Do thin spines learn to be mushroom spines that remember?

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Dendritic spines are the primary site of excitatory input on most principal neurons. Long-lasting changes in synaptic activity are accompanied by alterations in spine shape, size and number. The responsiveness of thin spines to increases and decreases in synaptic activity has led to the suggestion that they are ‘learning spines’, whereas the stability of mushroom spines suggests that they are ‘memory spines’. Synaptic enhancement leads to an enlargement of thin spines into mushroom spines and the mobilization of subcellular resources to potentiated synapses. Thin spines also concentrate biochemical signals such as Ca2+, providing the synaptic specificity required for learning. Determining the mechanisms that regulate spine morphology is essential for understanding the cellular changes that underlie learning and memory.

Introduction

The majority of excitatory synapses in the brain occur on dendritic spines. Mature spines have a bulbous head that forms part of an excitatory synapse and is connected to the dendrite by a constricted neck. Neighboring spines vary dramatically in size and shape (Figure 1). In adult hippocampus and neocortex, spine shapes differ categorically with >65% of spines being ‘thin’ and ∼25% being ‘mushroom’, having head diameters >0.6 μm [1, 2]. Under normal circumstances, ∼10% of spines in the mature brain have immature shapes: stubby, multisynaptic, filopodial or branched [1, 2, 3, 4]. These shapes can be recognized using light microscopy if the spine is properly oriented, but accurate identification and measurement of spine synapses, dimensions and composition requires reconstruction from serial section transmission electron microscopy (ssTEM). Here we evaluate evidence from the past few years that addresses the question of whether thin and mushroom spines represent distinct categories, or whether they instead switch shapes depending on synaptic plasticity during learning.

Section snippets

Maturation and stabilization of spines

Spines tend to stabilize with maturation [5]; however, a small proportion continues to turnover in more mature brains [5•, 6•, 7•]. The transient spines are thin spines that emerge and disappear over a few days, whereas mushroom spines can persist for months [5•, 6•]. Mushroom spines have larger postsynaptic densities (PSDs) [1], which anchor more AMPA glutamate receptors and make these synapses functionally stronger [8, 9, 10, 11, 12]. Mushroom spines are more likely than thin spines to

Distance-dependent or input-dependent regulation of spine shape

Differences in synapse dimensions might also compensate for distance-dependent differences in dendritic function [23]. Recent studies show that nearly all of the most distal synapses on the apical dendritic tufts of hippocampal CA1 pyramidal cells have large perforated synapses [24]. Perforations in synapses have been seen only on large mushroom spines and they seem to be transient results of intense presynaptic activation [4]. Nevertheless, the perforations categorically identify large

Spine necks regulate biochemical and electrical signals in large and small spines

Compartmentalization of Ca2+ within the spine head is controlled by spine neck dimensions in both mushroom and thin spines of CA1 pyramidal cells [26]: spines that have narrower or longer necks appear to retain more Ca2+ in their heads following synaptic activation than do wider shorter spines. Depending on the absolute concentration achieved, the localized increase in Ca2+ levels could modulate signaling cascades that strengthen or weaken spine synapses. The bidirectional diffusion of

Long-term potentiation converts ‘learning spines’ into ‘memory spines’

Long-term potentiation (LTP) is an enduring enhancement of synaptic transmission that is thought to be the cellular correlate of learning and memory. In the immature hippocampus, one effect of LTP is to increase spine head size [36, 37, 38•, 39••], which is followed by an accumulation of AMPA receptors at the synapse (Figure 2) [38]. Both large and small spines undergo the same absolute increase in head volume and surface area [37, 38•]. Recent work reveals a mobilization of recycling

Long-term depression converts ‘memory spines’ into ‘learning spines’

Long-term depression (LTD) also has an integral role in the processing and retention of information but, in contrast to LTP, LTD is a long-lasting reduction in synaptic transmission that results from low-frequency stimulation. Induction of LTD results in shrinkage [50] or retraction of dendritic spines [51] associated with a depolymerization of actin [52]. Perhaps the conversion of large ‘memory spines’ back into smaller ‘learning spines’ resets the plasticity potential of the dendrite.

Conclusions

Age-related and disease-related declines in cognitive ability are accompanied by decreases in spine density [53, 54••, 55••, 56••, 57]. Treatments aimed to counteract age-related cognitive decline result in an increase in numbers of thin spines specifically [56••], suggesting that thin spines are necessary to restore the potential for synaptic plasticity and learning in the aged brain. In addition, the structural stability and abundance of subcellular resources supports the hypothesis that

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank John Mendenhall and Gwen Gage for assistance on the figures. This work was supported by NIH grants NS21184, NS33574 and EB002170 to KMH.

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