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Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins.

ABSTRACT: CASK-interactive proteins, Caskin1 and Caskin2, are multidomain neuronal scaffold proteins. Recent data from Caskin1 knockout animals indicated only a mild role of Caskin1 in anxiety and pain perception. In this work, we show that deletion of both Caskins leads to severe deficits in novelty recognition and spatial memory. Ultrastructural analyses revealed a reduction in synaptic profiles and dendritic spine areas of CA1 hippocampal pyramidal neurons of double knockout mice. Loss of Caskin proteins impaired LTP induction in hippocampal slices, while miniature EPSCs in dissociated hippocampal cultures appeared to be unaffected. In cultured Caskin knockout hippocampal neurons, overexpressed Caskin1 was enriched in dendritic spine heads and increased the amount of mushroom-shaped dendritic spines. Chemically induced LTP (cLTP) mediated enlargement of spine heads was augmented in the knockout mice and was not influenced by Caskin1. Immunocytochemistry and immunoprecipitation confirmed that Shank2, a master scaffold of the postsynaptic density, and Caskin1 co-localized within the same complex. Phosphorylation of AMPA receptors was specifically altered by Caskin deficiency and was not elevated by cLTP treatment further. Taken together, our results prove a previously unnoticed postsynaptic role of Caskin scaffold proteins and indicate that Caskins influence learning abilities via regulating spine morphology and AMPA receptor localisation.

SUBMITTER: Bencsik N

PROVIDER: S-EPMC6856520 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins.

Bencsik Norbert N Pusztai Szilvia S Borbély Sándor S Fekete Anna A Dülk Metta M Kis Viktor V Pesti Szabolcs S Vas Virág V Szűcs Attila A Buday László L Schlett Katalin K

Scientific reports 20191114 1

CASK-interactive proteins, Caskin1 and Caskin2, are multidomain neuronal scaffold proteins. Recent data from Caskin1 knockout animals indicated only a mild role of Caskin1 in anxiety and pain perception. In this work, we show that deletion of both Caskins leads to severe deficits in novelty recognition and spatial memory. Ultrastructural analyses revealed a reduction in synaptic profiles and dendritic spine areas of CA1 hippocampal pyramidal neurons of double knockout mice. Loss of Caskin protei ...[more]

PMID: 31727973

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Project description:BackgroundSynaptic failure is one of the principal events associated with cognitive dysfunction in Alzheimer's disease (AD). Preservation of existing synapses and prevention of synaptic loss are promising strategies to preserve cognitive function in AD patients. As a potent natural anti-oxidant, anti-amyloid, and anti-inflammatory polyphenol, curcumin (Cur) shows great promise as a therapy for AD. However, hydrophobicity of natural Cur limits its solubility, stability, bioavailability, and clinical utility for AD therapy. We have demonstrated that solid lipid curcumin particles (SLCP) have greater therapeutic potential than natural Cur in vitro and in vivo models of AD. In the present study, we have investigated whether SLCP has any preservative role on affected dendritic spines and synaptic markers in 5xFAD mice.MethodsSix- and 12-month-old 5xFAD and age-matched wild-type mice received oral administration of SLCP (100 mg/kg body weight) or equivalent amounts of vehicle for 2 months. Neuronal morphology, neurodegeneration, and amyloid plaque load were investigated from prefrontal cortex (PFC), entorhinal cortex (EC), CA1, CA3, and the subicular complex (SC). In addition, the dendritic spine density from apical and basal branches was studied by Golgi-Cox stain. Further, synaptic markers, such as synaptophysin, PSD95, Shank, Homer, Drebrin, Kalirin-7, CREB, and phosphorylated CREB (pCREB) were studied using Western blots. Finally, cognitive and motor functions were assessed using open-field, novel object recognition (NOR) and Morris water maze (MWM) tasks after treatment with SLCP.ResultsWe observed an increased number of pyknotic and degenerated cells in all these brain areas in 5xFAD mice and SLCP treatment partially protected against those losses. Decrease in dendritic arborization and dendritic spine density from primary, secondary, and tertiary apical and basal branches were observed in PFC, EC, CA1, and CA3 in both 6- and 12-month-old 5xFAD mice, and SLCP treatments partially preserved the normal morphology of these dendritic spines. In addition, pre- and postsynaptic protein markers were also restored by SLCP treatment. Furthermore, SLCP treatment improved NOR and cognitive function in 5xFAD mice.ConclusionsOverall, these findings indicate that use of SLCP exerts neuroprotective properties by decreasing amyloid plaque burden, preventing neuronal death, and preserving dendritic spine density and synaptic markers in the 5xFAD mice.

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Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins.

Publications

Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins.

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