Karl J. Iremonger1'2 and Jaideep S. Bains1'3'*
1 Hotchkiss Brain Institute, Calgary, AB, Canada 2Department of Neuroscience, Calgary, AB, Canada 3Department of Physiology and Biophysics, Calgary, AB, Canada
Abstract: The release of vasopressin and oxytocin from the posterior pituitary is tightly coupled to the activity of magnocellular neurosecretory cell (MNC) bodies in the supraoptic (SON) and paraventricular (PVN) nuclei of the hypothalamus. These cell groups exhibit distinct patterns of activity which are regulated by a combination of synaptic inputs and intrinsic properties. The postsynaptic currents (intrinsic properties) that shape these bursts have been described extensively but examinations of the contributions of synaptic input to activity patterns in these cells are relatively sparse. Although the synaptic release of glutamate is necessary to initiate and sustain bursting, precisely how a brief depolarization associated with a synaptic current would ignite such a prolonged postsynaptic discharge is not clear. Here, we review recent work from our laboratory showing that unlike the majority of synapses in the brain, glutamate synapses onto MNCs release transmitter in an asynchronous fashion following a presynaptic action potential. This input is integrated by the postsynaptic neuron and may serve to activate the postsynaptic conductances necessary for the induction of patterned activity.
Keywords: glutamate; presynaptic; asynchronous; plasticity; PVN; magnocellular; burst
In the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, vasopressin (AVP) neurons are intermingled with neurons that produce oxytocin (OT). The axons of both cell groups project to the posterior pituitary, where individual fibres branch into roughly 2000-10,000 nerve endings (Leng et al., 1999). Each of these boutons contains dense core vesicles filled either with AVP or OT. Unlike traditional synaptic terminals which often require only a single action potential in the presynaptic terminal to cause the exocytosis of a
* Corresponding author. Tel.: 403-220-7585; Fax: 403-283-2700 E-mail: [email protected]
vesicle(s), MNC axon terminals require long bursts of action potentials to effectively release hormone into the blood (Leng et al., 1999). In vivo, OT and AVP cells show different spontaneous firing patterns that permit efficient hormone secretion. OT cells, in response to stimulation (suckling or during parturition), fire in short, high-frequency bursts (2-4 s, 40-80Hz) (Wakerley et al., 1973). AVP cells, on the other hand, fire at very low frequencies and show intermittent phasic bursts in which activity (firing in a range of 7-15 Hz) and quiescence alternate with a period of approximately 1-2 min. In rats, hyperosmolality elicits an increase in phasic firing in AVP neurons specifically (Poulain et al., 1977; Wakerley et al., 1978). Although OT neurons also increase their firing rate during a hypertonic challenge, they do not exhibit phasic firing (Brimble and Dyball, 1977; Poulain et al., 1977). Previous studies in vitro have shown that the release of both OT and AVP increases with neuronal firing rate (Dreifuss, 1973), but is optimal during bursting activity (Dutton et al., 1978; Bicknell and Leng, 1981). How these prolonged bursts are initiated, however, is a matter of some debate. In vivo there are clear demonstrations that synaptic glutamater-gic input is essential for these phasic bursts (Nissen et al., 1995; Brown et al., 2004), yet there have been few investigations that have attempted to explicitly understand how synaptic glutamatergic input contributes to phasic activity. In addition to potential synaptic contributions, there is a critical role for the summation of depolarizing after potentials (DAPs) following a brief burst of action potentials in the maintenance of phasic activity (Roper et al., 2003, 2004; Brown and Bourque, 2006). The mechanism responsible for the generation of these DAPs is contentious (Bourque et al., 1998), but recent reports indicate that they may result from the activation of Ca2+-sensitive non-specific cation conductances in magnocellular neurosecretory cells (MNCs) (Ghamari-Langroudi and Bourque, 2002). While DAPs are important, it is not known whether syn-aptic activity in particular can activate DAPs and shape this patterned discharge. To begin to address this question requires, first, a capitulation of the basic rules of synaptic transmission at synapses that relay information to MNCs.
The synapse is a specialized structure that allows for the chemical communication between cells in the nervous system. Although all synapses serve this same basic function, they do so in a number of different ways. For example, in auditory pathways, synapses are geared to favour precision. They transmit high-frequency information with great fidelity. By contrast, in the neuromuscular junction, synapses are designed to generate large, postjunctional potentials, while in some regions of the cortex, excitatory synapses are only effective if a number of them are activated simultaneously. This diversity, to a large degree, reflects the function of the system in which these synapses exist. In MNCs, precise spike timing in response to an afferent input is not critical for hormone release. Instead, these cells must integrate synaptic input from multiple afferent nuclei to generate patterns of activity that can support the release of a bolus of hormone into the blood. This integration is aided, in part by the high input resistance and slow membrane time constant of these cells (Tasker and Dudek, 1991). Glutamate is the primary fast excitatory neurotransmitter in the PVN (van den Pol et al., 1990), eliciting its effects through the activation of postsynaptic AMPA (Wuarin and Dudek, 1993) and NMDA (Bains and Ferguson, 1997, 1999) receptors. Since MNCs serve as the end effectors for a neural feedback circuit that orchestrates the central nervous system (CNS) response to perturbations in physiological homeostasis, the synapses onto these cells constitute the final integration of signals before the release of OT and AVP. Consequently, mechanisms that modulate either the rate at which glutamate-filled vesicles are released, or the postsynaptic efficacy of an individual quantum of neurotransmitter will impact neuroendocrine output. The efficacy of this transmission can be altered by various neuro-modulators through transient changes in either presynaptic neurotransmitter release probability (Bains and Ferguson, 1997; Kombian et al., 1997, 2000a, b, 2001; Schrader and Tasker, 1997; Daftary et al., 1998; Harayama et al., 1998; Inenaga et al., 1998; Oliet and Poulain, 1999; Shibuya et al., 2000; Boudaba et al., 2003; Gordon and Bains, 2003; Baimoukhametova et al., 2004; Hirasawa et al., 2004; Di et al., 2005) and/or postsynaptic changes in AMPA receptor function and the gating of voltage-gated ion channels (Randle et al., 1986; Hiruma and Bourque, 1995; Hirasawa et al., 2003; Brown et al., 2004).
The majority of these studies, however, operate on the assumption that a presynaptic action potential triggers the probabilistic and synchronized release of vesicles filled with glutamate within a few milliseconds of the presynaptic depolarization. While this is clearly the case for the majority of synapses in the brain (Lisman et al., 2007), it is not the case for glutamate synapses onto MNCs in
PVN (Fig. 1). In fact, we have shown recently that the majority (>60%) of glutamate synapses onto MNCs exhibit a form of delayed or asynchronous release in response to a single presynaptic action potential (Iremonger and Bains, 2007). Here, a single action potential triggers either zero, one or multiple release events during a temporal window that may extend for up to 100 ms following the presynaptic action potential (Fig. 2). Synaptically evoked waveforms kinetically similar to this delayed release have been reported previously in the PVN but, at that time, were ascribed to be indicative of recruitment of polysynaptic glutama-tergic circuits (Boudaba et al., 1997). Our experiments, however, show clearly that single synaptic stimuli can elicit all-or-none delayed responses, consistent with the idea that this delayed release reflects the activation of terminals that can release in an asynchronous fashion and does not reflect the activation of local glutamate circuits (Iremonger and Bains, 2007). Importantly, it appears that single neurons can receive inputs that are either exclusively synchronous, exclusively asynchronous or both synchronous and asynchronous. These observations of diverse presynaptic release profiles are consistent with the idea that the mode of release is regulated by the presynaptic neuron and is not dependent on the target neuron. This is an important consideration since release probability at inhibitory GABA synapses onto MNCs is regulated by the target cell itself (Oliet et al., 2007). Interestingly, while we consistently observe asynchronous release onto MNCs, we have rarely observed asynchronous release onto neighbouring parvocellular neurosecre-tory cells (<10% of synapses on over 300 cells tested). Consistent with our hypothesis that asynchronous release is an integral component of patterned activity, there are no reports of episodic discharges in parvocellular neurosecretory cells.
In the vertebrate CNS, similar asynchronous release profiles in response to a single action potential have been described previously at the granule
cell to stellate cell synapse in the cerebellum (Atluri and Regehr, 1998), in the calyx of Held (Wu et al., 1999) and at inhibitory synapses from interneurons to pyramidal cells in the hippocampus (Hefft and Jonas, 2005). Here, the release of neurotransmitter-filled vesicles lasts for tens to hundreds of milliseconds after a presynaptic action potential. Even synapses that do not show overt asynchronous release in response to a single action potential can often display robust episodes of prolonged release when the presynaptic nerve terminal is activated in a repetitive fashion (Otsu et al., 2004; Otsu and Murphy, 2004). This form of activity-dependent asynchronous release has been described previously in the hypothalamus (Kombian et al., 2000a); it manifests as a postsynaptic barrage of AMPA-mediated events lasting for several seconds in response to prolonged, high-frequency activation of glutamatergic afferents (Kombian et al., 2000a). It is not clear whether this short-term potentiation in the SON represents a summation of individual asynchronous epochs (such as those we have described in PVN) (Iremonger and Bains, 2007) or whether it requires the recruitment of other (unique) cellular mechanisms. Our observation that asynchronous release can be potentiated during short, physiologically relevant (Washburn et al., 2000) trains of stimuli suggests that it may share some features with previously described short-term potentiation in SON (Kombian et al., 2000a).
These unique properties raise the question of why these synapses in particular would exhibit asynchronous release. One plausible explanation is that since the rate of hormone release from MNC terminals is roughly proportional to their firing frequency (Leng et al., 1999), synaptic precision and timing are not essential features for successful operation of the magnocellular system. Instead, these cells are specialized to integrate inputs from several nuclei into a final "output" signal. Asynchronous glutamate release may provide a mechanism to amplify presynaptic activity and promote prolonged spiking in response to temporally dispersed afferent inputs and may be a particularly effective way to ensure a faithful neuronal response during intense physiological demand; in effect it may serve as the ignition switch for a prolonged discharge in MNCs. Previous work showing that asynchronous release in recurrently connected networks of hippocampal neurons is necessary for bursting (Lau and Bi, 2005; Wyart et al., 2005) supports the idea that this form of transmission may be functionally important for translating synaptic signals into specific patterns of neuronal activity. Since neurons that provide excitatory input to MNCs exhibit bursts of activity (Washburn et al., 2000), our observations that a brief afferent discharge can increase postsynaptic activity for a prolonged period of time indicates that asynchronous release is an important component of signal transfer at these synapses. Second, the prolonged depolarization (and spiking) mediated by asynchronous release may facilitate the opening of post-synaptic NMDA receptors and voltage-gated Ca2 + channels. The resulting Ca2 + influx may promote both the dendritic release of peptides (Ludwig and Pittman, 2003) and the induction of synaptic plasticity (Panatier et al., 2006a).
Mechanisms responsible for asynchronous release in PVN
Action-potential-dependent neurotransmitter release relies on the opening of presynaptic voltage-gated Ca2+ channels. More specifically, the N-type and P/Q type channels have been implicated in neuro-transmitter release in the vertebrate CNS (Lisman et al., 2007). The specific complement of Ca2+ channel subtypes may allow synapses to release transmitter with kinetically distinct profiles (Wu et al., 1999). In some brain regions, including the calyx of Held, the kinetics of transmitter release are deve-lopmentally regulated, mirroring the developmental changes in the expression of different Ca2 + channel subtypes (Fedchyshyn and Wang, 2005). Our observations indicate that asynchronous release in PVN, however, is present in both young (p22) and older (p44) animals suggesting that it is a conserved form of neurotransmission in this nucleus and is not sensitive to developmental regulation (Iremonger and Bains, 2007). Recent work in the hippocampus indicates that in addition to these possibilities, the mode of release may depend on the complement of Ca2+ channel subtypes expressed at the presynaptic nerve terminal (Hefft and Jonas, 2005). In particular, P/Q type Ca2+ channels may be important for synchronized transmitter release whereas N-type channels are necessary for asynchronous (Hefft and Jonas, 2005) or ectopic (Matsui and Jahr, 2004) release. This is consistent with the observation that N-type channels may be located a greater distance from the docked vesicle and thus their recruitment releases transmitter on a slower time scale (Wu et al., 1999). This is currently under investigation in our laboratory. In addition to different Ca2+ channels, asynchronous release may also be a consequence of a larger distance between the Ca2+ source and the Ca2+ sensor associated with the vesicle (Meinrenken et al., 2002; Fedchyshyn and Wang, 2005; Hefft and Jonas, 2005) or a poor Ca2+ buffering capacity in the presynaptic nerve terminal (Muller et al., 2007). Our observation that asynchronous release in particular is sensitive to low concentrations of the slow Ca2+ buffer, EGTA-AM (Iremonger and Bains, 2007) is consistent with any or all of these scenarios (Fig. 3). Additional mechanisms, such as a prolonged presynaptic Ca2+ transient (Atluri and Regehr, 1996) and the presence of different Ca2+ sensors (with different Ca2+ affinities) for asynchronous compared to synchronous release (Geppert et al., 1994; Nishiki and Augustine, 2004; Hui et al., 2005), also cannot be ruled out at this stage.
Evoked glutamate release and the regulation of MNC activity
Despite the obvious requirement for both synaptic and postsynaptic conductances in determining the firing patterns of MNCs (Nissen et al., 1995; Li and Hatton, 1996; Leng et al., 1999; Brown et al., 2004; Brown and Bourque, 2006), the interaction between these two factors has yet to be studied carefully in the PVN or SON. Summation of excitatory synaptic inputs is an obvious mechanism capable of evoking action potentials. The DAP which follows each action potential would then allow for maintenance of a plateau potential and repetitive spiking. Alternatively, prolonged glutamate release
may also directly recruit DAPs via activation of NMDA receptors and Ca2+ permeable AMPA receptors. It has been shown by several groups that magnocellular neurons have functional NMDA receptors (Hu and Bourque, 1992; Bains and Ferguson, 1997, 1999) and that glial cells within the SON release d-Serine (Panatier et al., 2006b), the endogenous co-agonist of the NMDA receptor. Since it has been suggested that the DAP is mediated by a Ca2 + -sensitive cation channel (Ghamari-Langroudi and Bourque, 2002), the Ca2+ influx resulting from NMDA receptor activation may contribute to the plateau potential that allows phasic burst firing in AVP neurons. In addition, this NMDA receptor activation may even be critical for the release of dendritic dense core vesicles. For example, it is known that priming of dense core vesicles is Ca2+-dependent as this can be achieved through application of thapsigargin or CPA, compounds that expel Ca2+ form internal stores (Ludwig et al., 2002) and that NMDA receptor activation can initiate dendritic Ca2+ spikes in MNCs (Bains and Ferguson, 1999). The Ca2+ influx resulting from NMDA receptor activation could alone, or in conjunction with Ca2+ induced Ca2+ release from internal stores, induce priming of dendritic dense core vesicle and their subsequent fusion. Although presently, we do not know if this indeed occurs, these are all testable ideas that will likely be answered within the next several years.
Glutamate synapses onto MNCs are geared to transmit signals for hundreds of milliseconds. This
extended temporal window can be further prolonged when synapses are repetitively recruited (Fig. 4). Under these conditions, the integration of these synaptic events by the MNCs may sufficiently depolarize the neuronal membrane and serve as an effective 'ignition switch' that activates the post-synaptic conductances necessary to sustain high-frequency discharges (Fig. 5). Asynchronous release may also be an ideal synaptic means by which peptides can be released from MNC dendrites. Finally, the asynchronous release discussed above indicates that glutamate synapses onto MNCs in PVN are capable of releasing multiple quanta. In some cases, these quanta may be released in an asynchronous fashion (as described here) or, if the right machinery is activated, multiple vesicles may be released simultaneously. For example, the recruitment of Ca2+ from intracellular stores by noradrenaline can synchronize the release of many quanta (multivesicular release) which may further increase postsynaptic excitability (Gordon and Bains, 2005).
The research highlighted here was supported by an operating grant from the Canadian Institutes for Health Research (CIHR). J.S. Bains is an Alberta Heritage Foundation for Medical Research (AHFMR) Senior Scholar. K.J. Iremonger is supported by studentships from the AHFMR and the Heart and Stroke Foundation of Canada.
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