The ability to flexibly navigate an environment relies on a hippocampal-dependent cognitive map. External space can be internally mapped at different spatial resolutions. However, whether hippocampal spatial coding resolution can rapidly adapt to local features of an environment remains unclear. To explore this possibility, we recorded the firing of hippocampal neurons in mice navigating virtual reality environments, embedding or not local visual cues (virtual 3D objects) in specific locations. Virtual objects enhanced spatial coding resolution in their vicinity with a higher proportion of place cells, smaller place fields, increased spatial selectivity and stability. This effect was highly dynamic upon objects manipulations. Objects also improved temporal coding resolution through improved theta phase precession and theta timescale spike coordination. We propose that the fast adaptation of hippocampal spatial coding resolution to local features of an environment could be relevant for large-scale navigation.

1Animals can flexibly navigate in their environment. This ability is thought to rely on an 2 internal cognitive map. An open question concerns the influence of local sensory cues on the 3 cognitive map and notably their putative contribution to setting its spatial resolution. Here 4 we compared the firing of hippocampal principal cells in mice navigating virtual reality 5 environments in the presence or absence of local visual cues (virtual 3D objects). Objects 6 improved the spatial representation both quantitatively (higher proportion of place cells) 7 and qualitatively (smaller place fields with increased spatial selectivity and stability). This 8 gain in spatial coding resolution was more pronounced near the objects and could be rapidly 9 tuned by their manipulations. In addition, place cells displayed improved theta phase 10 precession in the presence of objects. Thus the hippocampal mapping system can 11 dynamically adjust its spatial coding resolution to local sensory cues available in the 12 environment. 13All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

In area CA1 of the hippocampus, the selection of place cells to represent a new environment is biased towards neurons with higher excitability. However, different environments are represented by orthogonal cell ensembles, suggesting that regulatory mechanisms exist. Activity-dependent plasticity of intrinsic excitability, as observed in vitro, is an attractive candidate. Here, using whole-cell patch-clamp recordings of CA1 pyramidal neurons in anesthetized rats, we have examined how inducing theta-bursts of action potentials affects their intrinsic excitability over time. We observed a long-lasting, homeostatic depression of intrinsic excitability which commenced within minutes, and, in contrast to in vitro observations, was not mediated by dendritic Ih. Instead, it was attenuated by the Kv1.1 channel blocker dendrotoxin K, suggesting an axonal origin. Analysis of place cells’ out-of-field firing in mice navigating in virtual reality further revealed an experience-dependent reduction consistent with decreased excitability. We propose that this mechanism could reduce memory interference.

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Background: Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer’s disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro , ex vivo and in vivo. Results: Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

Background: Intracellular amyloid-beta oligomers (iAβo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking them has been reported. Methods: Here, the effects of human AD brain-derived (h-iAβo) and synthetic (iAβo) peptides on synaptic currents and action potential (AP) firing were investigated in hippocampal neurons in vitro, ex vivo and in vivo. Results: Starting from 500 pM, iAβo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-related fluorescence changes indicated that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAβo, indicating that iAβo can increase network excitability at a distance. Current-clamp recordings suggested that iAβo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. Conclusion: These results strongly indicate that iAβo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offer an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

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