We have investigated the in vivo
function of NMDAR specifically in FS–PV interneurons in regulating cortical brain rhythms and cognitive functions (Supplementary Table 1
). This work is based on a long-standing hypothesis connecting PV interneuron dysfunction, NMDAR hypofunction and disturbances in brain rhythms associated with cognitive tasks/functions. We find that NMDAR signaling in FS–PV interneurons is critical for the regulation of gamma oscillations during baseline conditions as well as for gamma rhythm induction. The data we present on optogenetic drive in the superficial cortical layers are specific to FS–PV interneurons, as PV-expressing cells in these laminae are only FS interneurons. That said, PV-expressing neurons are present throughout the brain. One alternative cell type that could impact our findings is PV-expressing thalamic neurons, which typically project to the granular layers in cortex. There is correlative (neurophysiological), causal (optogenetic) and computational (modeling) evidence that neocortical gamma oscillations depend crucially on local FS interneurons, but these studies also suggest that the tonic level of excitation to the neocortical circuit is a key. As such, alternations in these thalamic neurons could have impacted, for example, our baseline data.
The inability of the cortical network to induce additional gamma oscillations by direct activation of FS–PV interneurons might indicate an impairment of network flexibility. The results suggest that PV-Cre/NR1f/f mice exhibit spontaneous and evoked network abnormalities similar to those observed after low does administration of NMDAR antagonists.13
This is similar to findings in psychiatric patients, who display aberrant recruitment of cortical circuits and diminished evoked gamma rhythm in response to cognitive and sensory tasks.55
The reduced gamma-band activity after NMDAR antagonist treatment in PV-Cre/NR1f/f mice supports the hypothesis that FS–PV interneurons are an important target for pharmacological NMDAR blockade associated with altered gamma rhythms,13, 56
consistent with our computational model of the PV-Cre/NR1f/f cortical circuit.
We have further found a dissociation between the requirement for NMDAR in FS–PV interneurons during baseline behavior versus demanding cognitive tasks. Although the small age-dependent effects in the open field may be of interest in light of behavioral changes associated with transitions from adolescence to adulthood, our results suggest a subtle behavioral effect at most of NMDAR deficiency in PV interneuron in the unchallenged state. This finding is in contrast to the phenotypes of hyperlocomotion and stereotypical behaviors in mice with general NMDAR hypofunction.31, 32
Working memory includes executive components such as goal maintenance and interference control.57
It is difficult to establish the explicit role of executive components in rodent working memory tasks, and in addition, several cognitive processes and memory systems may be used in conjunction in the tasks.57
Although the selective working memory deficit in performance of the PV-Cre/NR1f/f mice at short delays in the discrete paired-trial variable-delay T-maze task most likely represent a complex network deficit, these data suggest that activation of NMDAR on PV interneurons is required for rapid initiation of the working memory encoding phase. In contrast, PV-Cre/NR1f/f mice displayed intact spatial reference memory, as measured in the Morris water maze task. In line with this, mice with deletion of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR-A specifically in PV-expressing interneurons58
do not show impaired spatial reference memory, but have reduced kainate-induced gamma oscillations in hippocampal slices. Our results point to a specific role for NMDAR in PV interneurons in memory tasks involving the neocortex, amygdala and hippocampus. A potential unifying feature of these forms of memory is their dependence on intact gamma rhythms, which are enhanced during exposure to novel environments,59
but might have a lesser role in long-term learning in the water-maze task or the longer intratrial intervals in the T-maze task.
Evidence supporting the important role of NMDAR in interneurons has recently been provided through genetic deletion of NMDAR in a mixed population of GABAergic interneurons, including PV interneurons.60
This deletion results in a wide range of behavioral phenotypes, including novelty-induced hyperlocomotion, PPI deficits and anxiety-like effects, which were not observed in PV-Cre/NR1f/f mice. Our model of a targeted adolescent disruption of NMDAR transmission specifically in PV interneurons provides a specific framework for understanding the role of NMDA transmission in PV interneurons for oscillatory activities in neuronal ensembles.
An important question is to what extent the observed circuit deficits depend on specific NMDAR-related activities, or represent a general hypoexcitability of PV interneurons conferred by diminished glutamatergic drive. It has been shown that reduced excitatory recruitment of PV interneurons through loss of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors affects ongoing and induced gamma oscillations in hippocampal slices,58
with corresponding deficits in working memory but not spatial reference memory. Our in vivo
physiological, behavioral studies and computational modeling suggest that such deficits, found in our mouse model as well, could reflect a general decrease in excitability of PV interneurons.
There is direct evidence for NMDAR hypofunction in psychiatric patients.61
Additionally, human genetic data for schizophrenia-associated genes have implicated the NMDAR signaling pathway and disruption of the neuregulin-1/ErbB4 pathway.62, 63, 64
PV interneurons express ErbB4 protein65
and the neuregulin-1/ErbB4 pathway has a role in gamma oscillations.66
However, we emphasize that the PV-Cre/NR1f/f mouse does not represent a model of schizophrenia, but rather contributes to the investigation of possibly one dimension of schizophrenia that includes cognitive defects. Further, under even the best circumstances, a mouse model is limited in its ability to recapitulate all complex cognitive dimensions that have evolved in humans.