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.

Effect of Aggressive Experience in Female Syrian Hamsters on Glutamate Receptor Expression in the Nucleus Accumbens

“…Although the molecular and physiological mechanisms mediating these postsynaptic changes are unknown, follow-up studies from our lab suggest PSD-95 and mGluR5 play a functional role in this synaptic structural plasticity (Peterson et al, 2015;Been et al, 2016;Gross et al, 2016). Furthermore, previous literature suggests that increases in mushroom head spines may be associated with increases in excitatory synaptic transmission and long-term potentiation; more specifically an increase in AMPAR expression (Malinow and Malenka, 2002;Muddashetty et al, 2007;Takahashi et al, 2009;Bencsik et al, 2019).…”

“…These correlations are not observed in females that did not have aggressive experience. Collectively, PSD-95, Caskin I, GluA1, and mGluR5 expression are all associated with increases in mature mushroom-like spines and increases in excitatory postsynaptic transmission (Malinow and Malenka, 2002;Muddashetty et al, 2007;Takahashi et al, 2009;Peterson et al, 2015;Been et al, 2016;Bencsik et al, 2019). Thus, the increases in PSD-95, GluA1, and mGluR5 observed in the NAc are correlated together, further supporting a common or linked mechanism of action (Goncalves et al, 2020).…”

“…An increase in PSD-95 in the NAc 24 h after aggressive experience significantly decreased to that of control females 1 week later (Dunn's test: d = 1.165, p = 0.013, df = 26). Finally, Caskin I protein expression was examined to assess if these changes in postsynaptic structural density may be linked to changes in specifically mushroom-like spines (Bencsik et al, 2019). There was no effect of aggressive experience on Caskin I expression in the NAc (one-way ANOVA: F = 0.668, p > 0.05, df = 2, 25) ( Figure 2B).…”

“…Interestingly, we did not detect any changes in Caskin I protein expression. Thus, the postsynaptic structural changes may have been independent of changes specifically in mushroomlike spines or our experimental procedure may not have been selective or sensitive enough to detect more subtle changes in expression (Bencsik et al, 2019). We next investigated if these changes in markers of postsynaptic structural density correlate with changes in excitatory synaptic transmission in the NAc.…”

Role of Exendin-4 in Brain Insulin Resistance, Mitochondrial Function, and Neurite Outgrowth in Neurons under Palmitic Acid-Induced Oxidative Stress

“…Several proteins such as actin [ 72 ] and FOXO [ 73 ] contribute directly to neuronal morphogenesis, dendritic branching, and stable neuronal connectivity remodeling [ 74 ]. In addition, dendritic spine morphology contributes to the memory function by affecting synaptic plasticity [ 75 , 76 ]. Several studies have mentioned that the morphology and number of dendritic spines influences memory processes and behavior patterns [ 77 , 78 ].…”