Theta/gamma Co-modulation Disruption After NMDAr Blockade by MK-801 Is Associated with Spatial Working Memory Deficits in Mice.

Abnormal N-methyl-D-aspartate receptor (NMDAr) function has been linked to oscillopathies, psychosis, and cognitive dysfunction in schizophrenia (SCZ). Here, we investigate the role of NMDAr hypofunction in pathological oscillations and behavior. We implanted mice with tetrodes in the dorsal/intermediate hippocampus and medial prefrontal cortex (mPFC), administered the NMDAr antagonist MK-801, and recorded oscillations during spontaneous exploration in an open field and in the y-maze spatial working memory test. Our results show that NMDAr blockade disrupted the correlation between oscillations and speed of movement, crucial for internal representations of distance. In the hippocampus, MK-801 increased gamma oscillations and disrupted theta/gamma coupling during spatial working memory. In the mPFC, MK-801 increased the power of theta and gamma, generated high-frequency oscillations (HFO 155-185 Hz), and disrupted theta/gamma coupling. Moreover, the performance of mice in the spatial working memory version of the y-maze was strongly correlated with CA1-PFC theta/gamma co-modulation. Thus, theta/gamma mediated by NMDAr function might explain several of SCZ's cognitive symptoms and might be crucial to explaining hippocampal-PFC interaction.

Heterogeneous spatial representation by different subpopulations of neurons in the subiculum.

The subiculum is a pivotal structure located in the hippocampal formation that receives inputs from grid and place cells and that mediates the output from the hippocampus to cortical and sub-cortical areas. Previous studies have demonstrated the existence of boundary vector cells (BVC) in the subiculum, as well as exceptional stability during recordings conducted in the dark, suggesting that the subiculum is involved in the coding of allocentric cues and also in path integration. In order to better understand the role of the subiculum in spatial processing and the coding of external cues, we recorded subicular units in freely moving rats while performing two experiments: the "size experiment" in which we modified the arena size, and the "barrier experiment" in which we inserted new barriers in a familiar open field thus dividing the enclosure into four comparable sub-chambers. We hypothesized that if physical boundaries were deterministic of the firing of subicular units a strong spatial replication pattern would be found in most spatially modulated units. In contrast, our results demonstrate heterogeneous space coding by different cell types: place cells, barrier-related units and BVC. We also found units characterized by narrow spike waveforms, most likely belonging to axonal recordings, that showed grid-like patterns. Our data indicate that the subiculum codes space in a flexible manner, and that it is involved in the processing of allocentric information, external cues and path integration, thus broadly supporting spatial navigation.