This Special Issue of Neurobiology of Learning and Memory brings
together 19 invited articles from work presented at the meetings of
the Molecular and Cellular Cognition Society (MCCS) over the past
year and from scientists involved in the Society. This includes the
Eleventh Annual MCCS Meeting held in Washington, D.C. in
October 2012 and the First Annual MCCS-Australia Meeting held
in Melbourne, Australia in February 2013. MCCS is an international
organization that seeks to facilitate discussion, collaboration and
interchange among laboratories studying the molecular and cellular basis of behavior. Meetings are held on a regular basis in the US,
Europe, Asia and Australia. We hope that this Special Issue provides a way for the broader research community to participate in
these discussions and to benefit from the collection of ideas and
novel experimental approaches that are the hallmark of cutting
edge research in this field.
Signaling at the synapse. Scaffolding proteins of the postsynaptic
density (PSD) organize glutamate receptors and signaling molecules at specific locations in neurons. Can Gao, Natalie Tronson,
and Jelena Radulovic of Northwestern University review findings
showing that knockout, knockdown, and knockin of the specific
glutamate receptor scaffolding proteins affect specific subsets of
behaviors. These authors also discuss clinical implications of these
findings, suggesting that approaches to control the function of PSD
scaffolds have the potential to restore normal behavior to individuals with psychiatric disorders. Jess Nithianantharajah and Seth
Grant from the University of Edinburgh describe the recent development of touchscreen tasks that can be used in both human and
rodent subjects to measure similar components of cognition. By
combining these tasks with genetic mutations in mice and genotyping in humans, they been able to genetically dissect behaviors,
identifying the role of particular gene products in aspects of cognition. They apply this to a group of Membrane Associated Guanylate
Kinase (MAGUK) proteins that mediate protein-protein interactions and assemble signaling complexes in the postsynaptic density, revealing that different paralogs have evolved specific roles
in cognition that are similar in mice and humans.
Cell–cell communication is also mediated by mechanisms that
function outside of the classical chemical synapse. An example of
this is the Notch pathway, an evolutionarily conserved signaling
system for cell-cell communication. Derya Sargin, Sheena Josselyn
and colleagues at the Hospital for Sick Children in Toronto describe
the results of studies that demonstrate that mice with reduced levels of Jagged 1, a ligand for the Notch1 receptor, have a selective
impairment in spatial memory formation. In contrast, mice with
reduced levels of other Notch1 ligands such as Deltal-like, have
normal memory. These results suggest that Jagged 1-Notch1 signaling is required for spatial memory. Gap junctions provide an
additional way for cells to communicate and these have been
linked to a number of roles in regulating the activity of neuronal
circuits. Metaplasticity refers to the idea that prior neuronal activity may alter thresholds for future plasticity promoting information storage. Owen Jones, Sarah Hulme and Wickliffe Abraham
from the University of Otago, Dunedin, New Zealand describe a
novel form of heterodendritic metaplasticity involving interactions
between stratum oriens and stratum radiatum in the hippocampus. Their work reveals that this form of metaplasticity is dependent on extracellular purinergic signaling involving adenosine A2
receptors and is blocked by several gap junction inhibitors suggesting that it depends on intracellular communication via gap
junctions.
Beyond neurons, glia and microglial regulate synaptic function.
Gary Morris, Bryce Vissel and colleagues at the Garvan Institute of
Medical Research in Sydney describe emerging roles for microglia,
the resident macrophages in the brain. These ramified cells have
plastic processes that they can rapid extend and contract to modulate synaptic and neural function by the release of cytokines and
growth factors. Microglia change in structure and function in neurological disorders such as Alzheimer’s and Parkinson’s Disease
and may contribute to the underlying pathology in these disorders.
The role of protein kinases in cognition. Cyclin-dependent kinase
5 (Cdk5) has been shown to modulate synaptic function by targeting NMDA receptors and PSD-95. Susan Su, Li-Huei Tsai and colleagues at MIT present findings that indicate that forebrain
specific deletion of Cdk5 in excitatory neurons in mice results in
impairments in spatial and contextual fear memory. Moreover,
the deletion of Cdk5 also results in hyperactivity that can be
blocked by administration of lithium. Taken together these findings demonstrate that expression of Cdk5 in excitatory neurons
is required for normal cognition and behavior.
The striatum is important for procedural and motor learning, as
well as reward-directed behaviors. Milica Cerovic, Riccardo Brambilla, and colleagues at the San Raffaele Scientific Institute discuss
cellular mechanisms of striatal synaptic plasticity and signaling
pathways underlying striatum-dependent behaviors, with a particular emphasis on endocannabinoids and Ras-ERK signaling.
Adult-born neurons are able to incorporate themselves into the
neural circuitry of the hippocampus and modulate memory, and
the mechanisms that regulate adult neurogenesis are an active
1074-7427/$ - see front matter  2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.nlm.2013.08.005
Neurobiology of Learning and Memory 105 (2013) 1–2
Contents lists available at ScienceDirect
Neurobiology of Learning and Memory
journal homepage: www.elsevier.com/locate/ynlme
area of investigation. In their review, Yung-Wei Pan, Daniel Storm
and Zhengui Xia at the University of Washington in Seattle
describe the role of ERK5, a MAP kinase whose expression in
restricted to neurogenic regions of the brain, in hippocampusdependent memory and relate this to the current evidence implicating neurogenesis in hippocampal function.
The regulation of protein synthesis and degradation in synaptic
plasticity and memory. It has been known for over 50 years that
new protein synthesis is required for long-term memory consolidation. Mimi Trinh of Takeda Pharmaceuticals and Eric Klann of
New York University discuss the evidence that the phosphorylation
of the translation initiation factor eIF2 a by at least three different
protein kinases is required for long-lasting synaptic plasticity and
long-term memory consolidation. In addition, Elham Taha, Kobi
Rosenblum, and colleagues at the University of Haifa review the
evidence that the regulation of translation elongation by eEF2 is
an additional mechanism required long-term memory consolidation. Translation initiation and elongation are not the only means
of regulating protein experssion, as new protein degradation also
appears to be required for long-term memory formation. Timothy
Jarome and Fred Helmsetter from the University of Wisconsin—
Milwaukee review the evidence that protein degradation via the
ubiquitin–proteasome system is critical for various forms of synaptic plasticity, as well as for the consolidation and reconsolidation of
long-term memory. Regulating protein expression during memory
formation likely depends on specific patterns of neuronal activity
and underlies the trial spacing effect. Gary Phillips, Ashley Kopec,
and Thomas Carew of New York University review the cellular
and molecular properties of neurons and circuits that underlie
training pattern sensitivity during long-term memory formation
and discuss mechanisms that support intertrial interactions during
the induction of long-term memory.
Epigenetic mechanisms of learning and memory. Recent work has
identified DNA methylation as one of the epigenetic mechanisms
regulating memory storage and dynamic changes in DNA methylation occur in response to experience. In their review of this topic,
Xiang Li, Timothy Bredy and colleagues from the University of
Queensland, Brisbane focus on the mechanisms of DNA demethylation, a complex process whose molecular machinery is just beginning to be elucidated. Importantly, the processes of DNA
demethylation are especially dynamic in neurons and understanding their molecular basis promises to identify novel mechanisms
by which experience regulated the activity of neural circuits. Epigenetic mechanisms have been linked to sensitization, a form of
non-associative learning in which a behavioral response is enhanced following an aversive stimulus. Elizabeth Rahn, David Sweatt and colleagues from the University of Alabama, Birmingham
examine sensitization across phyla from the long-term sensitization of withdrawal reflexes in Aplysia to sensitization of hyperarousal in mammalian models of post-traumatic stress disorder
to neuropathic pain. Together these various models have as a common underlying mechanism the epigenetic regulation of gene
expression. The Nr4a family of nuclear receptor transcription factors is a group of three activity-regulated genes that have been
found to play important roles in several kinds of hippocampusdependent learning and memory, and in mediating the enhancement of long-term memory by treatment with HDAC inhibitors.
Hypothesizing that these transcription factors also play a critical
role in hippocampal synaptic plasticity, Morgan Bridi and Ted Abel
from the University of Pennsylvania utilized a strain of mice
expressing a dominant-negative Nr4a transgene to block NR4A
transcription factor function. They found that the NR4A transcription factors are necessary both for transcription-dependent longterm potentiation and the enhancement of LTP by acute HDAC
inhibitor administration. They also demonstrated that the observed deficits in LTP were reversed by suppression of the dominant-negative transgene in adult mice.
Memory of addiction. It has been shown that the amygdala is
involved in associative learning that underlies drug addiction.
Yi-Xiao Luo, Lin Lu, and colleagues at Peking University discuss
preclinical studies of conditioned place preference and self-administration models that have examined the role of the amygdala in
acquisition, consolidation, retrieval, reconsolidation, and extinction of drug-related memory.
Stress and memory. Stress critically impacts learning and memory. In their studies, Shannon Moore, Geoffrey Murphy and colleagues at the University of Michigan in Ann Arbor explore the
effects of manipulating a stressor on short-term and long-term
memory in a novel object recognition task. These data studies provide important characterization of the impact of environmental
stressors on object tasks, which are commonly used to assess
memory in genetically modified mice and during aging.
Changes in neuronal firing properties with learning. Changes in
the excitability of a neuron, termed intrinsic plasticity, can result
from alterations in the number, activity or distribution of ion channels in the cell membrane. Megha Sehgal, James Moyer and colleagues at the University of Wisconsin-Milwaukee review how
intrinsic plasticity can shape adaptive changes within neural circuits, acting as a form metaplasticity to modulate the threshold
for changes in synaptic efficacy. This often overlooked form of plasticity may play a particularly important role in the cognitive defects that accompany aging. Joseph Tsien and colleagues at
Georgia Regents University describe their efforts to map real-time
episodic memory traces in the hippocampus of freely behaving
mice. They show that large-scale statistical methods are essential
to decipher and measure memory traces and neural dynamics in
real time, and how well-designed behavioral paradigms are key
to the examination of memory-coding cell assembly in the
hippocampus.