Assessing the contribution of grid cells to path integration and spatial learning

• Applicant: Mariana Gil, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280340021

The mammalian hippocampal-entorhinal system is thought to be responsible for the encoding of internal representations of space. Since the discovery of grid cells in the medial entorhinal cortex (MEC), neurophysiological data and computational models have suggested that these neurons serve path integration (PI), a highly conserved, self-motion-based navigation strategy. However, more direct empirical evidence supporting this hypothesis has been missing due to a lack of selective manipulations of grid cell activity and adequate behavioral assays. During the previous funding period, we overcame these limitations and directly tested this hypothesis. We achieved selective disruption of grid cell activity by removing N-methyl-D-aspartate glutamate receptors (NMDARs) from the retrohippocampal (RH) region. Of note, mice with disrupted grid cell activity exhibited impaired PI performance in the L-maze. Moreover, by using the same mice for in vivo electrophysiological recordings and behavioral tests, we were able to correlate the degree of NMDAR ablation with the degree of altered grid cell activity and the degree of PI impairment, providing strong experimental support for the hypothesis that grid cell activity underlies PI navigation. It is important to note that, in these experiments, NMDAR ablation occurred in all neuronal types within the MEC network. Although, it is noteworthy that such unspecific manipulation specifically affected grid cells, a more specific manipulation would allow us to better dissect the role of NMDAR signaling on PI and grid cell activity. Hence, in a next research funding period, we propose to evaluate the role of NMDAR signaling in different MEC neuronal subpopulations on grid cell firing and PI. To this end, we will generate mice lacking the functional NMDAR in different neuronal populations within the MEC, using RNAi-based conditional gene knockdown. We will inject a RNAi-NR1 construct in the MEC of different Cre-dependent mice lines targeting the four major excitatory and inhibitory neuronal subpopulations. We will test the mice for PI in the L-maze and perform in vivo electrophysiological recordings of MEC neuronal activity. The results of these experiments will provide the necessary information to further test underlying mechanisms that support PI navigation and spatial memory.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Hannah Monyer