Cellular Mechanisms

Whereas neurotransmitters are the first line ofbiochemical messengers carrying signals from one neuron to another, there are also intracellular biochemical signals, known as second messengers. After a neurotransmitter arrives at its target cell and activates its receptor, the next, intracellular step in signaling involves the second messenger system. Numerous second messenger systems have been described in neurons. A complex pattern ofinteraction occurs among these intracellular second messengers, but several consistent themes emerge concerning the role of second messenger systems in learning and memory.

Within the mushroom bodies, the Kenyon cells are the site of CS and US convergence. Exposing cultured Kenyon cells to acetylcholine (the neuro-transmitter conveying the CS signal from the antennal lobes) activates an ion current in these cells that has a high proportion ofcalcium ions (Ca2+; Menzel and Muller 1996). This means that in the intact animal, olfactory stimulation of the antennal lobes, which causes release of acetylcholine, increases the concentration of Ca2+ within Kenyon cells (fig. 3.2A).

Octopamine, the US neurotransmitter, also leads to changes within mushroom body neurons (fig. 3.2B). Octopamine release and the subsequent activation ofthe octopamine receptor stimulate adenylate cyclase activity within Kenyon cells (Hildebrandt and Muller 1995a; Evans and Robb 1993). The enzyme adenylate cyclase converts ATP into cyclic AMP (cAMP); cAMP then has a number of intracellular effects, including activation ofprotein kinases, especially protein kinase A (PKA). In addition to its effect on adenylate cyclase, octopamine, like acetylcholine, can increase intracellular Ca2+ levels within mushroom body neurons (Robb et al. 1994).

Thus, the arrival of the CS odor signal and the US sucrose signal at the mushroom bodies activates adenylate cyclase and increases intracellular Ca2+ levels. The arrival of both signals produces a greater change within mushroom body neurons than either signal would alone. Olfactory cues alone would lead to a transient increase in Ca2+ levels. Stimulation of sucrose receptors would lead to a transient activation of cAMP (through adenylate cyclase activation) and a transient increase in intracellular Ca2+ levels. If these two inputs arrive within the appropriate time interval, however, the two effects occur together, and the resulting intracellular change is different, at least quantitatively, from the effect produced by either signal alone.

These CS- and US-induced changes in mushroom body neurons not only have additive effects, but interacting effects as well (fig. 3.2C). Adenylate cyclase activity, and hence the amount of cAMP produced, is potentiated by Ca2+ (Abrams et al. 1991; Anholt 1994). The net effect on mushroom body cells is elevated intracellular Ca2+ from the CS input, followed by increased adenylate cyclase activity from the US input. The US-induced activation of adenylate cyclase is greater than usual because Ca2+ increases adenylate cyclase activity and because the US input arrives at a time when intracellular Ca2+ levels are still elevated as a result of the CS signal. The final outcome is a

Figure 3.2. Convergence ofodorCS and sucrose US signals in Kenyon cells of the honeybee mushroom body. (A) CS alone: CS-induced activity from the antennal lobes arrives in the mushroom bodies, triggering release of the neurotransmitter acetylcholine (ACh). Acetylcholine binds to a receptor (NR) and allows Ca2+ to enter the cell. The intracellular Ca2+ then activates Ca2+-dependent kinases, such as PKC and CaMKIV. (B) US alone: US-induced activity in the VUMmx1 axon arrives in the mushroom bodies, triggering release of the neurotransmitter octopamine (Oc), which binds to an octopamine receptor (OR). Octopamine has at least two effects on the cell: it activates adenylate cyclase (AC), leading to the conversion of ATP into cAMP, and it increases intracellular Ca2+ concentrations. cAMP then activates protein kinase A (PKA) by binding to the regulatory subunits (R), causing them to dissociate from their catalytic subunits (C). Once the catalytic subunits of PKA are dissociated from the regulatory subunits, their active site is exposed, and they can act on various target substrates within the neuron, altering neuronal function.

Figure 3.2. Convergence ofodorCS and sucrose US signals in Kenyon cells of the honeybee mushroom body. (A) CS alone: CS-induced activity from the antennal lobes arrives in the mushroom bodies, triggering release of the neurotransmitter acetylcholine (ACh). Acetylcholine binds to a receptor (NR) and allows Ca2+ to enter the cell. The intracellular Ca2+ then activates Ca2+-dependent kinases, such as PKC and CaMKIV. (B) US alone: US-induced activity in the VUMmx1 axon arrives in the mushroom bodies, triggering release of the neurotransmitter octopamine (Oc), which binds to an octopamine receptor (OR). Octopamine has at least two effects on the cell: it activates adenylate cyclase (AC), leading to the conversion of ATP into cAMP, and it increases intracellular Ca2+ concentrations. cAMP then activates protein kinase A (PKA) by binding to the regulatory subunits (R), causing them to dissociate from their catalytic subunits (C). Once the catalytic subunits of PKA are dissociated from the regulatory subunits, their active site is exposed, and they can act on various target substrates within the neuron, altering neuronal function.

Figure 3.2 (continued) (C) CS + US: If the increased intracellular Ca2+ from CS stimulation is still presentwhen the US signal arrives, it potentiates the ability of octopamine to activate adenylate cyclase, leading to the production of more cAMP and increasing the number of active catalytic subunits of PKA. For clarity, this illustration omits much of the detail relating to the Ca2+-dependent kinases PKC and CaMKIV. The mechanism of activation ofthese kinases is analogous to that shown for PKA.

Figure 3.2 (continued) (C) CS + US: If the increased intracellular Ca2+ from CS stimulation is still presentwhen the US signal arrives, it potentiates the ability of octopamine to activate adenylate cyclase, leading to the production of more cAMP and increasing the number of active catalytic subunits of PKA. For clarity, this illustration omits much of the detail relating to the Ca2+-dependent kinases PKC and CaMKIV. The mechanism of activation ofthese kinases is analogous to that shown for PKA.

chemical environment within neurons that have received both a CS and US signal that is very different from that in neurons that have received only a CS or US signal alone.

The best-known example of comparable intracellular events in a vertebrate comes from studies of long-term potentiation in the mammalian hippocampus (Bliss and Lomo 1973). Long-term potentiation is a model of synaptic plasticity that may be analogous to the cellular events that occur in learning and memory (Malenka and Nicoll 1999). The excitatory amino acidglutamate functions as a neurotransmitter in the hippocampus (and elsewhere). Glutamate activates one type of receptor, the AMPA receptor, as part of normal neurotransmission. A second type of glutamate receptor, the NMDA receptor, is also present in the hippocampus, but it is usually in an inactivated state caused by the presence of the magnesium ion, Mg2+. Because NMDA receptors are blocked in this way by Mg2+, they are not normally involved in neurotransmission within the hippocampus. However, when stimulation produces an action potential and depolarizes a hippocampal neuron, the Mg2+ blockade of the NMDA receptor ceases, and glutamate can then activate the NMDA receptor. Such activation leads to an increase in intracellular Ca2+

levels and recruits mechanisms that cause long-term changes in synaptic function (Bliss and Collingridge 1993). Here, too, we can observe the joint effect of the firing of multiple neurons that Hebb envisioned. In neurons of the mammalian hippocampus and in Kenyon cells of the honeybee brain, the arrival of two separate inputs in the correct order and within specific time intervals leads to intracellular changes that neither input can achieve alone.

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