Inhibition of hippocampal palmitoyl acyltransferase activity impairs spatial learning and memory consolidation

Protein palmitoylation, the thioester linkage of saturated 16-carbons palmitate to cysteine residues, is a reversible process that is dynamically regulated by specific cellular stimuli. Palmitoylation serves both to tether proteins to membranes and to direct their localization to specific membrane regions (Camp and Hofmann, 1993, Conibear and Davis, 2010, Rocks et al., 2010, Salaun et al., 2010, Kong et al., 2013, Vartak et al., 2014) and emerges as a crucial conserved mechanism to orchestrate the subcellular distribution of synaptic proteins. Palmitoylation participates in many aspects of neuronal development, regulation of neurotransmission and synaptic plasticity in the nervous system through the mobilization, localization, and compartmentalization of proteins (Ji and Skup, 2021). Protein palmitoylation is catalyzed by palmitoyl acyltransferase enzymes (PATs) (Fukata and Fukata, 2010, Montersino and Thomas, 2015, Fukata et al., 2016), and a family of 23 PATs enzymes has been identified in mammals. Most PATs are transmembrane enzymes located in the Golgi apparatus and the endoplasmic reticulum. In the brain, PATs ZDHHC2, ZDHHC5, ZDHHC8 and DHHC17 have been found in dendrites and spines to regulate the location, mobilization, and function of multiple signalling proteins, including ionotropic and metabotropic glutamate receptors (Hayashi et al., 2005, Hayashi et al., 2009, Noritake et al., 2009, Milnerwood et al., 2013, Zaręba-Kozioł et al., 2018), PSD-95, Cdc42, ẟ-catenin, among others. In the brain, palmitoylation has received attention because of its contribution to modulate synaptic plasticity through ionotropic and metabotropic glutamatergic receptor’s location, mobilization, and function in response to neural activity (Hayashi et al., 2009, Thomas and Huganir, 2013, Han et al., 2015, Jeyifous et al., 2016).Table 1.

It is well established that glutamatergic signalling modules long-term potentiation (LTP) and long-term depression (LTD). These two forms of synaptic plasticity have been extensively studied and are considered cellular correlates of learning and memory processes (Lüscher and Malenka, 2012, Takeuchi et al., 2013, Ji and Skup, 2021). Numerous studies have demonstrated that defects in protein palmitoylation are associated with several neurological disorders that lead to cognitive impairment (Fukata and Fukata, 2010, Cho and Park, 2016, Melo et al., 2020, Zaręba-Kozioł et al., 2018). Moreover, the deletion of the palmitoyl acyltransferase ZDHHC8 in mice through 22q11.2 chromosome deletion displays dendritic spine deficit and impairs structural plasticity (Mukai et al., 2008).

The role of palmitoylation in functional synaptic plasticity has been well documented and extensively investigated (Thomas and Huganir, 2013, Matt et al., 2019, Sohn and Park, 2019, Hayashi, 2020, Ji and Skup, 2021). However, just a few studies show the relevance of PATs in spatial memory (Milnerwood et al., 2013; Brigidi et al., 2014). Hence, the role of PATs activity in the different stages of distinct forms of hippocampus-dependent memories still needs to be better understood. To understand the impact of protein palmitoylation on learning and memory processes, we aimed to determine the effect of pharmacological inhibition of PATs on rat hippocampal plasticity and behavioral responses.

In this work, we studied the effect of PATs inhibition in the acquisition, consolidation, and retrieval of spatial hippocampal-dependent memories. We found that the inhibition of PATs activity in the dorsal hippocampus impairs the acquisition and consolidation but not retrieval of spatial memories. However, PATs inhibition did not interfere with the consolidation of non-hippocampal-dependent memories, like the object recognition memory. Additionally, we showed that PATs inhibition interferes with the synaptic plasticity, measured through the long-term potentiation (LTP) of the Schaffer Collaterals hippocampal pathway. In summary, these results suggest that protein palmitoylation modulates synaptic strength underlying acquisition and consolidation of spatial memory in the hippocampus.

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