By Brett Weiss
Synaptic plasticity entails the changes that take place between neurons at their synapses based on activity. Experience facilitates the activity leading to synaptic changes. The synaptic changes lead to memory formation and learning in general. The cellular mechanisms at play in synaptic plasticity include long-term potentiation (LTP) and long-term depression (LTD). LTP involves strengthening synapses, whereas LTD leads to decreasing efficacy of synapses. To initiate LTP, plasticity-inducing synaptic input triggers Ca2+ through NMDA receptors. AMPA receptors then accumulate in the post-synaptic site, giving rise to increased synaptic strength. Moreover, the NMDA receptor-associated influx of Ca2+ stabilizes LTP through activating signaling cascades that promote mRNA and protein synthesis. Using anisomycin (a protein synthesis inhibitor) or NMDA receptor blockers (antagonists), failure of LTP establishment occurs as well as failure to form long-term memories. These observations provide strong evidence that synaptic plasticity and subsequent synaptic strengthening occurs through LTP. The evidence also suggests that LTP maintenance and long-term memory formation requires plasticity related proteins (PRPs). PRPs would result from the expression of genes whose identities remain unknown. Some candidate genes have been implicated in this process, though. Immediate early genes (IEGs) have a rapid and transient response to synaptic activation. These genes include but are not limited to c-fos, egr-1, Arc, and Homer1a (there are actually hundreds of genes classified as IEGs). If these genes do in fact support maintenance of LTP and long-term memory formation, then scientists could potentially manipulate them to treat intellectual disabilities and for cognition enhancement in general in the future.
An interesting and very important study by Liu et al. (2012) showed that synaptic activity-induced expression of an IEG, c-fos, enabled the tagging of cellular ensembles of a memory trace (engram) in mice. In the study, a technique called contextual fear conditioning was used in order to generate a fearful memory in the mice. In contextual fear conditioning, the mouse pairs an unconditioned stimulus (foot shock) with a conditioned stimulus (environmental setting). After training the mice to associate the unconditioned stimulus with the conditioned stimulus, the mouse displays a ‘freezing’ behavior, a fearful response, when placed in the associated environmental setting (conditioned stimulus). The researchers in this study also used optogenetics whereby neurons of the hippocampus (the dentate gyrus, specifically) were infused with genetic tools (transgene components). The point of the use of the transgenes was that activation of the IEG (c-fos) promoter would facilitate expression of channelrhodopsin. Thus, whichever neurons expressed c-fos also expressed channelrhodopsin; and these neurons could then be activated with blue light in subsequent experimentation. These transgenic mice went through contextual fear conditioning, pairing foot shock to a particular context or environmental setting. After the training, the mice were placed in a context which had not previously been paired with the foot shock. Thus, the mice showed no ‘freezing’ behavior initially. However, when scientists flashed a blue light on the neurons, ‘freezing’ behavior ensued in the neutral context. Therefore, this study provides strong evidence that an IEG, c-fos, can act as a cellular marker for neuron activity in a learning situation. When the neurons that c-fos activity marked were reactivated with blue light, the learned behavior (‘freezing’) occurred in a neutral context, thus providing evidence that an IEG, c-fos, shows activity in cellular ensembles of a memory trace (an engram).
Patients with many psychiatric disorders such as major depression, post-traumatic stress disorder, bipolar disorder, and schizophrenia present with impairments in learning and memory. Thus, Gallo et al. (2018) posit that IEGs may have mutations and genetic aberrations in these disorders since they activate during processes of learning and memory. To date, little research has been done on immediate early genes in these psychiatric disorders. Moreover, future research on manipulating IEGs may pave the way for development of cognition-enhancing drugs.
Gallo FT, Katche C, Morici JF, Medina JH, &Weisstaub NV (2018). “Immediate Early Genes, Memory and Psychiatric Disorders: Focus on c-Fos, Egr1 and Arc.” Front Behav Neurosci 12(79).
Kim S, Kim H, & Um JW (2018). “Synapse development organized by neuronal activity-regulated immediate-early genes.” Exp Mol Med 50(4): 11.
Liu X, Ramirez S, Pang PT, Puryear CB, Govindarajan A, Deisseroth K et al. (2012). “Optogenetic stimulation of a hippocampal engram activates fear memory recall.” Nature 484: 381-385.
Minatohara K, Akiyoshi M, & Okuno H (2016). “Role of Immediate-Early Genes in Synaptitc Plasticity and Neuronal Ensembles Underlying the Memory Trace.” Front Mol Neurosci 8 (78).