Targeted deletion of AKAP7 in dentate granule cells impairs spatial discrimination.

Brian W Jones,Thomas J Younts,Christina A Sanford,Daniela Nachmanson,Margaret C Slack,Jenesa Chin,Pablo E Castillo,Alex Mckennon,Michael Weisenhaus,G Stanley Mcknight,Jennifer Deem

doi:10.7554/elife.20695

Brian W Jones, Thomas J Younts + Show 9 more

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https://doi.org/10.7554/elife.20695

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Abstract

Protein Kinase A (PKA) mediates synaptic plasticity and is widely implicated in learning and memory. The hippocampal dentate gyrus (DG) is thought to be responsible for processing and encoding distinct contextual associations in response to highly similar inputs. The mossy fiber (MF) axons of the dentate granule cells convey strong excitatory drive to CA3 pyramidal neurons and express presynaptic, PKA-dependent forms of plasticity. Here, we demonstrate an essential role for the PKA anchoring protein, AKAP7, in mouse MF axons and terminals. Genetic ablation of AKAP7 specifically from dentate granule cells results in disruption of MF-CA3 LTP directly initiated by cAMP, and the AKAP7 mutant mice are selectively deficient in pattern separation behaviors. Our results suggest that the AKAP7/PKA complex in the MF projections plays an essential role in synaptic plasticity and contextual memory formation.

Highlights

The hippocampal formation, which comprises the hippocampus and dentate gyrus (DG), plays a crucial role in the encoding and retrieval of episodic and spatial memories (Burgess et al, 2002)
Results from global AKAP7 KO mice suggested a critical role for AKAP7 in pattern separation, but the effects on behavior could be influenced by AKAP7 in brain regions other than the hippocampus
These results further demonstrate that the AKAP7 detected in the DG molecular layer in WT mice arises from dentate granule cell (DGC) and not axonal projections of the perforant path

Summary

Introduction

The hippocampal formation, which comprises the hippocampus and dentate gyrus (DG), plays a crucial role in the encoding and retrieval of episodic and spatial memories (Burgess et al, 2002). Previous theoretical studies predicted that one function of the DG is to accurately separate similar memories by orthogonally encoding discrete non-overlapping input patterns onto the CA3 field (Lee and Solivan, 2010; Rolls, 2013; Schmidt et al, 2012). This precise form of encoding is known as pattern separation (Gilbert et al, 2001; Kesner and Rolls, 2015; Leutgeb et al, 2007; Nakashiba et al, 2012). The cellular and molecular mechanisms that contribute to this functional role in pattern separation are incompletely understood

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