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Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 1. Carbachol (CCH)-induced {theta} oscillations of hippocampal CA1 field potential and of membrane potential of CA1 pyramidal cells depend on activation of GABAergic inputs. A: an example of recorded field potentials in hippocampal CA1: pre-CCH control (top), during CCH (50 µM, 30 min) and bicuculline application (BIC, 1 µM, 30 min). B: membrane potential traces of recorded CA1 pyramidal cells: pre-CCH (control), during CCH application (50 µM, 30 min; the membrane was slightly depolarized and action potential truncated; 2nd trace from top) and with membrane potential maintained at pre-CCH level by passing negative current (3rd trace), and during application of BIC (1 µM, 30 min). C: examples of CCH-induced intracellular {theta} activity in 4 different cells, shown at low amplification and without action potentials truncated.
  • CCH triggered a local  field potential (Fig. 1A; peak amplitude: 0.75 ± 0.03 mV, mean ± SE, n = 12, P < 0.05 from background noise; at 7.8 ± 0.8 Hz; n = 12), lasting for the post-CCH recording period of ~3 h (Huerta and Lisman 1995; Pitler and Alger 1992).
  • CCH induced  oscillation of membrane potential (7.8 ± 1.1 mV; n = 20; P < 0.05) in CA1 pyramidal cells (intracellular ; Fig. 1B), a response blocked by bath atropine sulfate (1 µM, n = 8, P < 0.05; not shown).
  • At one-third to one-half of the maximum depolarizing phase, action potentials were triggered (Fig. 1, B and C).
  • Bath-applied BIC (1 µM) eliminated the  field oscillation (by 97.5 ± 4.2%, n = 8, P < 0.05; Fig. 1A) and CA1 intracellular  activity (by 98.9 ± 3.4%, n = 10, P < 0.05; Fig. 1B).
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 2. Carbachol (CCH)-induced {theta} oscillations of hippocampal CA1 field potential and of membrane potential of CA1 pyramidal cells are associated with GABAergic postsynaptic depolarization. A: single pulse stimulation (50 µA, 50 µs) of the GABAergic inputs from interneurons evoked inhibitory postsynaptic potentials (IPSPs), which were gradually reduced and reversed to depolarizing responses during CCH application (50 µM; CCH), associated with increased amplitude values of {theta} activity. The averaged maximum IPSP values of each cell during 10-min stable recording period were defined as 100% baseline PSP. A minus sign was added to indicate its inhibitory nature. For clarity, only every other data point is shown with insets (calibration bars: 50 ms and 5 mV; dashed horizontal lines indicate potential level of {-}70 mV) showing representing traces at approximate time pointed by broken arrows. B: 3 of the traces are placed together for comparison. The depolarizing response was blocked by BIC (1 µM, 30 min; BIC + CCH). Membrane potential was maintained at the pre-CCH level by passing current. C: under voltage clamp at {-}74 mV, the evoked GABAergic response was an outward current (Control), which was reversed to inward during CCH application (CCH, 50 µM, 20 min). Arrowheads indicate the time of the stimulation.
  • The evoked IPSPs (Fig. 2A; peak response: 8.89 ± 0.29 mV, n = 89) were not altered by kynurenate (500 µM, n = 6), but abolished by BIC (1 µM; by 96.8 ± 3.7%; n = 8, P < 0.05), indicating GABAA receptor mediation and an absence of contamination of any obvious excitatory component in the evoked IPSPs.
  • Associated with the  activity was a gradual reduction in the IPSPs (n = 25) and the ultimate production of an "excitatory" response (Fig. 2, A and B; from pre-CCH 9.0 ± 1.2 mV as compared with +5.1 ± 0.4 mV 30 min after the CCH application; n = 10, P < 0.05).
  • These voltage changes in the GABAergic responses corresponded to a gradual change of an outward current (0.18 ± 0.03 nA) toward an inward current (0.19 ± 0.05 nA; n = 5, P < 0.05) under voltage clamp (Fig. 2C).
  • The intracellular  activity became evident when the GABAergic responses became depolarizing (Fig. 2A).
  • The reversed excitatory response was also sensitive to BIC (Fig. 2B), indicating the involvement of the same type of receptor channel before and after the CCH administration.
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 3. Carbachol shifts reversal potentials of GABAergic postsynaptic responses in hippocampal CA1 pyramidal cells. A: responses of CA1 pyramidal cells to activation of GABAergic inputs at different membrane potentials before (Control) and in the presence of bath 1 µM BIC (middle). The relationship between the maximum postsynaptic responses and membrane potential can be described with a straight line, determined with the least sum squares criterion and was flattened by BIC without changing the reversal potential (bottom). B: responses of CA1 pyramidal cells to activation of GABAergic inputs at different membrane potentials before (Control) and during CCH application (50 µM; middle). Membrane potential was maintained at the pre-CCH level by passing current. Arrowheads indicate the stimulation. C: left shows an example of CCH-induced reversal of GABAergic response that was above threshold for generation of action potentials. The postsynaptic response exhibits a similar relationship between the maximum responses and membrane potential. For clarity, only 2 traces are shown. The same intensity of stimulation of the GABAergic inputs triggered an action potential in the cells post-CCH (CCH) as compared with IPSP pre-CCH (Control; right). Inset shows the initial segment at ×3 magnification with action potential truncated. Arrowheads indicate the time when brief pulse of stimulation was delivered.
  • The evoked IPSPs in CA1 pyramidal cells depended on the membrane potentials (e.g., Fig. 3).
  • BIC virtually abolished the GABAergic postsynaptic responses no matter whether the postsynaptic responses were evoked at membrane potentials positive or negative to the reversal potential (Fig. 3A).
  • The reversal potential, however, was not changed by BIC (Fig. 3A; 81.3 ± 2.6 mV; n = 6).
  • This BIC effect contrasts with CCH-induced changes that were associated with a positive shift of the reversal potential (Fig. 3B; from 79.8 ± 3.2 to 68.4 ± 2.8 mV; n = 10, P < 0.05).
  • Figure 3C illustrates an example in which the CCH-induced reversal potential appears to be above the threshold (approximately 57 mV) for generation of action potential.
  • Thus single brief pulse of stimulation of the GABAergic inputs elicited action potential during post-CCH period in the cell, in contrast to inhibitory postsynaptic response before the CCH application (Fig. 3C).
  • The majority of cells (123 of 149), however, showed a rapid adaptation to depolarization (Fig. 3, A and B), resulting in a silent but depolarized state.
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 4. Carbachol (CCH)-induced {theta} oscillations of hippocampal CA1 field potential and of membrane potential of CA1 pyramidal cells depend on HCO3{-} formation. A: an example of recorded field potentials in hippocampal CA1: pre-CCH control (top), during CCH (50 µM, 30 min) and acetazolamide (ACET) application (1 µM, 30 min). B: membrane potential traces of recorded CA1 pyramidal cells: pre-CCH (control), during CCH application (50 µM, 30 min) in the presence of ACET (1 µM, 30 min). In the presence of 1 µM ACET, single pulse stimulation (50 µA, 50 µs) of the GABAergic inputs evoked an IPSP (Control), which was not altered by CCH application (50 µM, 30 min).
  • Bath ACET (1 µM), a carbonic anhydrase inhibitor, eliminated the CCH-induced changes in GABAergic postsynaptic responses (Fig. 4B).
  • Under such conditions, neither  field oscillation (n = 8; Fig. 4A) nor intracellular  activity (n = 10; Fig. 4B) was induced by CCH.
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 5. Intracellular administration of calexcitin associated with postsynaptic depolarization induced acetazolamide-sensitive intracellular {theta} in hippocampal pyramidal cells. A: before the application, the membrane potential of the CA1 pyramidal cell did not show {theta} activity. B: calexcitin application (associated with a depolarizing current of 0.4-0.6 nA during the off-period to evoke 4-8 spikes/s to load Ca2+) into the recorded neuron induced the intracellular {theta}. C: in the presence of 1 µM ACET, calexcitin application (associated with a depolarizing current of 0.4-0.6 nA during the OFF-period to evoke 4-8 spikes/s to load Ca2+) into the recorded neuron did not induce the intracellular {theta}.
  • 1999), into CA1 pyramidal cells mimicked CCH in inducing the intracellular  activity (Fig. 5, A and B; n = 10), when associated with a depolarizing current to load Ca2+.
  • The calexcitin-induced intracellular  activity was also prevented by bath ACET (1 µM) in six cells tested (Fig. 5C).
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 6. Rebound action potentials of hippocampal CA1 pyramidal cells evoked by GABAergic inhibition vary in occurrence and timing. A: in slowly adapting cells, an evoked IPSP can delay or reset the subsequent occurrence of spikes when the cells were depolarized. The vertical lines above the trace indicate the expected time for an action potential to occur if the cell continued to discharge at the same regular intervals observed immediately before the stimulus was delivered. Arrowhead indicates the stimulation. B: rebound depolarization was not evoked at resting membrane potential with single pulse (trace 1) or a train of 4 pulses at 100 Hz (trace 2) stimulation of the GABAergic inputs. C: rebound action potential at resting membrane potential requires too strong hyperpolarization (30 mV; trace 3 with action potential truncated), otherwise no rebound depolarization was evoked (trace 1). D: when depolarized, rebound action potential can be induced but with low safety and varied timing (with action potential truncated).
  • In some cells (26 of 149 neurons in which effects of membrane potential changes on the GABAergic postsynaptic responses were examined), discharges lasted for a period of elicited depolarization and an evoked IPSP appeared to be able to delay subsequent spikes (Fig. 6A).
  • No rebound action potential was observed with IPSPs of 8.9 ± 0.3 mV evoked at resting membrane potentials (73.8 ± 0.9 mV, n = 89; Fig. 6B, trace 1).
  • A train of pulses at 100 Hz was also ineffective (Fig. 6B, trace 2), suggesting that temporal summation of the unitary IPSPs is insufficient to evoke rebound depolarization.
  • Furthermore, no significant rebound depolarization (0.19 ± 0.12 mV, n = 75, P > 0.05) was evoked with intracellular negative pulses (up to 700 ms) sufficient to evoke 10.8 ± 1.4 mV potential changes (Fig. 6C, trace 1) from the resting membrane potential (74.8 ± 0.4 mV).
  • In addition, when evoked at depolarized membrane potentials, the occurrence and timing of individual "rebound" action potentials varied (Fig. 6D).
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 7. Carbachol (CCH)-induced {theta} GABAergic depolarization of hippocampal CA1 pyramidal cells enables GABAergic inputs to entrain CA1 pyramidal cells. A: {theta} rhythm stimulation evoked IPSPs before CCH application (Control). During CCH application (50 µM, 30 min; middle panel), the same pattern of stimulation entrained activity of the pyramidal cell. Action potentials were evoked at the 2nd, 3rd, and 5th pulses, with action potentials truncated. The evoked postsynaptic responses were abolished by BIC (1 µM, 30 min). B: schematic diagram of network and discharge relationship between CA1 pyramidal cells and GABAergic interneurons. Top: cholinergic inputs (synaptic or diffuse transmission) act on pyramidal cells, inducing HCO3{-} accumulation and enhanced HCO3{-} conductance through the GABAA receptor channels. The {theta} rhythmic activity of GABAergic interneurons can then directly be transmitted to the pyramidal cells, entraining their activity and altering signal processing. Bottom: peak discharge relationship of pyramidal cells (black rectangle) and interneurons (shadow oval) in {theta} rhythm in behaving and rapid eye movement (REM) sleep (based on O'Keefe and Recce 1993; Shen et al. 1997; Csicsvari et al. 1999). The arrow indicates the discharge shift of a place cell, starting from shadow rectangle, in relation to the {theta} activity as the animal travels into the place field of the place cell. GABA, GABAergic interneurons; Pyr, CA1 pyramidal cells; SCH, Schaffer collateral pathway. C: top left, top right, and bottom left are examples of traces without truncation, showing that the brief pulse of stimulation at 5.5 Hz elicited action potentials even though the 1st brief pulse of stimulation was insufficient to evoke action potential. Bottom right illustrates responses to co-stimulation of Sch at below-threshold intensity and GABAergic inputs at pre-CCH (Control) and post-CCH (CCH) periods. Inset shows the initial segment at ×3 amplification with action potential truncated. Arrowheads indicate the time when the brief pulse of stimulation was delivered.
  • On the other hand, in the presence of CCH, stimulation of GABAergic inputs elicited instantly phase-locked firing of pyramidal cells (Fig. 7, A and C; n = 14).
  • The postsynaptic GABAergic response to the first stimulation pulse usually did not reach action potential threshold (Fig. 7, A and C).
  • The postsynaptic GABAergic responses were sensitive to BIC, indicating the involvement of the same receptor channels (Fig. 7A).
  • Before the CCH administration, co-stimulation of Sch at the set intensity (50% below the threshold) and GABAergic inputs (50 µA, 50 µs) largely abolished the Sch stimulation-induced excitatory potential (by 89.5 ± 4.3%, n = 8, P < 0.05; Fig. 7C).
  • Action potentials, however, were evoked by co-stimulation of Sch at below-threshold intensity together with reversed GABAergic inputs in all cases (n = 8, P < 0.05; Fig. 7C, bottom right).
  • 1999) and reconfigures the operations of hippocampal networks into patterns of activity associated with GABAergic inputs (Fig. 7B).
  • Place cells thus fire in phase with progressively stronger GABAergic inputs from interneurons and at earlier phases of the  cycles as the rat moves toward the center of their place field (Fig. 7B) (Csicsvari et al.
  • The reversed response, although often not strong enough to reach threshold by itself, can entrain the pyramidal cells when stimulated at a  frequency (Fig. 7).
  • Furthermore, the reversed response can effectively enhance weak excitatory inputs to reach threshold (Fig. 7C) (Sun et al.
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 8. Carbonic anhydrase inhibitors impair rat spatial memory in vivo. A: the mean (±SE) escape latency across 16 trials (F15,270 = 22.93, P < 0.0001) in the watermaze by rats given a single dose (indicated with arrows) of saline (Saline, 0.5 ml) or ACET (5 mg/0.5 ml/day ip). B: percentage ratio in escape latency of the 1st trial of the day between the 2 groups. C-E: quadrant preference of saline- (n = 10; ** P < 0.0001; C) and ACET-injected rats (n = 10; D) and swimming distance (in 1 min; E). A platform for escape was placed in quadrant 4 during training. Insets are paths taken by representative rats with quadrant numbers indicated.
  • 1998) was sufficient to produce memory impairment (Fig. 8A).
  • The memory impairment became more significant as the training days progressed and was particularly evident in the first trial (65-70 min after the injection) of each successive day (Fig. 8, A and B).
  • Quadrant tests 24 h after the last training trial revealed that control rats spent the majority of their time searching in the quadrant (Quadrant 4; Fig. 8C) where the platform was previously placed and had been removed (F3,36 = 183.9, P < 0.0001; ANOVA and Newman-Keuls post hoc test), whereas the ACET group showed no preference to a particular quadrant (F3,36 = 1.59, P = 0.21; Fig. 8D).
  • The total swimming distances, however, did not differ between the two groups (Fig. 8E; P > 0.05), indicating that ACET did not grossly affect their sensory or locomotor activities.
Journal of neurophysiology.
Sun MK, Zhao WQ, Nelson TJ, Alkon DL      2001 Jan     >Caption source<
Extra large 
Theta rhythm of hippocampal CA1 neuron activity: gating by GABAergic synaptic depolarization.
Fig. 9. ACET administration does not affect retrieval of formed spatial memory. A: escape latency of the control rats during 3 more days of training trials. B and C: quadrant preference of these rats after a single dose of saline (0.5 ml, n = 5; B) or ACET (5 mg/0.5 ml, n = 5; C). No significant difference in quadrant preference (P > 0.05) was observed between the saline- and ACET-injected rats. Insets are paths taken by representative rats with quadrant numbers indicated.
  • The control rats were trained for 3 more days (Fig. 9A) and received the single injection of either ACET or saline 24 h after the last training trial.
  • Sixty-five to 70 min after the injection, a quadrant test in ACET-injected rats showed no significant difference (P > 0.05) in quadrant 4 preference (F3,16 = 132.9, P < 0.0001; Fig. 9C) from that of the saline control rats (F3,16 = 306.4, P < 0.0001; Fig. 9B).
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