SPIN90 Modulates Long-Term Depression and Behavioral Flexibility in the Hippocampus

Abstract

The importance of actin-binding proteins (ABPs) in the regulation of synapse morphology and plasticity has been well established. SH3 protein interacting with Nck, 90 kDa (SPIN90), an Nck-interacting protein highly expressed in synapses, is essential for actin remodeling and dendritic spine morphology. Synaptic targeting of SPIN90 to spine heads or dendritic shafts depends on its phosphorylation state, leading to blockage of cofilin-mediated actin depolymerization and spine shrinkage. However, the physiological role of SPIN90 in long-term plasticity, learning and memory are largely unknown. In this study, we demonstrate that Spin90-knockout (KO) mice exhibit substantial deficits in synaptic plasticity and behavioral flexibility. We found that loss of SPIN90 disrupted dendritic spine density in CA1 neurons of the hippocampus and significantly impaired long-term depression (LTD), leaving basal synaptic transmission and long-term potentiation (LTP) intact. These impairments were due in part to deficits in AMPA receptor endocytosis and its pre-requisites, GluA1 dephosphorylation and postsynaptic density (PSD) 95 phosphorylation, but also by an intrinsic activation of Akt-GSK3β signaling as a result of Spin90-KO. In accordance with these defects, mice lacking SPIN90 were found to carry significant deficits in object-recognition and behavioral flexibility, while learning ability was largely unaffected. Collectively, these findings demonstrate a novel modulatory role for SPIN90 in hippocampal LTD and behavioral flexibility.

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“…These findings demonstrate that their behavioral flexibility is intact. These results were surprising since previous studies have implicated NMDAR-LTD in behavioral flexibility (Nicholls et al, 2008;Kim et al, 2011Kim et al, , 2017Dong et al, 2013;Regan et al, 2015). This discrepancy could be for various reasons.…”

“…This discrepancy could be for various reasons. In several of these studies (Nicholls et al, 2008;Kim et al, 2011;Regan et al, 2015;Kim et al, 2017) constitutive knockouts were used, and so developmental factors may have introduced confounding variables. The difference between our study and previous pharmacological investigations (Ge et al, 2010;Dong et al, 2013) may relate to the nature of the pharmacological agents used.…”

The Intriguing Contribution of Hippocampal Long-Term Depression to Spatial Learning and Long-Term Memory

“…For example, genetic deletion of serum response factor (SRF) ( Etkin et al, 2006 ), or manipulation of neuregulin-signaling ( Ledonne et al, 2018 ), impairs both hippocampal LTD and object recognition memory. Moreover, SPIN90-knockout mice exhibit deficits in hippocampal LTD and object recognition memory ( Kim et al, 2017 ), Bcl-2 associated protein (Bax) knockout mice exhibit deficits in long-term, but not short-term memory, that are accompanied by LTD impairments ( Liu et al, 2014 ), and inhibition of LTD through antagonism of plasticity-related neurotransmitter receptors also prevents object recognition memory ( Goh and Manahan-Vaughan, 2013a , b ). Here, it is important to point out that a clear delineation has been proposed between the role of the perirhinal cortex in item recognition per se ( Aggleton et al, 2010 ) and the role of the hippocampus in item recognition at the level of item-place recognition and spatial elements of item recognition memory ( Wan et al, 1999 ; Brown and Aggleton, 2001 ).…”

“…One can assess reversal learning, and thereby behavioral flexibility, by then changing the location of the platform and examining how rapidly the animal builds a new representation (or continues to look for the platform where it was previously located). Inhibition of LTD prevents reversal learning ( Nicholls et al, 2008 ; Kim et al, 2011 , 2017 ; Dong et al, 2013 ; Mills et al, 2014 ) and also prevents extinction learning ( Kim et al, 2017 ), whereby due to changing contingencies a previous behavior should no longer be executed.…”

“…At a behavioral level this process would prevent generalization of memories and serve to optimize pattern separation. Behavioral evidence for this derives from studies that show that enhancement of LTD reduces fear memory generalization ( Cao et al, 2021 ) and that inhibition of LTD prevents both item-place recognition memory ( Dong et al, 2012 ; Goh and Manahan-Vaughan, 2013b ; Kim et al, 2017 ; Ledonne et al, 2018 ) and spatial information updating ( Kemp and Manahan-Vaughan, 2008b ; Popkirov and Manahan-Vaughan, 2011 ; Lemon and Manahan-Vaughan, 2012 ; Dong et al, 2013 ).…”