Abstract
SummaryEpisodic memory requires different types of information to be bound together to generate representations of experiences. The lateral entorhinal cortex (LEC) and hippocampus are required for episodic-like memory in rodents [1, 2]. The LEC is critical for integrating spatial and contextual information about objects [2, 3, 4, 5, 6]. Further, LEC neurons encode objects in the environment and the locations where objects were previously experienced and generate representations of time during the encoding and retrieval of episodes [7, 8, 9, 10, 11, 12]. However, it remains unclear how specific populations of cells within the LEC contribute to the integration of episodic memory components. Layer 2 (L2) of LEC manifests early pathology in Alzheimer’s disease (AD) and related animal models [13, 14, 15, 16]. Projections to the hippocampus from L2 of LEC arise from fan cells in a superficial sub-layer (L2a) that are immunoreactive for reelin and project to the dentate gyrus [17, 18]. Here, we establish an approach for selectively targeting fan cells using Sim1:Cre mice. Whereas complete lesions of the LEC were previously found to abolish associative recognition memory [2, 3], we report that, after selective suppression of synaptic output from fan cells, mice can discriminate novel object-context configurations but are impaired in recognition of novel object-place-context associations. Our results suggest that memory functions are segregated between distinct LEC networks.
Highlights
Layer 2 (L2) of lateral entorhinal cortex (LEC) contains several morphologically and electrophysiologically distinct subtypes of neurons, including pyramidal, multiform, and fan cells [18, 22, 23]
We investigated whether Sim1:Cre mice provide specific access to the reelin-positive fan cells in layer 2 (L2) of the lateral entorhinal cortex (LEC) (Figure S1)
We found that, following injection of Cre-dependent adeno-associated virus (AAV)-encoding GFP (AAV-FLEX-GFP) [21] into the superficial LEC of Sim1:Cre mice (n = 4), the majority of cells expressing GFP were located in L2a of the LEC (Figures 1A and 1B)
Summary
L2 of LEC contains several morphologically and electrophysiologically distinct subtypes of neurons, including pyramidal, multiform, and fan cells [18, 22, 23]. To establish whether the population of cells labeled in Sim1:Cre mice mapped onto a specific subtype, we injected AAV encoding a Cre-dependent fluorescent reporter (AAV-hSyn-DIO-hM4D(Gi)-mCherry) into the superficial LEC of Sim1:Cre mice (n = 5) and performed patch-clamp recordings in brain slices from labeled cells in L2a of LEC (n = 15 cells). Reconstruction of a subset of these cells (n = 12) revealed that their dendritic architecture was similar to previous descriptions of fan cells, with a polygonal soma and ‘‘fan-like’’ arrangement of primary dendrites. To test whether these cells provide synaptic output to the hippocampus, we injected AAV-encoding Cre-dependent channelrhodopsin-2 (ChR2; AAV-EF1a-DIO-hChR2(H134R)-EYFP) into the superficial LEC of Sim1:Cre mice (n = 5) to enable their optical activation (Figure 2B).
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