From Synapse to Nucleus

Synaptic transmission is best understood as the effects that a neurotransmitter, released by one nerve cell, exerts on a second nerve cell by virtue of its binding to a specific receptor. The activation of a receptor by its neurotrans-mitter triggers chemical changes inside the second nerve cell that alter its electrical activity. This occurs on the time scale of milliseconds to seconds. Operating on a much slower time scale, on the order of minutes to hours, are more complex chemical changes triggered by that very same neurotransmitter-receptor interaction. Thus, in addition to regulating ion channels, such interactions initiate cascades of chemical changes that eventually signal to the nerve cell's nucleus, where changes in gene expression - alterations in the amounts and types of proteins expressed by that cell - are induced. For example, synaptic transmission can alter the levels of ion channels or receptors expressed by a nerve cell. Consequently, at some later time point, when the first nerve cell again releases neurotransmitter onto that second nerve cell, the second nerve cell shows an altered response due to these changes in gene expression. This represents a unit of "molecular memory.'' Somehow, by summating these changes across the trillions of synapses in the brain, and integrating them over time, an organism learns and remembers and thereby adapts and responds to its environment.

We now know a great deal about the mechanisms by which synaptic transmission alters gene expression. The most important mechanism involves the activation of a class of proteins termed transcription factors (TFs), which bind to regulatory regions (called promoters) of specific genes and thereby increase or decrease the rate by which those genes are expressed. Hundreds of TFs are known, which exhibit three general mechanisms for their activation by synaptic transmission. Some TFs, expressed in nerve cells under basal conditions, are activated by cascades of ► second messenger and protein phosphoryla-tion pathways that are stimulated (or inhibited) when neurotransmitters bind to their receptors. A prototypical example is CREB (cAMP response element binding protein), which can be phosphorylated and activated by a wide range of second messenger cascades illustrated in Fig. 1. For example, in striatum, ► dopamine (via activation of the cAMP pathway) and ► glutamate (via activation of Ca2+ pathways) activate several different protein kinases, each of which phosphorylates CREB on the same serine residue, resulting in the activation of its transcrip-tional properties. The TFs Elkl and SRF (serum response factor) are regulated via similar mechanisms (Fig. 1). A related mechanism exists for another TF, termed NFkB (nuclear factor kB). At baseline, NFkB is bound to an inhibitor protein, IkB (inhibitor of kB), which sequesters NFkB in the cytoplasm. Upon activation of certain second messenger cascades, IkB is phosphorylated, leading to its degradation and the freeing up of NFkB to enter the nucleus where it exerts its transcriptional effects.

Other TFs are expressed at very low levels under normal conditions but are induced in nerve cells in response to neurotransmitter-receptor interactions. Examples include Fos (e.g., c-Fos, FosB) and Egr (early growth response) families of TFs. These TFs are induced because their promoter regions contain target sites for preexisting TFs such as CREB and SRF (see Fig. 1).

The third paradigm of TF activation operates for the steroid hormone receptor family of proteins, which are activated upon binding their respective hormone (e.g., glucocorticoids, gonadal steroids, etc.) and can therefore be viewed as ligand-activated TFs. Under basal conditions, steroid hormone receptors are bound by chaperone proteins which keep them in the cytoplasm. Steroid hormones, which readily permeate cell membranes, bind to the receptors and trigger their release from the chaperones and their movement to the nucleus. Once in the nucleus, the steroid receptors bind directly to responsive genes or bind to and inhibit other TFs (e.g., CREB, c-Fos).

An important principle of TF action is that most bind to DNA as dimers. Some bind as homodimers (e.g., CREB), whereas others must complex with distinct families of TFs: Elk1 dimerizes with SRF, Fos family proteins dimerize with Jun family proteins (to form an

Learning & Memory: Molecular Mechanisms. Fig. 1. Regulation of CREB activity in striatum. Stimulation of D1 dopamine receptors and glutamate receptors on striatal neurons activates several second messenger cascades. Not shown is the ability of several growth factor-associated receptors to stimulate some of the same cascades, for example, MAPK. Depicted in the cell nucleus is a model of binding sites from the cFos promoter including a serum response element (SRE), activator protein-1 element (AP-1), and a cyclic AMP (cAMP) response element (CRE). CBP, CREB binding protein; CREB, cAMP response element binding protein; MAPK, MAP kinase; NMDAR, NMDA receptor; PKA, protein kinase A; TBP, TATA binding protein. (From McClung CA, Nestler EJ (2008) Neuroplasticity mediated by altered gene expression. Neuropsychopharmacology 33:3-17.)

API (activator protein 1) complex), and so on. Together, this results in an incredibly complex array of transcrip-tional regulation during the normal process of synaptic transmission.

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