Muscarinic blockade slows and degrades the location-specific firing of hippocampal pyramidal cells - PubMed (original) (raw)

Comparative Study

Muscarinic blockade slows and degrades the location-specific firing of hippocampal pyramidal cells

E S Brazhnik et al. J Neurosci. 2003.

Abstract

The firing of rat hippocampal pyramidal cells is determined both by the animal's location and by the state of the hippocampal EEG. Because cholinergic transmission plays a role in EEG activity, we expected that its modification would alter place cell activity. We therefore investigated the effects on place cell activity of blocking muscarinic transmission with intracerebroventricular injections of scopolamine. Scopolamine reduced both the rate of place cell discharge inside firing fields and the spatial coherence of the fields; discharge outside of the fields also showed small increases. After injections, fields were shifted farther from their previous location than for saline controls, indicating reduced reproducibility after muscarinic blockade. Scopolamine increased the time rats were stationary, but changes in place cell activity persisted even after analysis was restricted to periods of walking, suggesting that the behavioral changes cannot account for the cell discharge changes. The scopolamine effects were dose dependent to an extent that varied between different measures. The firing rates of interneurons showed only a minor trend to decrease after scopolamine. Nevertheless, the spatial coherence of interneuron firing patterns was reduced, consistent with the recent demonstration that their positional firing is mediated by the location-specific firing of pyramids (Marshall et al., 2002). These results demonstrate that acetylcholine enhances positional firing patterns in the hippocampus. Muscarinic blockade weakens the positional firing of most place cells and therefore renders them less useful for precise representation of the environment. This effect may underlie the difficulties in spatial learning and problem solving caused by abnormalities of cholinergic transmission.

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Figures

Fig. 1.

Fig. 1.

Spatial firing pattern for two pairs of simultaneously recorded hippocampal cells before and at 0.5, 1, and 4 hr intervals after blockade of muscarinic transmission by scopolamine (3 μg per ventricle). Each circle is a color-coded firing rate map indicating the discharge rate of a place cell as a function of the position of a rat's head on the floor of a cylindrical chamber. Yellow pixels mark positions where no action potentials ever occurred. Orange, red,green, blue, and _purple_represent increasing firing rates where the breakpoints between color categories are taken from the control session for each cell; these breakpoints are indicated at the right of the control map for each cell. Muscarinic blockade caused a significant and long-lasting decrease in the firing rate of place cells throughout the field.

Fig. 2.

Fig. 2.

Recovery of place fields after 24 hr. The spatial firing patterns of four hippocampal pyramidal cells (A–D) are coded as in Figure 1. Firing rate maps are given for control sessions and sessions 1 hr and 24 hr after muscarinic blockade. Firing rate decreases, loss of spatial organization, and motion of the entire field are visible at 1 hr but mainly reversed by 24 hr.

Fig. 3.

Fig. 3.

Time course of the effect of muscarinic blockade on the spatial firing characteristics of place cells. The dashed line in each panel shows the mean across place cells for predrug control sessions (also plotted at time = 0). The mean (±1 SEM) is plotted for time after muscarinic blockade by scopolamine. The number of cells recorded at each time point is given near each data point in the overall rate plot of_A_. Values that differ from the predrug control according to the post hoc Fisher's PLSD test at least at the 0.05 level of significance are indicated with asterisks. Compared with control means, the overall mean firing rate for the session (F(6,561) = 4.0;p = 0.0006) (A), the mean rate in the largest firing field (F(6,561) = 12.9; _p_= 0.0001) (B), and the rate in the center of the largest field (F(6,561) = 10.9;p = 0.0001) (C) are all significantly reduced (multivariate ANOVA and Fisher's PLSD) from 0.5 to 4 hr after scopolamine. The trends for elevation of average firing rate outside the field (F(6,561) = 1.02; p = 0.41) (D) and reduction in field size (F(6,561) = 1.77; p = 0.10) (E) were not significant by the ANOVA (or even for any single time point), but the probability is only 1 in 32 that all five consecutive points would lie on the same side of the mean simply by chance. The smoothness of the rate map as measured by spatial coherence (F(6,561) = 30.8; p< 0.0001) (F) is significantly reduced between 0.5 and 4 hr after scopolamine. None of the 24 hr points are significantly different from controls, indicating recovery for all quantities.

Fig. 4.

Fig. 4.

Time course of the effect of muscarinic blockade on the spatial firing characteristics of theta cells. Overall firing rate for the session (F(5,180) = 0.50;p = 0.78) (A) and peak firing in the map of average rate (F(5,180) = 0.45; p = 0.81) (B) each show a nonsignificant reduction after scopolamine administration; any such effect has reversed by 4 hr. The coherence of positional firing patterns for these interneurons (F(5,180) = 2.52; _p_= 0.03) (C) shows a significant decrease at 1, 2, and 3 hr after injection but has substantially recovered by 4 hr.

Fig. 5.

Fig. 5.

Dose–response curves for intracerebroventricular scopolamine. The effects of 1.5, 3.0, and 6.0 μg per ventricle of scopolamine on the place cell measures overall rate (F(3,148) = 4.88;p = 0.003) (A), in-field rate (F(3,148) = 6.33; _p_= 0.0005) (B), center rate (F(3,148) = 6.20; _p_= 0.0005) (C), out-of-field rate (F(3,148) = 1.39; _p_= 0.25) (D), field size (F(3,148) = 6.33; p_= 0.0005) (E), and spatial coherence (F(3,148) = 20.7; p< 0.0001) (F) are plotted (mean ± 1 SEM). The number of cells for each dose is indicated near the data points in_A, and asterisks mark data points that differ significantly from the control value (dashed line). The dose–response curves show saturation for the overall, in-field, and field center rate measures. Out-of-field rate shows a rather large increase at the highest scopolamine dose. The decreases of field size and coherence are progressively greater at higher doses.

Fig. 6.

Fig. 6.

Scheme for how mechanisms of muscarinic transmission might produce the observed effects of scopolamine administration on place cells. Enhanced release of acetylcholine (ACh) by activity in afferents from the medial septal nucleus and nucleus of the diagonal band of Broca (MS-DB) during theta rhythm. a turns off potassium currents, increasing pyramidal cell (P) excitability (+), b suppresses proximal intrinsic (“Associational” Afferents) excitatory connections relative to distal extrinsic (“Sensory” Afferents) excitatory connections, and c activates interneurons (I), producing increased somatic inhibition (−). The latter two effects (b and_c_) work together to suppress out-of-field firing of place cells by reducing the effectiveness of afferent activity from other hippocampal place cells (grayed area). The first effect, reduction of potassium currents (a), enhances the in-field firing by triggering spikes in the dendrites that prevail despite the somatic inhibition and activate the axon (output). _Dashed lines_represent the “trigger zones” in the pyramidal cell membrane at the axon hillock and in the apical dendrites. According to this scheme, acetylcholine effectively switches the pyramidal cell from suppression of its distal inputs by high potassium conductance and heavily weighting its proximal inputs as integrated by the axon hillock (Proximal Trigger Zone) to suppression of its proximal inputs by somatic inhibition and heavily weighting its distal inputs as integrated by the active membrane in the apical dendrites (Distal Trigger Zone). Additional considerations are given in Results.

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