Generation of multi-innervated dendritic spines as a novel mechanism of long-term memory formation

Abstract

NMDA receptor-dependent long-term potentiation (LTP) at hippocampal CA1 synapses is a well-accepted mechanism underlying long-term memory (LTM) formation. However, studies with mice that lack threonine-286 autophosphorylation of αCaMKII have shown that hippocampal LTM can be formed despite absence of NMDA receptor-dependent CA1 LTP. After multiple training trials, LTM formation in these mutants is linked to the generation of multi-innervated dendritic spines (MIS), a spine that receives typically two presynaptic inputs. PSD-95 overexpression is sufficient for MIS generation and depends on mTOR signaling. LTM that involves MIS generation appears less modifiable upon retrieval in comparison to LTM without MIS generation. Taken together, MIS generation appears to be a novel LTM mechanism after multiple training trials, which may occur in diseases with impaired LTP or conditions affecting negative feedback CaMKII signaling at the synapse.

Effective expression of Drebrin in hippocampus improves cognitive function and alleviates lesions of Alzheimer's disease in APP (swe)/PS1 (ΔE9) mice

“…These pathologies contribute to the final outcome of neuronal and synaptic death . However, synaptic linkage is the foundation of information transmission between neurons at the distal ends of dendrites, and changes to this transmission play an important role in memory . Furthermore, learning and memory impairment observed in AD has a close relationship with hippocampal synaptic damage in its early stage .…”

“…[6][7][8][9] However, synaptic linkage is the foundation of information transmission between neurons at the distal ends of dendrites, and changes to this transmission play an important role in memory. 10,11 Furthermore, learning and memory impairment observed in AD has a close relationship with hippocampal synaptic damage in its early stage. 12,13 Developmentally regulated brain protein (abbreviated as Drebrin or Dbn, also known as Dbn1 in mouse)…”

Rapid Ultrastructural Changes of PSD and Extrasynaptic Axon-spine Interface Membrane during LTP Induced in Single Dendritic Spine

“…We observed a few spines containing segmented PSDs are innervated by multiple presynaptic boutons. An increase of multi-innervated spines has been reported to be associated with LTP (Giese et al, 2015;Nikonenko et al, 2003;Radwanska et al, 2011). However, probably due to the rare existence of multi-innervated spines (~1% of total spines), it is seldom reported in previous population EM studies that analyzed the ultrastructural correlates for LTP.…”

“…These studies revealed that LTP is correlated with, on average, an enlargement in spine and PSD size, a higher number of concave spine profiles, an increase in perforated PSD, and an increase in polyribosome containing spines (Desmond and Levy, 1986;Van Harreveld and Fifkova, 1975;Harris et al, 1992;Ostroff et al, 2002). Furthermore, LTP has been associated with generation of multi-innervating spines and boutons (Giese et al, 2015;Toni et al, 1999).…”

Down-Regulated Drebrin Aggravates Cognitive Impairments in a Mouse Model of Alzheimer’s Disease

“…The basic unit of information transmission between neurons is the synapse, which is composed of dendritic spines on the surface of dendrites and plays an important role in learning and memory [1,2]. The developmentally regulated brain protein drebrin (Dbn) contains adult type (Dbn A) and embryonic type (Dbn E) [3,4], distributed widely in the central nervous system and peripheral tissue.…”