevents expression of SRP through blockade of NMDA receptors expressed in parvalbumin+ neurons but does not impact expression of the adult OD shift.

(A) Mice were bilaterally implanted with VEP recording electrodes in layer 4 of binocular V1. After habituation to head-fixation and a gray screen for 2 days, SRP was induced over 4 days by repeatedly presenting sessions of an X° stimulus. On day 5, SRP expression was tested by presenting interleaved blocks of the familiar X° stimulus and a novel X + 60° stimulus. In order to test the acute impact of blocking NMDA receptors on SRP expression, 50 mg/kg of ketamine was then delivered systemically 15 min before re-acquiring VEPs elicited by the familiar X° stimulus and interleaved presentations of a second novel X - 60° stimulus. Mice were then allowed 2 days recovery and a complete washout of ketamine before re-testing SRP expression by again testing VEP magnitude in response to the familiar X° stimulus and a third novel X + 90° stimulus on day 7. (B) Significant SRP was expressed on experimental day 5 prior to ketamine delivery as the familiar X° stimulus elicited VEPs of greater magnitude than the novel stimulus. Delivery of 50 mg/kg ketamine (purple) had two notable impacts on the VEP: First, the overall magnitude of the VEP increased. Second, and most importantly, the significant difference in magnitude of VEPs elicited by familiar and novel stimuli was no longer present. This effect was acute, as SRP expression was again significantly apparent 2 days later. (C) The ratio of VEP magnitude elicited by the familiar stimulus over the novel. This ratio was close to 2 and not significantly different prior to or after recovery from ketamine administration but dropped significantly to approximately 1 during ketamine exposure. (D) We tested whether ketamine had a differential impact on VEP magnitude in PV GluN1 KO mice and WT littermate mice. (E) In the WT littermate mice (white bars) 50 mg/kg ketamine had a significant potentiating effect on VEP magnitude, consistent with our previous observation. In contrast, ketamine had no significant impact on VEP magnitude in the PV GluN1 KO mice (gray bars). (F) The selectivity of ketamine’s impact on the WT mice is observed by comparing the ratio of VEP magnitude during ketamine over baseline, which was significantly greater for WT mice than the PV GluN1 KO mice, in which the ratio was approximately 1. (G) In a separate group of mice, a similar protocol was then used to determine whether the OD ratio is affected by ketamine. (H) Ketamine impacted both the VEPs driven through the contralateral eye (blue) and ipsilateral eye (yellow) equally. (I) This scaled effect is demonstrated by a lack of significant difference between OD ratios prior to (white) and during 50 mg/kg ketamine (purple). (J) We next tested whether ketamine has any impact on the expression of adult OD plasticity by recording VEP magnitudes through either eye in a new group of adult mice before taking them through a standard 7 day MD protocol. (K) As anticipated, 7 days of contralateral eye MD induced a significant ipsilateral eye potentiation (yellow) and ketamine then further potentiated VEPs elicited through both contralateral (blue) and ipsilateral eyes. (L) The OD ratio shifts significantly from a ratio heavily biased towards the contralateral eye, to a less biased ratio. Ketamine administration did not significantly affect the magnitude of the OD shift. Significant comparisons are marked with an asterisk throughout while non-significant comparisons are marked with n.s. Error bars are standard error of the mean (S.E.M.).

DOI: http://dx.doi.org/10.7554/eLife.11450.019