It is important to start with a caveat that this review certainly cannot do justice to the full literature on the neurobiology of memory, but rather is necessarily simplified, and probably inaccurate at points, as any overview will fail to account for the true complexity of any field. However, an attempt to map questions from psychiatry and psychology onto mechanisms understood by neurobiology is an essential translational step that may promote insight into biological factors contributing to the pathophysiology of schizophrenia.
Current neurobiological models of memory suggest that there is significant, although not conclusive, data indicating that LTP processes are the biological substrate of memory.78–80
There is also significant evidence that biological processes that are engaged at, or soon after, the encoding of stimuli help to differentiate whether information will be solely represented in short-term memory or will be represented in long-term memory.80
Early LTP, which consolidates between 5 and 30 minutes after induction,78
is based on a reorganization of the actin cytoskeleton within postsynaptic spines. Specifically, significant depolarization of the spine results in the influx of calcium ions through voltage-sensitive N
-aspartate receptors. This calcium influx, in turn, activates calcium-sensitive protein kinases and protease calpain, which, by dissembling proteins (spectrim, actinin, Arc) that typically stabilize actin filaments, support changes in the postsynaptic density of the spine. In addition, during this process, additional alpha-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid receptors are added to the spine, which increases its response to glutamate. Thus, early LTP appears to specifically involve changes in the postsynaptic spine, increasing the availability of glutamate receptors and thus providing increased sensitivity to presynaptic neuron activity.
Late LTP involves the activation of additional processes. Specifically, in late LTP calcium ion entry into the neuron activates cell signaling cascades, including cyclic adenosine monophosphate, and associated increases in activation of regulatory proteins (such as protein kinase A, mitogen-activated kinases, extracellular signal–regulated kinases) that in turn modulate cyclic AMP-response element binding protein (CREB)-related gene expression.79
There are regional variations in the availability of different protein kinases, but they similarly act to modulate gene expression and protein synthesis. Reymann and Frey80
note that late LTP is dependent on the availability of plasticity-related proteins (PRPs). Although some PRPs are already available in neurons, this cache is typically depleted after about 8 hours; the availability of PRPs after 8 hours is dependent on initiation of CREB cycles to support gene expression in order to create additional PRPs. Modulatory neurotransmitters, such as dopamine or norepinephrine, appear central to the initiation of this additional process.81
Reymann and Frey80
specifically note that there is significant evidence of D5 receptors in the CA1 region that may act to support late LTP via dopaminergic effects on glycoprotein processing within these neurons and that similar effects are found for noradrenergic activity and glycoprotein activity in the dentate gyrus. Thus, induction of late LTP, in contrast to early LTP, requires heterosynaptic inputs, such as the activation of glutamatergic and dopaminergic receptors in area CA1 or glutamatergic and noradrenergic or muscarinic receptors in the dentate gyrus.19
Impact of Emotion on LTP
As noted above, neurotransmitters and neuroendocrines, which increase in response to emotional stimuli, such as norepinephrine, dopamine, and glucocorticoids, have significant effects on late LTP via their impact on glycoprotein processing. Studies that have manipulated neurotransmitter or neuroendocrine responses to emotional stimuli have demonstrated specific impairment in long-term memory but not short-term memory (cf 82