Molecular regulation of synaptogenesis during associative learning and memory

doi:10.1016/j.brainres.2014.11.054

Brain Research

Volume 1621, 24 September 2015, Pages 239-251

https://doi.org/10.1016/j.brainres.2014.11.054 Get rights and content

Highlights

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Biochemical pathways in adult synaptogenesis are described.
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Synaptogenesis plays a central role in associative learning and memory.
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Cell–cell contact and soluble factors released from astrocytes are important in synaptogenesis.
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Intracellular signaling pathways involving protein kinase C provide neuronal specificity which is required for associative memory.

Abstract

Synaptogenesis plays a central role in associative learning and memory. The biochemical pathways that underlie synaptogenesis are complex and incompletely understood. Nevertheless, research has so far identified three conceptually distinct routes to synaptogenesis: cell–cell contact mediated by adhesion proteins, cell–cell biochemical signaling from astrocytes and other cells, and neuronal signaling through classical ion channels and cell surface receptors. The cell adhesion pathways provide the physical substrate to the new synaptic connection, while cell–cell signaling may provide a global or regional signal, and the activity-dependent pathways provide the neuronal specificity that is required for the new synapses to produce functional neuronal networks capable of storing associative memories. These three aspects of synaptogenesis require activation of a variety of interacting biochemical pathways that converge on the actin cytoskeleton and strengthen the synapse in an information-dependent manner.

This article is part of a Special Issue titled SI: Brain and Memory.

Introduction

Recent research has shown that synaptogenesis is not only important during development, but also plays a central role in associative learning and memory. Synapse loss is found in patients with major clinical depression and in neurodegenerative disorders such as Alzheimer׳s disease, where it is associated with decreased memory and cognitive function. Conversely, antidepressants produce significant increases in the number of synapses in the adult brain. Synaptogenesis can be triggered by neuron–astrocyte or neuron–neuron contact, and mediated by cell-adhesion proteins including neurexin/neuroligin, Eph receptors, and cadherins, which activate intracellular signaling pathways involving cofilin, GTPases, and other proteins. It can also be triggered by soluble factors released from astrocytes, including BDNF, thrombospondins, and apolipoprotein E/cholesterol. For synaptogenesis to have a meaningful connection to associative learning and memory, a third process of synapse stabilization and maturation, which depends on neuron-specific synaptic activity, is also important. This process involves long-term changes to neuronal connectivity and cytoarchitectural changes mediated by intracellular proteins including protein kinase C, Rho GTPases, and cofilin, which convert unstable filopodia to stable mushroom synapses that can survive for the lifetime of an individual (Koleske, 2013). Drugs that enhance synaptogenesis, such as protein kinase C activators or TrkB receptor agonists, may be useful in restoring normal neuronal function in a variety of disorders.

Section snippets

Cell adhesion proteins

Synapses are structural elements between cells, so synaptogenesis necessarily involves the formation of new cell–cell contacts (Fig. 1). These trans-synaptic contacts are mediated by extracellular interactions between a variety of adhesion proteins including neuroligins, neurexin, cadherins, ephrin, SynCAMs, and leucine-rich-repeat proteins.

Synaptogenic factors secreted from astrocytes

In cultured neuronal and retinal cells, astrocyte-conditioned medium contains a variety of substances secreted from astrocytes that induce synaptogenesis. One of these was identified as a lipoprotein complex of apolipoprotein E (apoE) and cholesterol (Mauch et al., 2001, Ullian et al., 2001, Ullian et al., 2004, Fester et al., 2009, Goritz et al., 2005). The primary source of cholesterol is cholesterol synthesized in neurons and astroglia. Little or none crosses the blood–brain barrier (

Neuronal signaling pathways

Transduction of adhesion protein signals activates several neuronal signaling pathways that ultimately result in stabilization of the synapse to its mature mushroom morphology. These structural changes involve signaling pathways such as Rho GTPases and protein kinase C that modify the cytoskeleton.

Similarities and differences between associative learning and long-term potentiation

Many of the same biochemical pathways in learning are also important in long-term potentiation (LTP), and studies of LTP and long-term depression (LTD) have greatly improved our understanding of synaptic plasticity. Both require CaM-dependent protein kinases and PKC (Lisman et al., 2002), Eph receptors (Klein, 2009, Trabalza et al., 2012), and protein synthesis, and are strongly regulated by BDNF (Minichiello, 2009). Both involve reorganization of the actin cytoskeleton in dendritic spines (

Conclusion

Adult synaptogenesis and dendritic spine formation and maturation may be the principal physiological substrates for associative memory. The biochemical pathways that underlie these processes are complex and incompletely understood. Nevertheless, research has so far identified three pillars of synaptogenesis: cell–cell contact mediated by adhesion proteins, cell–cell biochemical signaling from astrocytes and other cells, and neuronal signaling through classical ion channels and cell surface

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Research ReportMolecular regulation of synaptogenesis during associative learning and memory

Highlights

Abstract

Introduction

Section snippets

Cell adhesion proteins

Synaptogenic factors secreted from astrocytes

Neuronal signaling pathways

Similarities and differences between associative learning and long-term potentiation

Conclusion

Brain Res.

Cell

Trends Neurosci.

Neurobiol. Dis.

Neuron

Trends Cell Biol.

J. Biol. Chem.

Neuron

Neurobiol. Learn. Mem.

Cell

Cell

Curr. Opin. Neurobiol.

Cell

Trends Neurosci.

Trends Neurosci.

Neuroscience

Mol. Cell. Neurosci.

Trends Neurosci.

Neuron

Neuron

Neurobiol. Dis.

Neurobiol. Aging

Mol. Cell. Neurosci.

Cell

Behav. Brain Res.

Neuron

Neuron

Neuropharmacology

Neuron

J. Biol. Chem.

J. Pharmacol. Sci.

Neuron

Mouse and rat BDNF gene structure and expression revisited

J. Neurosci. Res.

Protein synthesis required for long-term memory is induced by PKC activation on days before associative learning

Proc. Natl. Acad. Sci. USA

Primary changes of membrane currents during retention of associative learning

Science

Regulation of Hermissenda K+ channels by cytoplasmic and membrane-associated C-kinase

J. Neurochem.

Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors

Nature

The Coffin–Lowry syndrome-associated protein RSK2 regulates neurite outgrowth through phosphorylation of phospholipase D1 (PLD1) and synthesis of phosphatidic acid

J. Neurosci.

Classical conditioning induces long-term translocation of protein kinase C in rabbit hippocampal CA1 cells

Proc. Natl. Acad. Sci. USA

Distinct components of spatial learning revealed by prior training and NMDA receptor blockade

Nature

Afadin, a Ras/Rap effector that controls cadherin function, promotes spine and excitatory synapse density in the hippocampus

J. Neurosci.

Synapse-specific regulation of AMPA receptor function by PSD-95

Proc. Natl. Acad. Sci. USA

SynCAM, a synaptic adhesion molecule that drives synapse assembly

Science

Wealth of opportunity—the C1 domain as a target for drug development

Curr. Drug Targets

The diacylglycerol-binding protein alpha1-chimaerin regulates dendritic morphology

Proc. Natl. Acad. Sci. USA

Control of excitatory and inhibitory synapse formation by neuroligins

Science

Synapse loss in dementias

J. Neurosci. Res.

Identification of the phosphatidylserine binding site in the C2 domain that is important for PKC alpha activation and in vivo cell localization

Biochemistry

Characterization of the membrane binding mode of the C2 domain of PKC epsilon

Biochemistry

“Picolog,” a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo

Oncotarget

Research Report
Molecular regulation of synaptogenesis during associative learning and memory

Regulation of Hermissenda K⁺ channels by cytoplasmic and membrane-associated C-kinase