Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the infor- mation storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency.

Synaptic plasticity and memory: an evaluation of the hypothesis

Although over 100 molecules have been implicated in long-term potentiation and depression, no consensus on their underlying molecular mechanisms has emerged. Here we discuss the difficulties of providing molecular explanations for cellular neurobiological phenomena.

Can molecules explain long-term potentiation?

Hippocampal lesions produce memory deficits, but the exact function of the hippocampus remains obscure Evidence is presented that its role in memory may be ancillary to physiological regulation Molecular studies demonstrate that the hippocampus is a primary target for ligands that reflect body physiology, including ion balance and blood pressure, immunity, pain, reproductive status, satiety and stress Hippocampal receptors are functional, probably accessible to their ligands, and mediate physiological and cognitive changes This argues that an early role of the hippocampus may have been in sensing soluble molecules (termed here 'enteroception') in blood and cerebrospinal fluid, perhaps reflecting a common evolutionary origin with the olfactory system ('exteroception') Functionally, hippocampal enteroception may reflect feedback control; evidence is reviewed that the hippocampus modulates body physiology, including the activity of the hypothalamus-pituitary-adrenal axis, blood pressure, immunity, and reproductive function It is suggested that the hippocampus operates, in parallel with the amygdala, to modulate body physiology in response to cognitive stimuli Hippocampal outputs are predominantly inhibitory on downstream neuroendocrine activity; increased synaptic efficacy in the hippocampus (eg long-term potentiation) could facilitate throughput inhibition This may have implications for the role of the hippocampus and long-term potentiation in memory

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Hormones and the hippocampus

Neurosteroid hydroxylase CYP7B: vivid reporter activity in dentate gyrus of gene-targeted mice and abolition of a widespread pathway of steroid and oxysterol hydroxylation.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793%2800%2901779-8

Gene trap: a way to identify novel genes and unravel their biological function

Mice harboring random gene-trap insertions of a lacZ (b-galactosidase)-neomycin resistance fusion cassette (b-geo) were ana- lyzed for expression in the hippocampus. In 4 of 15 lines reporter gene activity was observed in the hippocampal formation. In the obn line, enzyme activity was detected in the CA1-3 hippocampal subfields, in hpk expression was restricted to CA1, but in both lines reporter activity was also present in other brain regions. In the third line, kin, reporter activity was robustly expressed throughout the stratum pyrimidale of CA1-3, with only low-level expression elsewhere. The final line (glnC) displayed ubiquitous expression of the reporter and was not analyzed further. Fusion transcripts for the first three lines were characterized; all encode polypep- tides with features of membrane-associated signalling proteins. The obn fusion identified a human cDNA (B2-1) encoding a pleckstrin homology (PH) domain, while hpk sequences matched the Epstein-Barr Virus (EBV) inducible G-protein coupled receptor, EBI-1. kin identified an alternative form of the abl-related nonreceptor tyrosine kinase c-arg. Electrophysiologi- cal studies on mice homozygous for the insertions revealed normal synaptic transmission, paired pulse facilitation and paired-pulse depres- sion at Schaffer collateral-commissural CA1 synapses, and normal long- term potentiation (LTP) in obn and kin. hpk mice displayed an increase in hippocampal CA1 long-term potentiation (LTP), suggesting a role for this receptor in synaptic plasticity. Hippocampus 1998;8:444-457. r 1998 Wiley-Liss, Inc.

http://www.pieta-research.org/PDFfiles/STEEL1998.pdf

Katherine A. Clark

Papers

Gene‐trapping to identify and analyze genes expressed in the mouse hippocampus