The Intriguing Contribution of Hippocampal Long-Term Depression to Spatial Learning and Long-Term Memory

Abstract

Long-term potentiation (LTP) and long-term depression (LTD) comprise the principal cellular mechanisms that fulfill established criteria for the physiological correlates of learning and memory. Traditionally LTP, that increases synaptic weights, has been ascribed a prominent role in learning and memory whereas LTD, that decreases them, has often been relegated to the category of “counterpart to LTP” that serves to prevent saturation of synapses. In contradiction of these assumptions, studies over the last several years have provided functional evidence for distinct roles of LTD in specific aspects of hippocampus-dependent associative learning and information encoding. Furthermore, evidence of the experience-dependent “pruning” of excitatory synapses, the majority of which are located on dendritic spines, by means of LTD has been provided. In addition, reports exist of the temporal and physical restriction of LTP in dendritic compartments by means of LTD. Here, we discuss the role of LTD and LTP in experience-dependent information encoding based on empirical evidence derived from conjoint behavioral and electrophysiological studies conducted in behaving rodents. We pinpoint the close interrelation between structural modifications of dendritic spines and the occurrence of LTP and LTD. We report on findings that support that whereas LTP serves to acquire the general scheme of a spatial representation, LTD enables retention of content details. We argue that LTD contributes to learning by engaging in a functional interplay with LTP, rather than serving as its simple counterpart, or negator. We propose that similar spatial experiences that share elements of neuronal representations can be modified by means of LTD to enable pattern separation. Therewith, LTD plays a crucial role in the disambiguation of similar spatial representations and the prevention of generalization.

Brain Single Cell Transcriptomic Profiles in Episodic Memory Phenotypes Associated with Temporal Lobe Epilepsy

“…There is also evidence to suggest that aberrations in synaptic development and plasticity are associated with age-related memory decline, as well as memory and other cognitive impairments in psychiatric, neurological, and neurodegenerative disorders 15,18 . 'Long-term potentiation' and 'synaptic depression,' processes known to be essential for new memory formation, were also top pathways for both neuronal cell types [19][20][21] .…”

Translational neuronal ensembles: Neuronal microcircuits in psychology, physiology, pharmacology and pathology

“…Beginning with correlated plasticity that can be extended to other plasticity types, it is postulated that correlated or timed activity between pre- and post-synaptic elements reinforce synaptic connections, while decorrelated or inverse timing between these elements weaken synaptic connections. These mechanisms generate long lasting changes in the synaptic weights of the network, so that some synapses are enforced [long-term potentiation (LTP)] and other are debilitated or disconnected long-term depression (LTD), producing preferent paths for the flow of activity, being this mechanism the basis to make new circuits for learning and making memory traces ( Kandel et al, 2014 ; Dringenberg, 2020 ; Stacho and Manahan-Vaughan, 2022 ). Besides the unique specialized fast acting synapses that connect neuron groups using postsynaptic ligand-gated ion channels ( Cockcroft et al, 1990 ; Ortells and Lunt, 1995 ; Auerbach, 2013 ), alternative communicating pathways - shared with non-excitable cells - are also present: e.g., volume transmission (paracrine communication), extra-synaptic and synaptic receptors coupled with G-proteins (GPCRs) that can or cannot form heteromeric complexes igniting diverse intracellular signaling cascades (e.g., Agnati et al, 1994 , 2006 ; Lefkowitz, 2000 ; Rasmussen et al, 2011 ; Latek et al, 2012 ; Fuxe et al, 2013 ; Tse and Wong, 2013 ), plasticity of GABAergic inhibitory neurons ( Rueda-Orozco et al, 2009 ; Castillo et al, 2011 ; Roth and Draguhn, 2012 ; Barberis, 2020 ), anti-Hebbian mechanisms, retrograde signaling, the role of neuromodulators, instructive signals and eligibility traces, different synaptic receptor types and sub-units, etcetera, have increased the complexity of synaptic plasticity ( Lamsa et al, 2007 ; Sjöström et al, 2008 ; Conde et al, 2013 ; Piochon et al, 2013 ; Johansen et al, 2014 ; Park et al, 2014 ; Ruan et al, 2014 ; Gerstner et al, 2018 ; Langille and Brown, 2018 ; Cingolani et al, 2019 ; Bannon et al, 2020 ; Magee and Grienberger, 2020 ; Speranza et al, 2021 ).…”

Role of mGlu5 in Persistent Forms of Hippocampal Synaptic Plasticity and the Encoding of Spatial Experience

“…Persistent synaptic plasticity refers to long-lasting (>24 h) changes in synaptic transmission and is expressed in the form of LTP and LTD, both of which facilitate hippocampus-dependent spatial memory [ 87 , 88 , 89 , 90 , 91 , 92 , 93 ]. For this reason, these processes are typically investigated in freely behaving rats and mice [ 93 ].…”

“…The hippocampus is an essential brain structure for the processing and encoding of spatial and associative representations of experience by means of long-term synaptic plasticity [ 87 , 93 , 178 ]. LTP and LTD are the cellular mechanisms that enable the storage of this kind of information [ 88 , 89 , 90 , 93 , 179 , 180 ]. Numerous studies have described the specific kinds of spatial information encoded by LTP and LTD, whereby a differentiation of the relative elements of spatial memory enabled by LTP and LTD has become evident.…”

“…Numerous studies have described the specific kinds of spatial information encoded by LTP and LTD, whereby a differentiation of the relative elements of spatial memory enabled by LTP and LTD has become evident. For example, LTP is expressed in response to the de novo acquisition of knowledge about a novel spatial environment [ 88 , 93 , 180 , 181 , 182 , 183 , 184 , 185 ], whereas LTD is facilitated upon the acquisition, or updating, of knowledge about discrete content features of an environment [ 4 , 88 , 89 , 90 , 180 , 186 , 187 , 188 , 189 ]. All hippocampal subfields reportedly show the same LTP-specific stimulus response related to novel spatial learning [ 88 , 180 , 186 ].…”