Memory Erasure Experiments Indicate a Critical Role of CaMKII in Memory Storage

Abstract

Summary The abundant synaptic protein, CaMKII, is necessary for long-term potentiation (LTP) and memory. However, whether CaMKII is required only during initial processes or whether it also mediates memory storage remains unclear. The most direct test of a storage role is the erasure test. In this test, a putative memory molecule is transiently inhibited after learning. The key prediction is that this should produce persistent memory erasure. We conducted this test using transient viral (HSV) expression of dominant-negative CaMKII-alpha (K42M) in the hippocampus. This produced persistent erasure of conditioned place avoidance. As an additional test, we found that expression of activated CaMKII (T286D/T305A/T306A) impaired place avoidance, a result not expected if a process other than CaMKII stores memory. Our behavioral results, taken together with prior experiments on LTP, strongly support a critical role of CaMKII in LTP maintenance and memory storage.

Calcium/calmodulin‐dependent kinase II and memory destabilization: a new role in memory maintenance

“…It is plausible to propose that the expression of a highly active form of CaMKII increases memory destabilization, resulting in the memory impairment phenotype observed in Rossetti et al . (), which is in agreement with Cao et al . ;.…”

“…A less substantial piece of evidence for the role of CaMKII activation inducing memory destabilization can be conjectured from the results reported by Rossetti et al . (). Rossetti et al .…”

“…Rossetti et al . () showed that viral‐induced expression of αCaMKII T286D/T305A/T306A gene (a hyperactive form of αCaMKII) in the hippocampus, blocks previously learned place‐avoidance behavior. It is plausible to propose that the expression of a highly active form of CaMKII increases memory destabilization, resulting in the memory impairment phenotype observed in Rossetti et al .…”

Memory formation depends on both synapse-specific modifications of synaptic strength and cell-specific increases in excitability

“…In the canonical form of LTP found at CA1 hippocampal synapses, LTP induction depends on a particular type of glutamate receptor, NMDAR, and on a biochemical cascade initiated and sustained by the abundant synaptic protein calcium/calmodulin-dependent protein kinase II (CaMKII) 3 . Importantly, genetic modifications that interfere with NMDAR or CaMKII function not only block LTP, but also produce profound deficits in learning and memory storage 4–6 . Conversely, nearly all mutations that enhance memory also enhance LTP 7 .…”

Mechanisms of fear learning and extinction: synaptic plasticity–fear memory connection

“…Since then, substantial progress has been made (e.g., Takeuchi et al 2014), especially recently with the introduction of several new methodologies, including multi-electrode array stimulation and recording, optogenetics, chemogenetics, and advanced molecular genetics. Unsurprisingly, strong support for the SPM hypothesis came from studies in the hippocampus, the region in which LTP was discovered (e.g., Whitlock et al 2006; Garner et al 2012; Ramirez et al 2013; Rossetti et al 2017). However, studies of fear conditioning provided what appears to be the most direct evidence yet that associative LTP at inputs to the LA may constitute a mechanism for encoding the CS-US association and storing fear memories in the course of auditory fear conditioning (Rogan et al 1997; McKernan and Shinnick-Gallagher 1997; Tsvetkov et al 2002; Shumyatsky et al 2002; Rumpel et al 2005; Shumyatsky et al 2005; Cho et al 2012).…”