CREB1 Encodes a Nuclear Activator, a Repressor, and a Cytoplasmic Modulator that Form a Regulatory Unit Critical for Long-Term Facilitation

TLDR

Although CREB seems to be important for memory formation, it is not known which of the isoforms of CREB, CREM, or ATF1 are expressed in the neurons that undergo long‑term synaptic changes and what roles they have in memory formation. We identified a single Aplysia CREB1 gene homologous to mammalian CREB and CREM, and characterized its three encoded proteins—CREB1a, CREB1b, and CREB1c—in the sensory neurons mediating the gill‑withdrawal reflex. CREB1a acts as a transcriptional activator necessary and sufficient for long‑term facilitation upon phosphorylation, CREB1b represses long‑term facilitation, and cytoplasmic CREB1c modulates both short‑ and long‑term facilitation, together forming a regulatory unit that converts short‑ to long‑term synaptic changes.

Abstract

Although CREB seems to be important for memory formation, it is not known which of the isoforms of CREB, CREM, or ATF1 are expressed in the neurons that undergo long-term synaptic changes and what roles they have in memory formation. We have found a single Aplysia CREB1 gene homologous to both mammalian CREB and CREM and have characterized in the sensory neurons that mediate gill-withdrawal reflex the expression and function of the three proteins that it encodes: CREB1a, CREB1b, and CREB1c. CREB1a is a transcriptional activator that is both necessary and, upon phosphorylation, sufficient for long-term facilitation. CREB1b is a repressor of long-term facilitation. Cytoplasmic CREB1c modulates both the short- and long-term facilitation. Thus, in the sensory neurons, CREB1 encodes a critical regulatory unit converting short- to long-term synaptic changes.