HIPPOCAMPUS 6:294-305 (1996)
Physiological Properties of Anatomically Identified
Basket and Bistratified Cells in the CAl Area of the
Rat Hippocampus In Vitro
Eberhard H. BuhV Tibor Szilagyi,l,2 Katalin
Halasy,1,3 and Peter Somogyi 1
IMRC Anatomical Neuropharmacology Unit, Oxford
University, Oxford, England; 2Department of Physiology,
University of Medicine and Pharmacy, Tirgu Mures,
Romania; 3Department of Zoology and Cell Biolog1j,
f6zsef Attila University, Szeged, Hungary
ABSTRACT:
Basket and bistratified cells form two anatomically distinct
classes of GABAergic local-circuit neurons in the CA 1 region of the rat
hippocampus. A physiological comparison was made of intracellularly
recorded basket (n = 13) and bistratified neurons (n = 6), all of which
had been anatomically defined by their efferent target profile (Halasy et
al., 1996).
Basket cells had an average resting membrane potential of -64.2 ±
7.2 vs. -69.2 ± 4.6 mV in bistratified cells. The latter had considerably
higher mean input resistances (60.2 ± 42 .1 vs. 31.3 ± 10.9 MU) and
longer membrane time constants (18.6 ± 8.1 vs. 9.8 ± 4.5 ms) than basket cells. Differences were also apparent in the duration of action potentials, those of basket cells being 364 ± 77 and those of bistratified cells
being 527 ± 138 p.s at half-amplitude. Action potentials were generally
followed by prominent, fast afterhyperpolarizing potentia Is which in basket cells were 13.5 ± 6.7 mV in amplitude vs. 10.5 ± 5.1 in bistratified
cells. The differences in membrane time constant, resting membrane potential, and action potential duration reached statistical significance (P <
0.05).
Extracellular stimulation of Schaffer collateral/commissural afferents
elicited short-latency ex citatory postsynaptic potentials (EPSPs) in both
cell types. The average 10-90% rise time and duration (at half-amplitude) of subthreshold EPSPs in basket cells were 1.9 ± 0.5 and 10.7 ±
5.6 ms, compared to 3.3 ± 1.3 and 20.1 ± 9.7 ms in bistratified cells, the
difference in EPSP rise times being statistically significant. Basket and bistratified EPSPs were highly sensitive to a bath applied antagonist of
non-N-methyl-D-aspartate (NMDA) receptors, whereas the remaining
slow-rise EPSP could be abolished by an NMDA receptor antagonist.
Increasing stimulation intensity elicited biphasic inhibitory postsynaptic
potentials (IPSPs) in both basket and bistratified cells.
In conclusion, basket and bistratified cells in the CA 1 area show prominent differences in several of their membrane and firing properties. Both
cell classes are activated by Schaffer collateral/commissural axons in a
feedforward manner and receive inhibitory input from other, as yet
unidentified, local-circuit neurons. © 1996 Wiley-Liss, Inc.
KEY WORDS:
ward
GABA, interneuron, inhibition, postsynaptic, feed for-
Accepted for pub li catio n May 1, 1996.
Address correspondence and reprint requests to E.H. Buhl, MRC
Anatomica l Neuropharmaco logy Un it, Oxford Un iversi ty, Ma nsfield Rd .,
Oxford OX 1 3TH, UK .
© 1996 WlLEY-LISS, [Ne.
INTRODUCTION
Hippocampal interneurons, or non-principal cells,
share two co mmon properties. First, they have a dense
local axonal arbor whi ch may either target princi pal cells,
other local-ci tcuit neurons, or a mixture of both
(Somogyi et aI., 1983.; Schw.rrLkroin and Kunkel ,
1985; G ulyas et al. , 1993b; Halasy and Somogyi, 1993;
H an et al., 1993; Buhl et al., 1994a,b). Second , it appears that most interneurons investigated to date store
the inhibitory neurotransmittet l'-aminoburytic acid
(GABA) in their tetminals (Somogyi et al ., 1983b, 1984,
1985; Sotiano and Frotschet, 1989; Halasy and
Somogyi, 1993; Halasy et al., 1996). Apart from these
common characteristics, however, interneurons must be
tegatded as a conglom erate of heterogeneous, albeit distinct, cell classes. With respect to their anato mi cal properties, non-ptincipal cells may be segregated into several
categories, differing with respect ro their content of peptide neurotransmittets (Somogyi et al. , 1984; Kosab et
al ., 1985; Sloviter and Nilavet, 1987), calcium-binding
proteins (N itsch et al ., 1990; G ulyas et al ., 1991), and/or
efferent target profile (So mogyi et al ., 1983a, 1985;
Gulyas et al., 1993b; Halasy and Somogyi, 1993; Buh/
et al., 1994a,b; Sik et al., 1995). However, these features
are not necessarily mutually exclusive; on the contrary,
for example, neurons sllch as the dentate gyrus hilat perforant pathway-associated (HIPP) cells (H an et al .,
1993) ptesumably correspond to the class of somatostatin-positive hilar neurons.
With respect to their physiological properties, however, distinctions berween diffetent classes of GABAergic
neuron are either blurred or are yet to be established. As
yet, there is some degtee of general consensus that interneurons per se may differ from ptincipal cells in many
of theit inttinsic properties, such as short-duration ac-
INTERNEURON PROPERTIES IN RAT HIPPOCAMPUS
Don potentials. the absence of spike frequency adaptation. a largeamplitude fast afrerhyperpolarizing potential (fAHP). or prominent
outward rectification (Schwarrzkroin and Mathers. 1978; Ashwood
et al .. 1984; Schwarrzkroin and Kunkel, 1985; Misgeld and
Frotseher. 1986; Lacaille and Williams, 1990; Scharfman et al .. 1990;
Scharfman 1992). Moreover, (some) interneurons have also been
hown to differ from principal cells with respect to their glutamate
=eptor expression (Baude et al., 1993; M cBain et al., 1994; Poncer
et al ., 1995) and the kinetic properties of their glutamate receptors
(uvsey et al. , 1993; McBain and Dingledine, 1993; Perouansky and
Yaari, 1993) as well as their synaptic currents (Livsey and Vicini,
1992). T here are, however. considerably fewer data available for the
correlatio n of anatomical classes of interneurons with their physiological properties. because of the requirement for a stringent morphological or immunoeyrochemical identification of recorded neurons. By usi ng such a muhidisciplinary approach, it was, for example.
possible to establish that fast-spiking basket cells contain the calciumbinding protein parvalbumin (Kawaguchi et al., 1987 ; Srk et al. ,
1995), whereas a bistratified cell has been shown to be calbindin immunoreactive (Srk et al. , 1995). The physiological properties of interneurons have also been com pared with respect to their laminar
position (Kawaguchi and Hama, 1988; Lac.1.i.lle and Schwartzkroin .
1988; Lacaille and W illiams, 1990; Lacaille, 1991). Although these
studies provided compelling ~"Vid ence for the physiological heterogeneiry of hippoc.1mpal non-principal cells. the relationship between
me variabiliry in physiological properties and the patterns of synaptic connections of interneurons remained elusive, largely because the
hippocampal laminae are fur from homogeneous with regard to
meir complement of GABAergic interneurons (Lac.1.i.lIe and
Sch\varrzkroin, 1988; Kawaguchi and H ama. 1988; G ulyas et al .•
1993b; Han et al., 1993; Buhl et al. . 1994.1; McBain et al ., 1994) .
With hippocampal layering being a relatively poor indicator of
interneuronal diversiry, the co ncept of grouping non-principal cells
with respect to their efferent con nectiviry appears to be a more suitable approach toward ca tegorizing GABAergic neurons (Somogyi
et al., 1983a.b; Gulyas et al. , 1993b; Halasy and Somogyi, 1993;
Buhl er aI. , 1994a.b). Moreover, the advent of routin ely combinmg in vitro intracellular recording techniques with correlated light
and electron microscopy has now provided the opportuniry to define the physiological properties and synaptic effects of interneurons which have been characterized wirh respect to their target sekcciviry (Buhl et al. , 1994a.b; Buh l et al. . 1995). T his study will
provide such a physiological comparison between twO classes of
GABAergic hippocampal interneurons in the pyramidal cell layer
of the CAI area. The data presented in the accompanying article
(Halasy et al. , 1996) demonstrate nOt only the GABAergic nature
of basket and bistratified cells. but also distinct differences in the
pattern of their afferent and efferent con nections.
MATERIALS AND METHODS
lice Preparation
Young adult female Wistar rats (> 150 g) were deeply anesmetized with intramuscularly inj ected ketamine (lOO mg/kg) and
295
xyl3""line (1O mg/kg). Then the animals were perfused with ~ 30 ml
of chilled artificial cerebrospinal fluid (ACS F). and their brains
were removed and immersed in chilled ACSF. Using a Vibrosli ce
(Cam pden Instruments, Loughborough. UK) . 400-/Lm-thick
slices were cut in the horizontal plane. The sli ces were transferred
co a recording chamber and maintain ed at 34-35°C at the interface between oxygenated ACSF and a humidified atmosphere saturated with 95% 0 2 /5% C O 2. Th e flow rate was adjusted co 1.5
rnI /min. and the slices were allowed co recover for > 1 h . During
the initial part of the experiment (perfusion, cutting, 30-45 min
incubation). the ACSF waS composed of (in mM) 256 sucrose,
3 .0 KCI. ] .25 NH2P04. 24 NaH C0 4 , 2.0 MgS0 4 • 2.0 CaClz and
10 gl ucose. Subsequently, the sucrose in the ACSF was replaced
by equiosmolar NaCI (I26 mM). All drugs were kept as concentrated scocks. which were diluted in ACSF and then bath applied.
T he excitatory amino acid blockers 6-cyano-7-nitroquinoxal inc2,3-dione (CNQX) and DL-2-am ino-5-phosphonopenta noic acid
(AP5) were obtai ned from Tocris Cookson (Bristol , UK) and bicuculline hydrochloride was purchased from Sigma, (Poole, UK).
Intracellular Recordings and Data Analysis
Micropipettes were pulled from standard wal l borosilicate capillaries, filled with 2% bioeyrin in 1. 5 M KCH 3S0 4• and usually
beveled co a D C resistance of 80- 150 MO. Neurons were impaled in or close co the cell body layer of the hippocampal CA 1
area. Putative interneurons were identified by their distinct physiological properties (see below). Recordings were made in bridge
mode using Axoclamp or modified Axoprobe (both Axon
Instruments, Foster Ciry. CA) intracellular amplifiers. Postsynaptic potentials were elicited with a fine-tipped bipolar tungsten
stimulation electrode with a tip separation of ~5 0 /Lm. Data were
acquired using PCM instrumentatio n recorders and stored on
videotapes. Experimental data were redigitized at 10-20 kH1. with
a 12 Bit NO board (RC Electronics C omputerscope, Santa
Barbara, CA) and analyzed with co mm ercially available sofrware
(Axograph. Axon Instrum ents. Foster C ity. CA) . All data are expressed as mean :!: SO. Statistical analysis was performed using a
non-parametric statistic.-u test (Mann-Whirney U-test).
Resting membrane potentials were taken as the difference between surFace D C potential following electrode withd rawal and
the steady-state membrane potential without the injection of bias
current. M embrane time co nstants were determined by fitting single exponentials co the decay of small-anlplitude «5 m V) hyperpolarizing current pulses. Simi larly, input resistances were
ca lculated from the maximum voltage deflection of small hyperpolarizing current pulses. Using rheobasic current pulses. spike
amplitudes were taken from the baseline to the peak of the action potenti als, whi le spike duration was measured at half-anlplitude. The ampl itudes of fAH Ps were measured from the shoulder of the preceding action potentials. Whenever late AHPs were
seen to fo ll ow trains of action potentials, single exponential fun ctions were fitted to determine their decay characteristics.
Variations in the rate of firing were calculated From rhe respective interspike intervals and numericall y expressed as percent
changes of the initial discharge rate. The rise time o f excitarory
296
RUHL ET A L.
postsynaptic potentials (EPSPs) was determi ned as the interval
between 10 and 90% of their respective peak ampli tudes, and
EPSP duratio n was taken at half-amplitude, excludin g events that
were apparencly curtailed by inhibitory postsynaptic potentials
(IPSPs). T he time-to-peak of IPSPs was determined at depolarized membrane po tentials and extrapolated from the preceding
stimulus artifac t.
RESULTS
All cells included in the analys is had resting membrane potentials of min imally - 55 mV witho ut requiring hyperpolarizing
bias current. Moreover, the cells remained stable fo r at least 30
min reco rding tim e and , upo n depolarizatio n, co uld fire sustained
trains of high-frequency action potentials. Furtherm ore, onl y
those cells were included for analysis which co uld be recovered
for light microscopic analysis, followed by the post hoc c1ecrron
microscopic scrutiny of their synaptic target profi le (for full
an atomical description, see accompan ying article). In this regard,
it has been previously established that, with respect to their efferent output, CA l pyramidal cell layer interneurons predom inancly faU into three distinct categories: axo-axonic, basket, and
bistratifled cells (Buhl et al ., 1994a). Below, we summarize and
co mpare the physiological properties of two types of stringently
identified in terneuro ns, basket cells (n = 13) and bistratifled cel ls
(n = 6).
Membrane and Firing Properties
In co mparison, basket cells (n = 13) had significantly more depolarized resting membrane potenti als (- 64.2 ::':: 7.2 m V) than
bistratifled cells (n = 6; - 69.2 ::'::4.6 mY; P < 0.05). Likewise,
basket cells had significantly fas ter membrane time constants
(9 .9::':: 4.6 ms) when compared to bistratifled cells (18 .6 ::':: 8.1
ms). However, altho ugh basket cells had, on average, considerably lower input impedances (3 1.3 ::':: 10.9 vs. 60.2 ::':: 42 Mo' in
bistratified cells), this difference was not staristicall y signifi ca nt
(P = 0.056) . O nly basket cells at membrane potentials more de-
polarized than approximately - 60 m V tended to fi re spo ntaneous
actio n po tentials, although it sho uld be emphasized that the sampling of neurones with extensive labeling and therefo re prolo nged
recording periods may have biased these data toward the inclusio n of cells with relatively hyperpolarized membrane potentials
and, accordingly, little spo ntaneous activity.
Bo th types of interneuron had non-overshooting action potentials, the mean s for basket and bimatifled cells being 63.6 ( ::'::
12.7) mV and 69.8 ::'::5.0) mV (P > 0.05), respectively. Action
po tentials were generally brief due to a rapid rate of fall (Fig. 1)
and were found to be significa ntly faster in basket cells (0.4 1 ::'::
0.09 vs. 0.53 ::':: 0.14 ms in bistratifled cells).
In response to depolarizing current pulses, both groups of ncuron could display a variery of different firin g patterns. O nly a mino riry of cells fi red non-accommodating trains of action potentials (Fig. 2A, D ; n = I each; adaptation rate < 10%; note: the
widely used terms spike frequency acco mmodation and adaptatio n are here regarded as syno nymous) , although this firing pattern has commonly been associated with GABAergic interneurons
(Connors and G utnick, 1990; Scharfman, 1992). Although the
majority of cells assumed a tegular firing pattern, they revealed varying degrees of spike frequency adaptation, the respective changes
in the rate of firin g ranging from 14 to 88% (Fig. 2B; mean for all
cells 42 ::':: 3 1%; n = 12) in basket cells and 20-88% (Fig. 2E;
mean for all cells 54 ::':: 34%; n = 6) in bistratified cells. Finally,
three basket (Fig. 2C) and twO bimatified cells (Fig. 2F) showed a
burst-like fi ring pattern in response to a depolarizing current pulse.
Interestingly, different firing patterns may not be mutually exclusive, as they could be observed within individual cells. Accordingly,
it was possible to switch cells from bursting into regular firing mode
by means of a constant depolarizing current injection (Fig. 2E,F),
although this property was no t systematically investigated.
W hen the firin g freq uency of basket (n = 4) and bistratifled
(n = 3) neurons was determined from the fi rst in terspike in terval,
all cells revealed a linear current-frequency relationship (Fi g.
3A, D ). Differences, however, were apparent with respect to the
slope of the individual curves; i.e., across cells, the same increment
in current intensity could affect the respective fi ring rates to a variable degree. W hen current- frequency plots were determined from
C, 0 : Bistratlfied cell
A, B: Basket cell
A
c
B
D
~
A, C : 1 ms
S, D: 30ms
FIGURE 1.
Action potential. in both basket (A) and bistratified
cells (C) are characterized by their short duration which, when measured at half-amplitude, is generally less than 600 /LS. In both types
of interneurons action potentials have a rapid rate of fall , which is
in the same range as their rate of rise. Action potentials of basket
(8) and bisteatified (D) ceUs are foUowed by a short-latency fast afterhyperpolacization.
I
INTERNEURON PROPERTIES IN RAT HIPPOCAMPUS
297
D·E Bistratified cells
A-C Basket cells
D
A
0.5 nA
0.4 nA
E
B
0.1 nA
0.5nA
c
F
0.1 nA
0.5 nA
FIGURE 2.
Intrinsic firing patterns of three basket (A-C) and
two bistratificd cells (D-F). Within the same group of cells the firing pattern and the degree of spike frequency adaptation could vary
significandy. Both basket (A) and bistratified cells (D) could discharge with a train of non-accommodating action potentials in re-
sponse to a depolarizing current injection, thus corresponding to the
firing pattern which is generally assumed to be associated with fastspiking interneurons in cortical areas. Interestingly, a large proportion of both basket (B) and bistratified cells (E) showed a marked
me first and last interspike interval of 200 ms depolarizing current pulses, differences were apparent in the respective slo pes of
cells which exhib ited marked spike frequency adaptation (Fig.
3 B,E; solid symbols). Towards the end of a current pulse, these
cells showed a linear, but disproportionally smaller in crease in their
firi ng rates in response to regular increases in current intensity (F ig.
3 B,E; solid symbols con nected by broken lines).
The regularity of neuronal discharge was assessed by plotting
me respective fi ring frequencies, again taken as me recip rocal val ue
of successive interspike intervals, during the injection of a constant
depolarizi ng current pulse (Fig. 3C,F). It was clear that cells with
no apparent accom modatio n of meir firing rate maintained remarkably constant interspike intervals or discharge rates, respecri,'e1y (Fig. 3C,F; open symbols). Both basket and bimatified cells
which revealed marked reductions of their firing rate had relatively
uniform patterns of adaptation. Thus, a sharp drop of firin g rate
occurred during the first 50-70 ms of the pulse, and then cells resumed discharging at a rela tively co nstant frequency during the re-
degree of spike frequency adaptation. Moreover some basket (C) and
bi-stratified cells (F) were also capable of firing a burst of action potentials, which were riding on a depolarizing envelope. Note, however, that in one instance d,e firing mode of a bistratified cell could
be changed from bursting (F) to a regular firing/adapting behavior
(E) hy depolarizing the cell from - 62 mY (F) to - 57 mY (E) . The
cells in A and C are also illustrated in Figures 4 and 3 of the accompanying article.
mainder of the pu lse. Occasional ly the regular firing pattern of
basket (n = I) and bimatifled cells (n = \) could be d isru pted by
sp ike doublets or triplets (Figs. 3C, 4A,O), here defined as an action potential following anomer with very short latency.
Afterpotentials
W ithout exceptio n, action potentia Is in basket an d bistratified
cells were followed by a short-latency fAHP (F igs. \ , 2, 4A,O).
Although, on average, basket ceUs had more pronounced fAHPs
than bistratified cells (13.5 :t 6.7 [n = 12] vs. 10. 5:t 5. 1 mV
[n = 6]) , this difference did not reach statistical signifi can ce. Both
basket and bistratified cells co uld reveal prom inenr depo larizing
afterpotentials (OAPs; Fig. 4 B, E; arrows). T hese were most
promi nent during the period of strongest spike frequency adaptation and could be of sufficient amplitude to trigger spike doublets and triplets (for more derail, see Buhl et al. , 1994b) . Only
a fraction of basket cells (5113; 39%) displayed OAPs, thus dif-
298
BUHL ET AL.
A
A~C :
Basket cells
D
'so
D-F: Bistratified cells
300
02
0.4
O.B
0.8
current increment [nl\)
current increment [nAI
B
2SO
. 0
E
200
~
~
>-
>-
u
u
c
,~
I
I
,
~
100
'"
'"c
c
·c
§
~
SO
so
• e- · -
...
.
01
0.2
0.3
0.4
0.5
06
... -0.2
07
• • -tI _ .... .
0.6
0.8
current increment (nAI
0.'1
current Increment [nAI
C
F
:lOO
•..-..
1.2
1.4
200
2SO
i;'
c
,
~
,.:;r
f
1902922
o,~~--~--~--~--~,,~~~
so
100
ISO
200
time (ms]
FIGURE 3.
Firing characteristics of basket (A- C; open and solid
circles) and bistratified cells (D-F; open and solid squares). The instantaneous firing frequency (expressed as the inverse of the first interspike interval [ISI]) of both basket (A) and bistratihed cells (D)
increased linearly with the amount of injected depolarizing current
(in A,B,D,E expressed as current increment above threshold intensity) . The respective slopes, i.e., the rate of frequency increase per
current step, of individual cells showed great variability. In basket
and bist.ratified cells which exhibited spike frequency adaptation
(B,E: solid symbols), the respective cnerent/frequency slopes differed
markedly when taken from the first and last ISI (first ISIs connected
by continuous line, last ISTs linked by broken line) of a 200-ms depolarizing current pulse. In contrast, the slopes of first and last interspike intervals in non-adapting or weakly adapting ceUs (B: open
circles) remained relatively constant. T he regularity and pattern of
firing in basket (C) and bistratihed ceUs (F) was assessed by plot-
o
SO
100
ISO
200
time [ms]
ri ng the inverse of successive intcrspike intervals (as a measure of
firing frequency) against time. It is apparent that non-adapting cells
(open symbols; two sweeps in each celJ at sanle intensity) assume a
regular firing pattern, whereas adapting cells (solid symbols; in C
four sweeps at variable intensities, in F two sweeps with identical
Clurent intensity) decelerate markedly during the first 50- to 70-ms
interva1 of the current puJse and then resume firing at near-steadystate levels. Intersweep variability was relatively minor. Only infrequently occnering doublets (C) preseoted a minor disruption in the
overall regularity of firing patterns. When comparing two sweeps
which contained doublets with two successive sweeps which were
without doublets, it is, however, obvious that despite the dramatic
increase in firing frequency (i.e., a very short inlerspike interval) ,
the overall firing pattern remains remarkably unaffected. Cell codes
correspond to Table I of the accompanying article.
INTERNEURON PROPERTIES IN RAT HIPPOCAMPUS
A·C: Basket cells
299
D·F: Bistratified cells
o
A
-=J
A: 40ms
D:1OOms
1
B
~w
\~
1.0 nA
E
~
20 ms
c
F
1.0 nA
0.7 nA
~
200 ms
FIGURE 4.
Both basket (A-C) and bisttatificd cells (D-F) could
sbow complex afterpotentials resembling those of hippocampal principal cells. In these instances a fast afterhyperpolarizing potential
(see also Fig. IB,D) was followed by a depolarizing afterpotential
(OAP; B,E arrows). Occasionally DAPs were of sufficient amplitude
lO trigger spike doublets (D,E) or even triplets (A,B). Prominent
DAPs were frequently observed in conjunction with marked fre-
quency adaptation (A,D). Moreover, in these cells, trains of action
feri ng from bistratified cells where OAPs appear to be a more regular feature (5/6; 83%). Similarly, following occasionally single
(Fig. I D), but more frequently bursts of action potentials, both
basket and bisrratified cells could reveal prominent late afterhyperpolarizing potentials (IAHPs; Fig. 4C,F), although this feature
was considerably less prominent in basket cells (n = 2/13; 15%)
when co mpared to bisrratified cells (5/6; 83%). Generally, the
amplitude of iAHPs was positively correlated with the burst duratio n and number of action potentials. A1IIAHPs decayed slowly
(> 1 s) back to baseline, and their decay could be well fitted with
a si ngle exponential function. With respect to their respective
mean time constants of decay, basket (1.24 :!: 0.20 s) and bistratified cells (0.96 :!: 0.97) appeared to be relatively similar.
Final ly, it is noteworthy that, with the exception of one bistratified cell, the occurrence of IAHPs predominantly coincided with
prominent DAPs (617 cells).
Postsynaptic Responses
potentials were often followed by a long-lasting afterhyperpolarization (C,F; clipping of depolarizing response indicated by stippled
line; the cell in F is different from that shown in D and E). Note
the clipping of action potentials in B and E. Broken lines in A indicate off-line adjustment of bridge balance. The cell in D and E is
also iIIusttated in Figure 9 of the accompanying article.
Using low stimulation intensities, which were invariably subthreshold for concomitantly recorded pyramidal cells (data not
shown), basket as well as bisrratified cells could be orthodromically activated at very short latencies «4 ms), thus minimizing
the likelihood of polysynaptic pathways contributing to the early
part of EPSPs. Although synaptic responses could be elicited from
several stimulation sites, such as stratum lacunosum-moleculare,
the data reported here resulted from placing the stimulation electrode into stratum radiatum, usually at the CA1/CA3 border region, thus presumably stimulating predominantly Schaffer collateral/commissural input fibers .
Afferent stimulation at the threshold for synaptic responses (Fig.
SA,G) invariably elicited EPSPs in basket as well as bistratified
cells. The analysis of single sweeps revealed that small-amplitude
300
BUHL ET AL.
EPS Ps in both types of interneuro ns frequently had a fragmented,
mul ti-peaked appearance (Fig. 5G, H ), the latter feature generally
smoothin g out in averaged traces (Fig. 5A- E). Subthreshold EPSPs
in basket cel ls (n = 9) had an average rise-ti me of 1.9 ± 0 .5 ms,
whereas that of bistratified cells (n = 4) was determined to be
3.3 ± 1.3 ms. T his d ifference was statistically significant (P <
0.05) . Likewise, th e mea n duration of EPSPs in basket cells
A-F: Basket cell
~
,
----------~------------------
(10.7 ± 5.7 ms) was considerably shorter than that of bistratifiecl
cells (20.1 ± 9.7 ms), although this difference did nOt reach statisti cal significa nce (P = 0 .09). When stimulating Schaffer collateral /comm issural afferents with maximal intensity, all cells reached
fi ring threshold . Suprathreshold EPSPs general ly elicited one (Fig.
5E) an d occasio nally two action potentials.
W ithout exception, stimulation intensities had to be adjusted
G-L: Bistratified cell
G
4 Volts
B,~
H
-J ~_
~~~
C,
threshold
_-
-, "---____---------.J---.r----'"
---.JI'\.
7 Volts
low intenSity
medium intensity
_ _- 12 Volts
D
~.....:.~
________
hi9_hin_ten_Sity
36 Volts
E
K
G-J : superimposed
A-D superimposed
L
JlOmv
20 ms
F
-67 mV
11 Volts
FIGURE 5.
Synaptic responses in basket (A-F) and bistratifled
ceUs (G-L) foUowing extraceUnlar stimnlation of the Schaffer collateral/commissural pathway (arrowheads dellote stimnlus artifacts).
Low stimulus intensities (A,G) usually resulted in excitatory postsynaptic potentials (EPSPs) without apparent inhibitory postsynaptic
potentials (IPSPs) _ Increasing the stimnlation intensity frequendy
recruited short-latency IPSPs (G-£, I-K; asterisks), which curtailed
the duration of the EPSPs_Late IPSPs (D,1; solid squares) were only
apparent at higher stimnlation intensities. Traces A-F and L represent averages of four to 30 trials, G-K represent single sweeps. Note
the characteristic "fragmented" appearance of EPSPs (G,H) . In all
tested basket (F) and bistratifled cells (L) the EPSP amplitude increased with membrane hyperpolarization. Fast IPSPs (asterisks) reversed in the range of the presumed chloride equilibrium potential.
The cell in A-F is also illustrated in Figure 5 of the accompanying
article.
TNTERNEURON PROPERTIES IN RAT HIPPOCAMPUS
A
A, B: Basket cell
301
C, 0 : Bistratified cell
c
Slim. Schalfer coIL
D
B
~
20
m,
0.9 nA
-69mV
control
FIGURE 6.
Inhibitory responses in inhibitory cells. Schaffer colIatuallcommissural pathway- evoked IPSPs suppress repetitive firing in CA I basket (A,B) and bistratified cells (C,D) . Strong stimuli
rttntited short-latency IPSPs (asterisks) in both basket (A) and bistr.l1ified (C) cells. The resulting hyperpolarization was effective i11
suppressing current-induced firing for periods greater than 50 ms
and frequently reducing the rate of firing during the remainder of
the pulse (data not shown). The control traces (B,D) ilhL"rate that
in the absence of the synaptic stimulus, the cells fired throughout
the current pulse. Note that some reduction of the firing rate of the
cell shown in C aod 0 is due to spike frequency adaptation.
Arrowheads denote stimulation artifacts.
considerably higher rhan response threshold (0 evoke fast IPS Ps
(Fig. 56-0, H- J). Increasing rhe srimularion strength resulted in
an amplirude increase of rhe fasr IPSP and eventually, ar high inu:nsiries, the appearance of a lare IPSP (Fig. 50-E, J-K). The
peak latency of the fast JPSP in basker cells was 2 1.4 :t 4.2 ms
(n = 6) , which did nor d iffer significantly from thar of bisrrarified cells (25.7 :t 7.8 ms; n = 4). Likewise, rhe response reversal
of the fasr IPSPs in basker and bisrrarified cells was very similar
E-H : Bistratified cell
5mv I
A-D: Basket cell
20 ms
A
control
E
-
B
-----1----------------------------------10jiM CNOX
~
1
48V
--I
7V
F
10jiM CNOX
1
7V
16V
c
co ntrol
G
-----j~-----------------------1
20V
H
D
r-.
1
48V
FIGURE 7.
Excitatory amino acid receptor pharmacology of
Schaffer collateral/commissural pathway-evoked EPSPs in a CAl
bask", (A-D) and a bistratified cell (E-H) . At lower stimulation intcnsities, bath application of the non-NMDA receptor antagonist
CNQX (1 0 I'M) resulted in a dramatic reduction of Schaffer colIa.uallcommissural EPSPs (A,B,E,F). In the presence of CNQX,
higher stimulation intensities uncovered a CNQX-resistant EPSP
with slower rise and decay kinetics (C,G). This CNQX-insensitive
~-------------------------------20V
EPSP could be largely blocked by bath application of the NMDA
receptor antagonist AP5 (D,H; 30 f'M)- Note that all traces in A-H
were obtained in a low concentration of bicuculJine (l I'M) to reduce polysynaptic IPSPs_ Membrane potential in A -71 mY, in
B -64 mY, in C and 0 -67 mY, in E and F -88 mY, and in G and
H -77 mY. Arrowheads denote stimulation artifacts. The cell in A-D
is also illustrated in Figure 3 of the accompanying article.
302
BUHL ET AL.
c
A
2 ~M bicuculline
control
~ 10mv
100 ms
·62 mV
/ 2 ~M bicuculline
" control
FIGURE 8.
Short-latency IPSPs in basket cells are mediated by
GABAA receptors. In this basket cell the Schaffer collateral/commissural compound postsynaptic potential comprised a short-latency
EPSP, which was followed by a fast IPSP (asterisks) and a late IPSP
(solid square). The fast IPSP reversed around -66 mV (A), suggesting that chloride is the major charge carrier. (B) Addition of initially 1 I'M (middle trace) , followed by 2 I'M of the GABAA recep-
tor antagonist bicuculline methochloride to the bath, resulted in a
reduction of the early IPSP and a concomitant increase of the late
IPSP amplitude. Subsequently, the voltage dependency of the predominating late LPSP (C; solid square) was explored. Whereas the
reversal of the small remaining early IPSP remained unchanged (C;
asterisk) , the late IPSP reversed around -99 mY, indicating the involvement of GABA s receptors.
(Fig. 5F,L; - 69.0 ::':: 2.S vs. -72.0 ::':: 2.0 mY). T he peak latency
of the late component of the compound rpsp was 135 ::':: 29 ms
in basket cells and 137 ::':: 17 ms in bistratified cells. T he reversal
of the late rpsp appeared to be at rather hyperpolarized membrane pote ntials (approx. - 90 m y), although this parameter was
difficul t to determine unless its amplitude was enhanced fo llowing the pharmacological blockade of GABAA receptors (Fig. SC).
The efficacy of rps ps to inhibit firing of inhibitory neurons
wa., tested by delivering a shock to the Schaffer/collatera l co mmissural pathway during depolarization-induced repetitive firi ng
in bo th basket and bistratified cells (F ig. 6A,C). Initially all cells
responded with one to twO short-latency action potentials, followed by a hyperpolarizing IPSP, wh ich was effective in suppress ing fir ing for periods exceed ing 100 ms. Control responses
at the same current intensity (Fig. 6B,0) were also a.nalyzed to
ascertain that the quiescent period was not due to a prolonged
AHP followi ng a burst-li ke discharge.
duce or completely elimi nate the evoked EPSp (Fig. 7 B,F). In the
presence of CNQX, a substantial increase of the stimulation intensity in conj unction with membrane depolarization could serve
to uncover a residual EPSp with slower kinetics (Fig. 7C,G) . T his
residual co mpo nent proved ro be sens itive to bath application of
the NMDA receptor a.ntagonist M 5 (30 JLM ; Fig. 70 ,H).
Both the time course a.nd reversal potential of the early phase
of Scha.ffer collateral/commissural pathway-evoked rpsps suggest
that at least part of the compo und postsynaptic response is med iated by GABAA reccprors (Fig. SA). This notio n, however, could
only be adequately verified in basket cells (n = 2) . In the illustrated example, bath applicatio n of initially I JLM of the GABAA
receptor a.ntagonist bicuculline resulted in a substantial reduction
of the fast IPSP, whereas 2 JLM diminished mOSt of the early hyperpolarization (Fig. SB). Interestingly, the late IPSP nOt only remained, but also grew in amplitude co ncomitant with increasing
GABA A receptor blockade. Further hyperpolarization revealed that
the bicucuIli ne-resistant IpSP reversed around - 99 mV (Fig. 8C).
Amino Acid Receptor Pharmacology
Scha.ffer collateral/commissural pathway-evoked EpSPs in
both cell classes invariably showed a conventio nal voltage dependence (Fig. 5F,L), with their amplitudes increasing at more hyperpolarized membrane potentials. Such EpSPs were pharmacologically explored in th ree basket and three bistratifi ed cells using
subthreshold stimulatio n intensities (Fig. 7 A and E). After monitoring the control responses for > I 0 min, the slices were superfused with 10 JLM of the non-N-methyl-D-aspartate (NMDA)
receptor a.ntagonist CNQX, which could either substantially re-
DISCUSSION
Comparative Physiology of Hippocampal and
Cortical Interneurons
T here is general agreement that, in principle, it is possible to
physiologically d istinguish a substantial fraction of hi ppocampal
interneurons from principal cells by virtue of their distinct membrane and firing properties. Differences from principal cells were
INTERNEURON PROPERTIES IN RAT HiPPOCAMPUS
reported with respect to membrane time constants, membrane
rectification. action potential duration, spike frequency adaptation , as well as afterpotentials (Ashwood et al .. 1984;
Schwartzkroin and Kunkcl , 1985; Misge1d and Frotscher, 1986;
Lacaille and Williams. 1990; Scharfman et a1., 1990; Buhl et al.,
1994a,b; 1995). Moreover. it was also noted that interneurons as
st/ch may be physiologically heterogeneous (Kawaguchi and
Hama . 1988; Lacaille and Schwarrzkroin, 1988). However, since
the sample in these studies presumably originated from an
anatomically heterogeneous pool of local-circuit neurons. it has
remained unresolved whether the noted differences were due to
variabiliry within or across classes of interneurons. Indeed, recent
observations on hippocampal axo-axonic cells, defined by their
efferent connectiviry, indicated a surprising variery of firing patterns and afterpotentials in response to depolarizing current pulses
(Buhl et al. , 1994b) . T he present study corroborated this finding
by revealing a similar degree of inter-individual heterogeneiry
within the basket and bistratifled cell classes. The majoriry of neurons do not correspond to the rather firm ly established concept
of most interneurons being non-adapting, wide-band transformators of in co ming excitation , generally lacking complex afterpotentials (Connors and Gutnick, 1990; Hamill et al. . 1991;
Scharfman, 1992). Only a fraction of basket and bimatifled cells
in our sample displayed such properties. With regard to the remainder, the app31'ent discrepan cies to previous studies may be
resolved, since, in the absence of detailed morphological verification, the sanl pling of putative local-circuit neurons in earlier studies could have been heavil y biased toward those displaying properties traditionall y associated with interneurons.
Despite th e aforementioned variabiliry of physiological properties within given classes of hippocampal interneurons, a statistica l comparison berween basket and bistratified cells revealed a
number of differences, among which spike duration and membran e time constant reached the level of statistical signifi cance. In
this respect, very similar parameters were recently found to segregate rwo populations of rat neocortical layer V interneurons, referred to as "fast-spiking" and "low-threshold spike (LTS)" cells,
showing prominent differences in their membr311e time co nstants,
action potential duration , and input resist311ce (Kawaguchi, 1993;
Deuchars and T homson, 1995). In a similar way to cortical "fastspiking" cell s, their hippocampal equivalents have been also
shown to contain the calcium-binding protein parvalbumin
(Kawaguchi et .1.1., 1987; Kawaguchi and Kubota, 1993). the latter being a marker for hippocampal basket 311d axo-axonic cells
(Kosaka et al., 1987) . Regarding their membr311e and firing properties. the group of bistratified cells may correspond to cortical
"LTS cells. " This notion is further supported by the observation
that, like the bisrratified cell illustrated in Figure 2E 311d F, LTS
cells consistently fire low-threshold spikes at hyperpolarized membr311e potenti als (Kawagucl1i, 1993) and contain the calcium binding protein calbindinD28k (Kawaguchi and Kubota. 1993),
the latter being a marker for cortical interneurons with an efferent target profile enriched in dendritic shafts 311d spines (DeFelipe
et al. . 1989). Finally, further similarities berween co rtical LTS
cells and hippocampal bisrratifled cells were noted by S,k et al.
(1995), who demonstrated calbindin D28k immunoreacriviry in a
bistratifled cell labeled in vivo. However. the degree of homology
303
berween these rwo classes of local-circuit neurons requires furth er
assessment, owing to the recent discovery of other cortical interneurons. such as regular spiking non-pyramidal cells. with an
overlapping spectrum of physiological properties (Kawaguchi,
1995).
Schaffer Collateral/Commissural Activation of
Basket and Bistratified Cells
Previous studies predicted that certain hippocampal interneurons, such as the dentate MaPI' cell (Han et al ., 1993), are predominantly activated in a feedforward manner, because of the
complete spatial segregation of their dendrites from the recurrent
axon collaterals of principal cells. In contrast, another distinct rype
of hippocampal interneuron , irnmunopositive for mGluR 1Cl' as
well as so matostatin and projecting to the stratum lacunosummoleculare in rhe CA1 area (Baude et al., 1993; McBain et al.,
1994). has been shown to receive mainly recurrent pyramidal cell
input (Blasco-Ibanez and Freund. 1995; Maccaferri and McBain,
1995). Although basket cells in the CA3 and CA 1 regions of
Ammon 's horn are known to be involved in tecurrent microcircuits (Gulyas et aI. , 1993a.b; Buhl et aI., 1994.1.). data presented
above provide clear evidence that CA 1 basket cells are also activated by at least one of the major extrinsic excitatory inputs. the
Schaffer collateral/commissural pathway. Likewise. bistratifled
an d axo-axonic cells (Buhl et aI., 1994b) are also in volved in fcedforward mi crocircuits. Although the latter classes of pyra midal cell
layer interneurons possess a relatively l31'ge proportion of their
dendrites deeply invading the oriens-alveus border regio n. where
they mingle with the bulk of pyramidal cell axon collaterals (Buhl
et aI., 1994b; Halasy et al .• 1996), unequi vocal evidence is as yet
missing as to whether these neurons also partici pate in recurrent
.
.
.
micrOCirCUits.
Both the voltage dependence and rhe fast kinetics of compound EPSPs resulting from the bulk stimularion of Schaffer collateral/co mmissural afferents indicate that these responses are
largely medi ated by AMI'A-rype glutamate receptors. And indeed,
orthodromically elicited EI'SPs in both basket and bistratified cells
were sensitive to the action of a bath applied non-NMDA glutamate receptOr antagonist. Moreover. ir is reasonable to assume
that much of the early AMI'A receptor-mediated EPSP was of
monosynaptic origin, owing to the considerably longer latency of
disynaptically (recurrent) elicited EI'SPS in CA1 interneurons
(Maccaferri 311d McBain. 1995). However, it also appears that
some of the response may have been mediated by NMDA receptors. as indicated by the slow kinetics as well as the sensitiviry of the residual EI'SP to a bath-applied NMDA receptor antagonist. T hese results thus complement previous work providing
pharmacological evidence for the presence of NMDA receptors
on anatomically identified CA 1 axo-axo nic cells (Buhl et al. .
1994b). Moreover, data on hippocampal interneurons in general
have repeatedly prompted very simi lar conclusions (Sa], et al. ,
1990; Lacai lle, 1991 ; McBain and Dingledine, 1993; Perouansky
and Yaari, 1993).
Interestingly, basket and bistratifled cells showed a significant
difference in the rise time of Schaffer collateral/co mmissurally
elicited EPSPs. Quite conceivably this EPSP par31Jlerer may have
304
BUHL ET AL.
been, at least in part, determined by the equally prominent di fference in the membrane time constants of basket and bistratifl ed cells. Several other facto rs may have shaped the £PSP kinetics. among them variabili ty in the pro perties of AMPA receptors
(Li vsey a nd Vi cini , 1992; Livsey et al ., 1993) and a differential
d egree of electrotoni c attenuatio n (Thurbo n et al ., 1994; reviewed
in Spruston et al. . 1994) . With respect to the fas t rise time ofbasket cell £ PSPs. the jimctional consequence, following the acti vatio n of excitatory synaptic affetents. will be that basket cell action
potentials will generall y precede those of bistratifled cells. H ence
basket cell-evoked IPSPs will presumably precede those mediated
by bistratified cells in postsynaptic pyramidal cells, and it is perhaps no coincidence that bas ket cell- mediated unitary [PS Ps also
have significantly faster kinetics when co mpared to bisttatifled cell
effects (Buhl et aI. , 1994 a). It therefote appeats that two independent factots favor basket cells to be rather effi cient in rapidly
prov iding a perisomatic increase in membrane conductance. In
co ntrast. the tempo ral properties o fbistratifled cell-evoked lPSPs
may render them mo re effective in shunting N MDA receptor-m ediated conductances (Staley and Mody, 1992).
GABAergic Control of Basket and
Bistratified Cells
Previo us studies, using either dual recording techniques o r extracellular bulk stimulatio n of synaptic afferents, demonstrated
t1ut physiologically and /o r anatomicalIy identified interneurons
receive inhibitory input fro m other, as yet unidentified , local-circui t neurons (Misgeld and Frotscher, 1986; Lacaille et al ., 1987;
Scharfma n et aI. , 1990 ; LacaiUe, 199 1; Buhl et al. 1994 b). In this
respect. bas ket and bistratifled cells corres po nded well to this general pattern . sin ce Sch.ffer coll ateral /co mmissural flber acti vatio n
elicited biphasic [PSPs which were pres um ably mediated by both
G ABA A and GABA~ teceptors. Because basket (D eller et aI. ,
1994) and bistratified cells are directl y targeted by excitatory extrinsic afferents and have been shown to target other intern euro ns synaptically (Buhl et aI. , 1994a; Sfk et al ., 1995; Halasy et
aI. , 1996), they may not o nly have a key role in the feedfo rward
co nrro l of principal cells (Buzsaki , 1984; Cobb et al ., 1995), but
also parti cipate in shaping neuronal acti vity across the GABAergic
network (Buzsa ki and C hrobak, 1995) .
Acknowledgments
The authors thank P. Jays, F.D . Kenn edy, D . Latawiec, and
J .D .B. Roberts for expert techni cal support. L. Lyford for secretarial assistance, and S.c. C obb. S.V . Karnup . and V.V. Stezhka
fo r contributing some of the experimental data. K.H . was suppo rted by the W ellcome T rust.
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