DPP6 Loss Impacts Hippocampal Synaptic Development and Induces Behavioral Impairments in Recognition, Learning and Memory.

Lin Lin,Jakob J Gutzmann,Heather A Cameron,Rose-Marie Karlsson,Daniel Abebe,Ya-Xian Wang,Ronald S Petralia,Jonathan G Murphy,Dax A Hoffman

doi:10.3389/fncel.2018.00084

Abstract

DPP6 is well known as an auxiliary subunit of Kv4-containing, A-type K+ channels which regulate dendritic excitability in hippocampal CA1 pyramidal neurons. We have recently reported, however, a novel role for DPP6 in regulating dendritic filopodia formation and stability, affecting synaptic development and function. These results are notable considering recent clinical findings associating DPP6 with neurodevelopmental and intellectual disorders. Here we assessed the behavioral consequences of DPP6 loss. We found that DPP6 knockout (DPP6-KO) mice are impaired in hippocampus-dependent learning and memory. Results from the Morris water maze and T-maze tasks showed that DPP6-KO mice exhibit slower learning and reduced memory performance. DPP6 mouse brain weight is reduced throughout development compared with WT, and in vitro imaging results indicated that DPP6 loss affects synaptic structure and motility. Taken together, these results show impaired synaptic development along with spatial learning and memory deficiencies in DPP6-KO mice.

Highlights

DPP6 is well known as an auxiliary subunit of Kv4-containing A-type K+ channels (Nadal et al, 2003) that regulate the excitability and plasticity of neurons and other excitable cells (Hoffman et al, 1997; Spruston and Johnston, 2008)
Following our previous studies showing that DPP6 impacts synaptic plasticity and synapse development and function in the hippocampus (Sun et al, 2011; Lin et al, 2013), we hypothesized that DPP6 knockout (DPP6-KO) mice would have impaired learning and memory
The platform remained in the same position throughout training, the starting position changed on each trial to prevent the use of egocentric strategies to find the platform

Summary

Introduction

DPP6 is well known as an auxiliary subunit of Kv4-containing A-type K+ channels (Nadal et al, 2003) that regulate the excitability and plasticity of neurons and other excitable cells (Hoffman et al, 1997; Spruston and Johnston, 2008). DPP6 co-expression enhances Kv4 channel surface expression, increases conductance and accelerates channel activation, inactivation and recovery from inactivation (Nadal et al, 2001; Kaulin et al, 2009). DPP6 is a type II transmembrane protein with about 90% of the protein located in the extracellular C-terminus and only a short intracellular sequence following a single transmembrane domain (Strop et al, 2004). We have reported previously, using a heterologous expression system, that the intracellular N-terminal and transmembrane regions of DPP6 associate with Kv4.2 and accelerate channel kinetics. The extracellular domain is required for DPP6 subcellular trafficking and promotes Kv4.2 surface expression (Lin et al, 2014). Our previous study of DPP6 knockout (DPP6-KO) mice showed that decreased A-type K+ current expression in CA1 hippocampal pyramidal neuron distal dendrites leads to hyperexcitable dendrites, enhanced dendritic action potential back-propagation, DPP6 Loss Impacts Memory increased calcium electrogenesis, and a lowered threshold for the induction of long-term synaptic potentiation (Sun et al, 2011)

Methods

Results

Conclusion