NMDA receptors in granule cells have a typically… , neuroscience jobs in california

a

b

c

Fig. 5. Blockade of IA elicits rapid, AMPA receptor-driven mitral cell

inhibition. (a) In the continuous presence of 4-AP (6 mM), IPSCs evoked

in mitral cells by glomerular stimulation were only slightly reduced by

D, L-AP5 (50 µM), but were completely blocked by subsequent addition

of NBQX (5 µM). (b) The fraction of the IPSC supported by AMPA

receptors, as estimated from the AP5-induced reduction in IPSC charge,

averaged 70% in the presence of 4-AP, as compared with only 14% under

control conditions. (c) 4-AP accelerated the kinetics of IPSCs measured

in response to the dual-component synaptic input, which was most

apparent when the currents were normalized (lower trace). 4-AP

reduced the time-to-peak of the IPSC as well as the decay time constant,

as shown for 11 cells on the right.

as in many neurons IA is nearly completely inactivated at the rest-

ing potential18,36, IA in granule cells is only half-inactivated at rest

(–66 mV), making a large fraction of IA channels available to

affect synaptic inputs. IA channels in granule cells also appear to

have higher expression in dendrites. A preferential dendritic local-

ization of IA has been shown in other neurons15,37, but IA chan-

nels may have a particularly robust effect on spiking in granule

cells, owing to their high input resistance (∼1 GΩ)12, their axon-

less morphology and a low density of sodium channels.

• volume 2 no 12 • december 1999

articles

The function of IA in discriminating synaptic inputs based

on their duration relies also on the nature of the incoming

synaptic traffic within the olfactory bulb. In many neurons, volt-

age-dependent magnesium block greatly reduces NMDA recep-

tor-mediated responses38,39, thus limiting the magnitude of any

prolonged depolarization that would be available to outlast IA.

However, the convergent mitral–granule cell connectivity in the

bulb generates a large glomerular stimulation-evoked depolar-

ization in single granule cells that overcomes magnesium block

of NMDA receptors. NMDA receptors in granule cells have a

typically high sensitivity to magnesium12, emphasizing that gran-

ule cells have an IA-mediated mechanism to regulate their

excitability while having receptors and voltage-gated channels

with typical intrinsic properties.

Timing of inhibition in the olfactory bulb

Blockade of IA with 4-AP reduced the onset time and accelerated

the decay kinetics of mitral cell inhibition, reflecting the faster

AMPA receptor-mediated drive onto granule cells. The more

rapid inhibition was in part due to a reduction in the latency to

spike firing in granule cells, as well as enhanced GABA release

driven by local, AMPA receptor-mediated depolarizations in the

granule cell spine. The faster inhibition in 4-AP implies that IA

functions in the olfactory bulb circuit to generate inhibition fol-

lowing prolonged NMDA receptor activation. Such long-lasting

reciprocal inhibition (∼200 ms) might be required for appropri-

ate downstream coding of odorant information carried by sin-

gle mitral cells, whereas prolonged lateral inhibition would inhibit

the delayed spiking that occurs in other mitral cells in response to

an odorant40. Prolonged inhibition is also proposed as a general

requirement for circuits whose functions rely on oscillations and

neuronal synchronization7, as in the case of olfactory sensory

information processing in some systems41,42.

The IA-mediated mechanism for generating slow inhibition

is also advantageous, as it allows for dynamic regulation. Mod-

ulation of IA could occur through the action of protein kinases

and intracellular calcium43–46 or through changes in the granule

cell membrane voltage. Inactivation of IA in response to a pre-

vious depolarizing input would produce inhibition with short-

ened kinetics but with a larger peak amplitude. Such inhibition

might be most effective against a rapid train of action poten-

tials occurring in response to high concentrations of odor47. By

controlling the relative effectiveness of the AMPA and NMDA

receptor-mediated synaptic inputs, regulation of IA allows fine-

tuning of inhibition according to the demands on the bulb net-

work.

METHODS

Horizontal slices (400 µm) were prepared from olfactory bulbs taken

from 10–23 day-old Sprague-Dawley rats, as described12, and viewed

under DIC optics (Axioskop, Carl Zeiss). All experiments were done at

room temperature (20–24°C).

Measurement of synaptic responses. Synaptic responses were recorded

using a base extracellular bath solution that contained 125 mM NaCl,

25 mM NaHCO3, 1.25 mM NaH2PO4, 25 mM glucose, 2.5 mM KCl, 2

mM CaCl2 and 1 mM MgCl2 at pH 7.3 and was oxygenated with 95%

O2/5% CO2. Granule cell EPSPs and EPSCs were recorded with picro-

toxin (50 µM) added to the bath and with patch pipets (8–13 MΩ) that

contained 125 mM potassium gluconate, 2 mM MgCl2, 2 mM CaCl2, 10

mM EGTA, 2 mM Na-ATP, 0.5 mM Na-GTP and 10 mM HEPES, adjust-

ed to pH 7.3 with KOH. Mitral cell IPSCs were recorded using pipets

(1–3 MΩ) with equimolar replacement of potassium gluconate with KCl.

Voltage-clamp recordings were done using series-resistance compensation

(60–90%) at a holding potential between –70 and –80 mV. Data acqui-

1111

© 1999 . •

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