Chemical Senses Vol. 30 No. suppl 1 © Oxford University
Press 2005; all rights reserved
Long-term Potentiation in the Accessory Olfactory Bulb: A Mechanism for Olfactory Learning
1 Department of Integrative Physiology, Kochi Medical School, Nankoku, Kochi 783-8505, Japan and 2 Division of Adaptation Development, Department of Developmental Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan
Correspondence to be sent to: Hideto Kaba, e-mail address: kabah{at}med.kochi-u.ac.jp
Key words: adrenergic receptor, calcium channel, glutamatergic, mating, NMDA receptor, noradrenaline, pheromone
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Introduction |
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 Top Introduction Induction of LTP at...NA gates the induction...NA suppresses glutamate release...NA allows the postsynaptic...AcknowledgementsReferences |
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One context of olfactory learning that has been investigated in some detail concerns the memory, established at mating, and formed by the female mouse to the odours (pheromones) of the mating male. This olfactory memory is vital for mitigating pregnancy block that might otherwise be induced by his pheromones (Keverne and Rosser, 1986
). Pheromones from an unfamiliar
male, for which no memory has been formed, activate the vomeronasal system with their
receptors in the vomeronasal organ, thereby initiating a neuroendocrine reflex that
suppresses prolactin secretion from the pituitary (Keverne, 1983). The removal of luteotrophic support results
in a fall in progesterone levels and a return to oestrus. Therefore, it has been
hypothesized that the pheromonal memory functions as a gate to suppress or modulate the
specific pheromonal signal (Brennan et
al., 1990;
Kaba and Nakanishi, 1995;
Brennan and Keverne, 1997;
Brennan, 2001).
The pheromonal memory is acquired with one trial learning, depends upon mating and
lasts for several weeks (Keverne and de la Riva,
1982;
Kaba et al., 1988). The
neural changes underlying memory formation occur in the accessory olfactory bulb (AOB),
the first relay in the vomeronasal system, independently of the main olfactory system and
the hippocampus (Brennan et al.,
1990;
Kaba and Nakanishi, 1995;
Brennan and Keverne, 1997).
Microcircuits in the AOB include the prominent reciprocal dendrodendritic synapse between
mitral cells, a single class of projection neurons and granule cell interneurons.
Glutamate released from mitral cell dendrites activates the dendrites of granule cells,
which in turn mediate GABAergic dendrodendritic inhibition back onto mitral cell
dendrites (Jia et al., 1999;
Taniguchi and Kaba, 2001). This
feedback inhibition at the reciprocal synapses regulates mitral cell activity (Jia et al., 1999;
Taniguchi and Kaba, 2001). The
formation of the pheromonal memory requires the association of the pheromonal and the
mating signals in the AOB. The mating signal is conveyed by noradrenergic projections
from the locus coeruleus. Artificial vaginocervical stimulation (Rosser and Keverne, 1985) or mating (Brennan et al., 1995) promotes the release of
noradrenaline (NA) in the AOB. Blockade of 
-adrenergic receptors in the AOB
immediately after mating prevents the formation of the pheromonal memory (Kaba and Keverne, 1988), as does removal of noradrenergic
innervation of the AOB prior to mating (Rosser
and Keverne, 1985). Furthermore, memory formation is associated with
neurochemical and morphological changes at the mitral–granule cell reciprocal
synapses (Brennan et al.,
1995;
Matsuoka et al., 1997,
2004).
Despite advances such as these, however, an important void in our knowledge of electrophysiological aspects has remained: a long-lasting increase in synaptic strength, known as long-term potentiation (LTP), has been little investigated. Moreover, the cellular and synaptic mechanisms underlying noradrenergic modulation of pheromonal learning are also unknown. To address these questions, we have carried out a series of experiments in AOB slices.
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Induction of LTP at the mitral-to-granule cell synapse in the AOB |
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TopIntroductionInduction of LTP at...NA gates the induction...NA suppresses glutamate release...NA allows the postsynaptic...AcknowledgementsReferences |
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We have initially analyzed synaptic transmission and its plasticity in coronal slice preparations of the mouse AOB using the field potential recording technique. A recording electrode was placed in the external plexiform layer where reciprocal dendrodendritic synapses between mitral and granule cells are formed. A stimulation electrode was placed on the lateral olfactory tract (LOT) to stimulate mitral cell axons antidromically. Stimulation of mitral cell axons evoked two negative field potentials. The first potential was not blocked by the non-N-methyl-D-aspartate (NMDA) receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), but it was abolished by the sodium channel blocker tetrodotoxin. The second potential was blocked by CNQX. Therefore, the first potential represents the antidromic activation of mitral cells and the second potential reflects monosynaptic activation of granule cell dendrites via non-NMDA receptors. We measured the maximal initial slope of this second field potential to monitor the strength of glutamatergic transmission from mitral to granule cells.
In the hippocampus, high frequency stimulation at 100 Hz effectively induces LTP of synaptic transmission. However, such high frequency stimulation of mitral cell axons was not effective in triggering LTP at the mitral-to-granule cell synapse. By contrast, theta frequency stimulation effectively induced LTP. The stimulation consisted of a 10 Hz, 20 pulse train applied 5, 10 or 20 times at 3 min intervals. Five or 10 trains of theta frequency stimulation induced only short-term potentiation that decayed back to its control value, whereas 20 trains induced LTP that maintained potentiated for at least 3 h. Theta frequency stimulation-induced LTP was blocked by bath application of the NMDA receptor antagonist DL-2-amino-5-phosphonopentanoic acid (AP5), indicating that this form of LTP depends on NMDA receptor activation.
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NA gates the induction of LTP via the activation of 2-adrenergic receptors
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TopIntroductionInduction of LTP at...NA gates the induction...NA suppresses glutamate release...NA allows the postsynaptic...AcknowledgementsReferences |
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If LTP at the mitral-to-granule cell synapse underlies pheromonal learning, then NA should gate the induction of LTP. We tested this possibility by pairing NA with theta frequency stimulation that is subthreshold for LTP induction. Ten trains of theta frequency stimulation were not sufficient to induce LTP. However, when the 10 trains was paired with NA application, robust LTP was induced. These results indicate that NA can gate the induction of LTP. NA-enhanced LTP was also blocked by the NMDA receptor antagonist AP5.
We determined which type of adrenergic receptors was responsible for NA-induced LTP.
NA-induced LTP was blocked by the -adrenergic receptor antagonist phentolamine,
but not by the ß-adrenergic receptor antagonist propranolol. Furthermore, NA-induced
LTP was blocked by the 2-adrenergic receptor antagonist idazoxan, but
not by the 1-adrenergic receptor antagonist prazosin, clearly
demonstrating that NA enhances LTP induction via -receptors of the
2-type. This is substantiated by the fact that the
2-adrenergic agonist clonidine mimics the effect of NA on LTP
induction.
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NA suppresses glutamate release from mitral cell dendrites |
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TopIntroductionInduction of LTP at...NA gates the induction...NA suppresses glutamate release...NA allows the postsynaptic...AcknowledgementsReferences |
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How does NA gate LTP induction at the mitral-to-granule cell synapse? We addressed this question using whole-cell patch-clamp techniques. First, we examined the effect of NA on stimulus-evoked excitatory postsynaptic currents (EPSCs) recorded from a granule cell. QX-314 was added to the pipette solution to block regenerative sodium currents. EPSCs were elicited by stimulation of the LOT every 30 s. NA suppressed evoked EPSCs and this effect was mimicked by the
2-adrenergic agonist clonidine.
Secondly, we addressed the question of whether NA acts on the pre- or postsynaptic
neuron by recording miniature EPSCs (mEPSCs) from a granule cell in the presence of
tetorodotoxin and picrotoxin. Picrotoxin was added to block GABAergic transmission from
granule to mitral cells. NA reduced the frequency of mEPSCs, while the amplitudes of
mEPSCs were little affected. This conclusion was supported by the cumulative probability
distributions of amplitudes and inter-event intervals. On average, the mean frequency
decreased during NA application to 50% of the control frequency, whereas the mean
amplitude was not significantly affected. The effect of NA on mEPSCs was reproduced by
the 2-adrenergic agonist clonidine. Taken together, our results
demonstrate that NA suppresses glutamatergic transmission from mitral to granule cells by
a presynaptic mechanism downstream from calcium entry.
Thirdly, we examined the effect of NA on calcium currents in mitral cells, because
calcium entry through high-voltage-activated channels is essential for transmitter
release. Calcium currents were isolated by blocking sodium currents with tetorodotoxin
and potassium currents by including CsCl in the patch pipette. External calcium was
replaced with Ba to increase the amplitude of the current. NA suppressed
high-voltage-activated calcium currents and the effect of NA was mimicked by the
2-adrenergic agonist clonidine.
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NA allows the postsynaptic granule cell to fire more action potentials during theta frequency stimulation |
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TopIntroductionInduction of LTP at...NA gates the induction...NA suppresses glutamate release...NA allows the postsynaptic...AcknowledgementsReferences |
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So far, we have looked at the effect of NA on low frequency stimulation-evoked EPSCs and spontaneous EPSCs, but the frequencies of discharge of the mitral-to-granule cell synapse during pheromonal learning may be much higher. Therefore, we finally tested the effect of NA on a postsynaptic granule cell maintained in the current clamp mode during theta frequency stimulation of the LOT. NA reduced the depolarizing plateau due to its suppressive action on EPSCs. Conversely, the postsynaptic granule cell reliably fired action potentials when subjected to a 10 Hz train of stimuli.
In summary, NA suppresses glutamate release via the presynaptic activation of
2-adrenergic receptors. This action of NA allows the postsynaptic
granule cell to fire more action potentials during theta frequency stimulation, thereby
enhancing the induction of LTP at the mitral-to-granule cell synapse.
Our studies indicate that LTP in the AOB shares essential features with pheromonal memory consolidation and therefore pheromonal memory might be understood at the cellular level through studies of LTP.
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Acknowledgements |
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TopIntroductionInduction of LTP at...NA gates the induction...NA suppresses glutamate release...NA allows the postsynaptic...AcknowledgementsReferences |
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G.-Z.H. was in receipt of a JSPS postdoctoral fellowship. This work was supported in part by research grants from the JSPS and the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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