Long-term potentiation of synaptic transmission in the hippocampus is the primary experimental model for investigating the synaptic basis of learning and memory in vertebrates. The best understood form of long-term potentiation is induced by the activation of the N-methyl-D-aspartate receptor complex. This subtype of glutamate receptor endows long-term potentiation with Hebbian characteristics, and allows electrical events at the postsynaptic membrane to be transduced into chemical signals which, in turn, are thought to activate both pre- and postsynaptic mechanisms to generate a persistent increase in synaptic strength.

A synaptic model of memory: long-term potentiation in the hippocampus

I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

The field of neuroscience has, after a long period of looking the other way, again embraced emotion as an important research area. Much of the progress has come from studies of fear, and especially fear conditioning. This work has pin- pointed the amygdala as an important component of the system involved in the acqui- sition, storage, and expression of fear memory and has elucidated in detail how stimuli enter, travel through, and exit the amygdala. Some progress has also been made in understanding the cellular and molecular mechanisms that underlie fear conditioning, and recent studies have also shown that the findings from experimental animals apply to the human brain. It is important to remember why this work on emotion succeeded where past efforts failed. It focused on a psychologically well-defined aspect of emo- tion, avoided vague and poorly defined concepts such as "affect," "hedonic tone," or "emotional feelings," and used a simple and straightforward experimental approach. With so much research being done in this area today, it is important that the mistakes of the past not be made again. It is also time to expand from this foundation into broader aspects of mind and behavior

http://gruberpeplab.com/3131/LeDoux_2000_Emotioncircuitbrain.pdf

Emotion Circuits in the Brain

Rapid progress in deciphering the biological mechanism of Alzheimer's disease (AD) has arisen from the application of molecular and cell biology to this complex disorder of the limbic and association cortices. In turn, new insights into fundamental aspects of protein biology have resulted from research on the disease. This beneficial interplay between basic and applied cell biology is well illustrated by advances in understanding the genotype-to-phenotype relationships of familial Alzheimer's disease. All four genes definitively linked to inherited forms of the disease to date have been shown to increase the production and/or deposition of amyloid β-protein in the brain. In particular, evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the β-amyloid precursor protein by the protease called γ-secretase has spurred progress toward novel therapeutics. The finding that presenilin itself may be the long-sought γ-...

Alzheimer's Disease: Genes, Proteins, and Therapy

Glutamate neurotoxicity and diseases of the nervous system

Long-term potentiation of synaptic transmission in the hippocampus is the leading experimental model for the synaptic changes that may underlie learning and memory. This review presents a current understanding of the molecular mechanisms of this long-lasting increase in synaptic strength and describes a simple model that unifies much of the data that previously were viewed as contradictory.

/pdf/long-term-potentiation-a-decade-of-progress-1y4lo4uwwe.pdf

Long-Term Potentiation--A Decade of Progress?

Marijuana affects brain function primarily by activating the G-protein-coupled cannabinoid receptor-1 (CB1)1,2,3, which is expressed throughout the brain at high levels4. Two endogenous lipids, anandamide and 2-arachidonylglycerol (2-AG), have been identified as CB1 ligands5,6. Depolarized hippocampal neurons rapidly release both anandamide and 2-AG in a Ca2+-dependent manner6,7,8. In the hippocampus, CB1 is expressed mainly by GABA (γ-aminobutyric acid)-mediated inhibitory interneurons, where CB1 clusters on the axon terminal9,10,11. A synthetic CB1 agonist depresses GABA release from hippocampal slices10,12. These findings indicate that the function of endogenous cannabinoids released by depolarized hippocampal neurons might be to downregulate GABA release. Here we show that the transient suppression of GABA-mediated transmission that follows depolarization of hippocampal pyramidal neurons13 is mediated by retrograde signalling through release of endogenous cannabinoids. Signalling by the endocannabinoid system thus represents a mechanism by which neurons can communicate backwards across synapses to modulate their inputs.

Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses.

https://www.cell.com/neuron/pdf/0896-6273(95)90046-2.pdf

Evidence for silent synapses: Implications for the expression of LTP

PSD-95 is a neuronal PDZ protein that associates with receptors and cytoskeletal elements at synapses, but whose function is uncertain. We found that overexpression of PSD-95 in hippocampal neurons can drive maturation of glutamatergic synapses. PSD-95 expression enhanced postsynaptic clustering and activity of glutamate receptors. Postsynaptic expression of PSD-95 also enhanced maturation of the presynaptic terminal. These effects required synaptic clustering of PSD-95 but did not rely on its guanylate kinase domain. PSD-95 expression also increased the number and size of dendritic spines. These results demonstrate that PSD-95 can orchestrate synaptic development and are suggestive of roles for PSD-95 in synapse stabilization and plasticity.

http://science.sciencemag.org/content/sci/290/5495/1364.full.pdf

PSD-95 Involvement in Maturation of Excitatory Synapses

The primary psychoactive ingredient in cannabis, Δ^9-tetrahydrocannabinol (Δ^9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.

https://science.sciencemag.org/content/sci/296/5568/678.full.pdf

Roger A. Nicoll

Papers

Long-Term Potentiation--A Decade of Progress?

Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses.

Evidence for silent synapses: Implications for the expression of LTP

PSD-95 Involvement in Maturation of Excitatory Synapses

Endocannabinoid signaling in the brain.