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

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.

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

“…It is a binding partner of the Kv4-containing A-type K+ channels which are important for determining cellular excitability. Based on available studies in mouse and human, one could hypothesize that FTLD-TDP associated risk variants reduce the amount of functional DPP6: Dpp6 knockout mice show a reduction of hippocampal glutamatergic synapses and impaired hippocampus-dependent learning behavior and memory [50,81], DPP6 LOF mutations in humans have been associated with neurodevelopmental disorders [48] and autoantibodies against DPP6 were found to be the cause of a multifocal neurologic disorder of the central and autonomic nervous system [7,34,83]. The identification of two DPP6 LOF mutations in our FTLD-TDP patient cohort is further in line with a LOF disease-risk mechanism.…”

Loss of DPP6 in neurodegenerative dementia: a genetic player in the dysfunction of neuronal excitability

“…A recent study on Dpp6 knockout (KO) mice suggested a structural function in the formation of filopodia, the precursor of the dendritic spines, and in cellular stability through the binding to the extracellular matrix, thus directly affecting dendritic arborization, spine density and synaptic function [ 46 ]. Furthermore, DPP6 loss has been shown to determine memory and learning impairments in young Dpp6-KO mice [ 45 ]. Patients affected by anti-DPPX syndrome, with autoantibodies targeting DPP6 and causing reduced protein expression, have memory deficits and neuronal hyperexcitability, features that are improved when DPP6 expression levels are increased [ 27 ].…”

Autoimmune seizures and epilepsy

“…Defective dendritic A-type K + currents with enhanced excitability, lower threshold for LTP, and reduced synaptic and extrasynaptic Kv4.2 expression in DPP6 (DPPX) -/mice (191). Impaired synaptic development, and learning and memory deficits in DPP6 -/mice (192).…”