Figure 1. Schematic illustration of heterosynaptic modulation. The synapse between a neuron and its target cell can be modulated by other neurons. The amount of neurotransmitter released by the presynaptic neuron (PRE) can be increased or decreased by a modulatory neuron (MOD-1) acting at the presynaptic terminal. Alternatively, the response of the postsynaptic cell (POST) to the transmitter released by the presynaptic neuron can be increased or decreased by a modulatory neuron (MOD-2). In some cases, synaptic plasticity results from modulation of both the presynaptic and the postsynaptic neuron.

Figure 2. Presynaptic contributions to heterosynaptic facilitation of sensorimotor neuron synapses in Aplysia. (a) Activation of modulatory interneurons (MOD) by sensitizing stimuli increases the duration of the sensory neuron (SN) action potential. This in turn increases calcium current (I_Ca) through voltage-gated calcium channels which results in greater calcium influx, enhanced transmitter release and a larger excitatory postsynaptic potential in the motor neuron (MN). (b) Mechanisms of short- and long-term facilitation in the sensory neurons. Sensitizing stimuli result in release of serotonin (5-HT) from modulatory interneurons. Serotonin activates two G protein-coupled receptors to initiate two second-messenger cascades (dashed lines): diacylglycerol (DAG) and cyclic adenosine monophosphate (cAMP). These second messengers, acting through their respective protein kinases (PKC and PKA), affect multiple ion channels and cellular processes including a spike duration-independent (SDI) process that regulates transmitter release. The combined effects lead to enhanced transmitter release when a subsequent action potential occurs in the sensory neuron. Long-term facilitation occurs when the modulatory interneurons are activated repeatedly, which leads to regulation of transcription and translation and to growth (solid lines). There is also a long-term modulation of at least one of the membrane channels (g_K,S). Positive (+) and negative (–) signs indicate enhancement and suppression of cellular processes, respectively (see text for additional details). Circles containing dots represent synaptic vesicles in a storage pool (SP) and a readily releasable pool (RP).

Figure 3. Presynaptic inhibition in the stomatogastric ganglion. Modulatory commissural neuron 1 (MCN1) is a projection neuron that innervates the crustacean stomatogastric ganglion. Activation of MCN1 initiates the gastric mill rhythm, which is composed of two phases: protraction and retraction. MCN1 excites both protractor (LG) and retractor (INT-1) neurons, but differences in synaptic signals (i.e. slow versus fast) and heterosynaptic inhibition within the circuit regulate the timing of these activations to produce a rhythmic, alternating output. Dark lines represent active components of the circuit whereas light lines represent components that are inactive. (a) Retraction phase. Initially, retractor phase neurons (e.g. INT-1) are activated by a fast excitatory synapse from MCN1. INT-1 inhibits the LG neuron. (b) Protraction phase. The slow excitatory input to the LG protactor neuron from MCN1 eventually overpowers the inhibition from the retractor and the protractor begins to fire action potentials. This neuron makes chemical inhibitory synapses with the retractor neuron and the axon of MCN1 that terminate the retraction phase. Because the MCN1 cell body is remote from this inhibition, MCN1 continues to fire action potentials. Slow decay of the slow excitation from MCN1 and an electrical synapse between MCN1 and the protractor prolong the protraction phase.

Figure 4. Heterosynaptic modulation in the hippocampus. (a) Schematic representation of a rodent hippocampus. Three input pathways are shown: the perforant path (PP) from entorhinal cortex (EC), the fimbrial pathway (FP) and the commissural fibres (CF). Granule cell neurons (GN) in the dentate gyrus (DG) receive inputs from the EC via the PP. In turn, the GNs synapse with pyramidal neurons in the CA3 region by a pathway referred to as mossy fibres (MF). CA3 pyramidal neurons synapse with other CA3 neurons and with CA1 pyramidal neurons by a pathway referred to as the Schaffer collaterals (SC). Axons of CA1 pyramidal neurons carry information out of the hippocampus. The CF pathway brings information from the contralateral hippocampus and synapses on both the CA1 and CA3 pyramidal neurons. (b) Heterosynaptic modulation in CA3. Induction of long-term potentiation (LTP) to one set of DG mossy fibres (DG-1) produces depression (–) in another set of mossy fibres (DG-2) that were inactive and enhancement (+) of transmission at synapses from the FP and SC–CF. (c) Heterosynaptic long-term depression (LTD) in CA1. Induction of LTP at one set of inputs to a CA1 pyramidal neuron (Schaffer collaterals or commissural pathway) produces LTD at inactive synapses from the same pathways.