cJun and CREB2 in the Postsynaptic Neuron Contribute to Persistent Long-Term Facilitation at a Behaviorally Relevant Synapse

Abstract

Basic region leucine zipper (bZIP) transcription factors regulate gene expression critical for long-term synaptic plasticity or neuronal excitability contributing to learning and memory. At sensorimotor synapses of Aplysia, changes in activation or expression of CREB1 and CREB2 in sensory neurons are required for long-term synaptic plasticity. However, it is unknown whether concomitant stimulus-induced changes in expression and activation of bZIP transcription factors in the postsynaptic motor neuron also contribute to persistent long-term facilitation (P-LTF). We overexpressed various forms of CREB1, CREB2, or cJun in the postsynaptic motor neuron L7 in cell culture to examine whether these factors contribute to P-LTF. P-LTF is evoked by 2 consecutive days of 5-HT applications (2 5-HT), while a transient form of LTF is produced by 1 day of 5-HT applications (1 5-HT). Significant increases in the expression of both cJun and CREB2 mRNA in L7 accompany P-LTF. Overexpressing each bZIP factor in L7 did not alter basal synapse strength, while coexpressing cJun and CREB2 in L7 evoked persistent increases in basal synapse strength. In contrast, overexpressing cJun and CREB2 in sensory neurons evoked persistent decreases in basal synapse strength. Overexpressing wild-type cJun or CREB2, but not CREB1, in L7 can replace the second day of 5-HT applications in producing P-LTF. Reducing cJun activity in L7 blocked P-LTF evoked by 2 5-HT. These results suggest that expression and activation of different bZIP factors in both presynaptic and postsynaptic neurons contribute to persistent change in synapse strength including stimulus-dependent long-term synaptic plasticity.

New learning while consolidating memory during sleep is actively blocked by a protein synthesis dependent process

“…We have not determined whether the brief training with anisomycin during the inactive phase produces only 24 hr memory, or also a more persistent memory. If the training produces a persistent memory, it could require changes in CREB2 expression 6 hr or more after training, similar to the post-synaptic increases seen by Hu et al (2015) for persistent synaptic plasticity. However, since they found that CREB2 expression decreases presynaptically but increases postsynaptically, examining expression in the whole buccal ganglia might not find these changes, if presynaptic and postsynaptic changes balance one another.…”

“…It is important to note that CREB2 transcription could still have a major role in the regulation of memory formation in our system. Hu et al (2015) showed that post-synaptic increases in CREB2 and c-jun underlie a persistent increase in synaptic strength, along with presynaptic decreases. In our behavioral paradigm, a full training during the active phase produces separable long-term (24 hr) and persistent (48 hr and longer) memories (Levitan et al, 2010).…”

“…In most experiments, the expression of target mRNAs was normalized to the expression of Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) mRNA, whose expression is not thought to be regulated by training, and which has been used extensively as a housekeeping control gene ( e.g. , Hu et al, 2015). In a single experiment (that shown in Figure 8B) that was performed much earlier than the rest of the experiments, histone H4 was used as the housekeeping gene.…”

Specific Downregulation of Hippocampal ATF4 Reveals a Necessary Role in Synaptic Plasticity and Memory

“…These studies target pathways, such as PERK and HRI kinases. Additionally, a recent study on Aplysia sensorimotor long-term facilitation (LTF) provided evidence that LTF in this system requires increased post-synaptic ApCREB2 expression/activity (Hu et al, 2015). Interestingly, elevating ApCREB2 post-synaptically increased synaptic strength while doing this pre-synaptically decreased synaptic strength.…”

Dietary Quercetin Ameliorates Memory Impairment in a Murine Model of Alzheimer’s Disease with Obesity and Diabetes, Suppressing ATF4 Expression

“…ATF4 plays several critical roles in cellular physiology. For example, ATF4 expression is induced as a component of the integrated stress response (ISR) that regulates cellular amino acid supply, protects against oxidative stress [4], and supports normal postsynaptic function [5,6]. The ISR is implicated in several disease states [7] such as obesity and diabetes [8].…”