β‐adducin (Add2) KO mice show synaptic plasticity, motor coordination and behavioral deficits accompanied by changes in the expression and phosphorylation levels of the α‐ and γ‐adducin subunits

Abstract

Adducins are a family of proteins found in cytoskeleton junctional complexes, which bind and regulate actin filaments and actin-spectrin complexes. In brain, adducin is expressed at high levels and is identified as a constituent of synaptic structures, such as dendritic spines and growth cones of neurons. Adducin-induced changes in dendritic spines are involved in activitydependent synaptic plasticity processes associated with learning and memory, but the mechanisms underlying these functions remain to be elucidated. Here, β-adducin knockout (KO) mice were used to obtain a deeper insight into the role of adducin in these processes. We showed that β-adducin KO mice showed behavioral, motor coordination and learning deficits together with an altered expression and/or phosphorylation levels of α-adducin and γ-adducin. We found that β-adducin KO mice exhibited deficits in learning and motor performances associated with an impairment of longterm potentiation (LTP) and long-term depression (LTD) in the hippocampus. These effects were accompanied by a decrease in phosphorylation of adducin, a reduction in α-adducin expression levels and upregulation of γ-adducin in hippocampus, cerebellum and neocortex of mutant mice. In addition, we found that the mRNA encoding β-adducin is also located in dendrites, where it may participate in the fine modulation of LTP and LTD. These results strongly suggest coordinated expression and phosphorylation of adducin subunits as a key mechanism underlying synaptic plasticity, motor coordination performance and learning behaviors.

TDP-43 regulatesβ-adducin(Add2) transcript stability

“…This brain-specific Add2 mRNA shows dendritic localization. 24,26 In this work we confirmed that TDP-43 interacts with the Add2 PAS DSE in vitro and observed that depletion of TDP-43 in tissue culture cells results in the down-regulation of both the chimeric and endogenous Add2 transcripts. Apparently, this effect was not mediated by the Add2 DSE, as substituting the Add2 DSE with viral E-SV40 and L-SV40 DSEs, which are not TDP-43 targets, still resulted in a decrease of Add2 mRNA levels in vivo after TDP-43 depletion.…”

“…In fact, Add2 has a key role in the assembly of synapses, control of synaptic plasticity and stability, associated to LTP, LTD, motor abilities and learning. [22][23][24][25] The evidenced involvement of TDP-43 in Add2 mRNA stability can be considered relevant also at the light of its possible impact on the neurodegenerative processes associated to ALS and FTLD. The exact molecular mechanisms associated to ALS and FTLD are not completely understood, since TDP-43 cytoplasmic inclusions might have a toxic gain of function or loss of function by sequestering nuclear TDP-43 (or both), disrupting its role in RNA metabolism.…”

“…Thus, one of the pathological processes associated to disease could be alteration of the stability of specific transcripts and, consequently, variation in the expression levels of the corresponding genes. 14 In the specific case of Add2, considering its role at synapti c-terminals, [22][23][24][25] alteration of Add2 levels due to changes in TDP-43 levels and/or activity may directly affect neurological functions in disease states. However, the understanding of the fine mechanism involving TDP-43 in Add2 mRNA stability and its possible connection to disease states still need additional studies.…”

“…It is involved in the assembly of synapses, in the control of synaptic plasticity and synapses stability. 22,23 Add2 genetic inactivation in mice leads to motor coordination, behavioral and learning deficits, associated with impairment in LTP and LTD. 24,25 Erythroid and neuronal Add2 expression is correlated with the use of tissue specific alternative promoters and polyadenylation sites (PAS). In particular, proximal polyadenylation sites (2 or 3, depending on the species) are active in erythroid tissues while one distal PAS (A4 PAS) is exclusively used in brain.…”

Bioinformatic Prediction and Confirmation of β-Adducin as a Novel Substrate of Glycogen Synthase Kinase 3

“…␤-Adducin is a cytoskeleton-associated protein that is predominantly expressed in the brain, where it is a constituent of synapses, dendritic spines, and growth cones (35)(36)(37). It has been shown to regulate neuronal cytoarchitecture, long-term potentiation, motor coordination, and learning (37)(38)(39). Therefore, we were interested to see whether ␤-adducin is a novel brain substrate of GSK3.…”