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Neural Plasticity of the Hippocampal (CA1) Pyramidal Cell - Quantitative Changes in Spine Density Following Handling and Injection for Drug Testing

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Neural Plasticity of the Hippocampal (CA1) Pyramidal Cell - Quantitative Changes in Spine Density Following Handling and Injection for Drug Testing J. Anat. (1991), 174, pp. 229-238 229 With 3 figures Printed in Great Britain Neural plasticity of the hippocampal (CA1) pyramidal cell - quantitative changes in spine density following handling and injection for drug testing C. H. HORNER, M. O'REGAN* AND E. ARBUTHNOTTt Department of Anatomy, * Department of Statistics and t Department of Physiology, Trinity College, Dublin 2, Ireland (Accepted 10 August 1990) INTRODUCTION Plasticity of the central nervous system is a well documented phenomenon. Following Ramon y Cajal's (1911) discovery of dendritic spines it became apparent that these structures can change in response to a wide spectrum of conditions, including disease states, administration of chemical substances, non-physiological stimulation and manipulation of factors such as food intake and sleep. Examples of the early findings are found in the published work of Demoor (1898), Monti (1895) and Querton (1898). Although plasticity has been demonstrated in many areas, the neural circuitries of the hippocampus possess remarkable capacities for both functional and structural changes (Alger & Teyler, 1976; Deadwyler, Dudek, Cotman & Lynch, 1975; Lee, Stanford, Cotman & Lynch, 1977; Lynch, Gall & Dunwiddie, 1978; McWilliams & Lynch, 1978). This study demonstrates the plastic nature of the hippocampus in response to the sensory stimuli of handling and injection. Although the mechanisms of action of drug groups are generally investigated using biochemically- and physiologically-based studies, morphological changes following drug administration have been recorded (Arbuthnott & Folan, 1983; Bigotte & Olsson, 1983; Shikai & Miyakawa, 1981). The tricyclic antidepressant group of drugs is a frequently used treatment for depression, a common psychiatric disorder. The means by which these drugs alleviate depressive symptoms, after approximately three weeks, has been much researched and debated. The biogenic monoamine theory of depression (Coppen, 1967) suggests that a neurotransmitter deficiency at the synaptic junction is responsible. However, the relationship between the acute primary effects of tricyclic antidepressants on the neurotransmitter levels (Ross & Renyi, 1975) and their clinical lag in effectiveness is poorly correlated (Pollock et al. 1986). Therefore the possibility of involvement of postsynaptic receptors in the mediation of antidepressant action has been suggested (Sulser, 1983; Fuxe et al. 1983). A process requiring time for change to occur, such as long-term morphological alterations, may explain the three weeks delay in clinical improvement. Since the synaptic junction is the site of action of these drugs, whether it be on the neurotransmitter levels or the postsynaptic receptor, this study involved a quantitative assessment of the spine density of several dendritic types, the dendritic spines being the site of the majority of synapses (Gray, 1959; Colonnier, 1968). The hippocampus was chosen as the area for study since it is considered part of the 'limbic system" and so has been linked with emotional and behavioural changes (MacLean, 1952; Kluiver & Bucy, 1939). It also has a highly organised structure which is readily identified (Brodal, 230 C. H. HORNER AND OTHERS 1981). In particular the pyramidal cells of area CAl were chosen for this study, these being the site of synapse of the Schaffer-commissural collaterals within the intrinsic circuit of the hippocampal formation. MATERIALS AND METHODS Young outbred male Wistar albino rats, supplied by the Wellcome Research Animal Laboratory at Trinity College, Dublin, were used in this study. They were eight weeks old at the start of treatment and had a mean weight of 226 g (208-244 g). They were reared in pairs under the same conditions receiving water and rat/mouse diet by Odlum's ad libitum. All animals were free from grossly detectable pathology. The animals were divided into three groups identified as control, drug and saline. The control group (n = 6) received no treatment and were unhandled except for weekly weighing. The drug group (n = 5) had daily intraperitoneal injections of clomipramine (Anafranil), a tricyclic antidepressant, for 22 days. The dose administered was 10 mg per kg body weight. The saline group (n = 5) served as handled controls. They received daily intraperitoneal injections of normal saline of the same volume and were handled in the same way as the drug-treated group. Following 22 days of treatment, the animals were anaesthetised with 6% sodium pentobarbitone (Sagatal) using a dose of 0A44 ml per kg. The animals were artificially ventilated using 95 % 02/5 % CO2 until vascular perfusion was initiated through the left ventricle using a dilute fixative consisting of 1 % paraformaldehyde/ 1 -25 % glutaraldehyde in 0-2M cacodylate buffer initially, followed by a concentrated fixative of 4% paraformaldehyde/5 % glutaraldehyde in 0-2M cacodylate buffer. The crania were removed and stored in concentrated fixative at 4°C overnight. The brains were dissected out, bisected in the midsagittal plane and blocks of hippocampal tissue were taken from each cerebral hemisphere using Paxinos & Watson's stereotaxic atlas (1982) as a guideline. A modified Golgi-Kopsch technique described by Riley (1979) was used for impregnating the neural tissue. The blocks were immersed in fixative for five days, rinsed and further immersed in 0-75 % silver nitrate for two days while being kept in the dark. Approximately 30 ml of each solution were used per block of tissue. Post- impregnation, the blocks were dehydrated, orientated and shelled in paraffin wax for sectioning. Thick coronal sections of 120,um were cut using a sliding microtome. Thick sections are favoured for Golgi-impregnated neural tissue (Feldman, 1976; Fitch, Juraska & Washington, 1989; Uylings, Kuypers, Diamond & Veltman, 1978) since they enable viewing of the wide dendritic field and yet permit focusing at x 100 oil magnification. Spine density on pyramidal cell (CA1) dendrites was estimated at three loci. The first was a 50,sm segment of apical dendrite starting 50,um from the origin of this dendrite at the apex of the cell body. The second was a 25,cm section of basal dendrite beginning 25 ,um from its origin at the perikaryon base and finally a 25,tm segment of oblique dendrite from its point of origin of the apical dendrite (Fig. 1). Visible spines were counted over these sections of dendrites. Twenty estimations for each type of dendrite for each animal were made, choosing clearly visible dendrites which were relatively straight. All protrusions whether pedunculated or stubby, with or without terminal bulbous expansions, were counted as spines if they appeared to be in direct continuity with the dendritic shaft (Feldman & Dowd, 1975). The dendritic diameter and the exact length of dendrite over which the spines were counted was measured Spine density plasticity in hippocampal neurons 231 Terminal tuft Apical 50 um .I Fig. 1. The apical, basal and oblique dendritic loci chosen for estimation of spine density. using semi-automatic image analysis. Using the same system, the spine length and diameter of the spine head of a typical spine on the segment of dendrite being assessed were recorded. These values were applied to the geometrical equation devised by Feldman & Peters (1979) which produces estimates of 'true' spine density which are corrected for dendritic diameter and size of the spines. A nested analysis of variance was used to compare the three group means. In the case of significant group differences a Newman-Keuls test was performed to find the groups between which the difference existed. RESULTS On examination of the pyramidal cells in the hippocampal sections at low magnification ( x 10) there were no obvious differences between cells within or between groups. At higher magnification ( x 40) there appeared to be differences between the density of spines on cells. Although not the case for all cells, the greater spine numbers appeared to be in the drug-treated and saline-injected animals (Fig. 2). At x 100, oil immersion, spine counts were performed to confirm or negate this impression. Spine density is defined as the number of dendritic spines per micron of dendrite. A total of 900 estimates of spine density was made, twenty estimates per locus per animal were recorded and the mean per group calculated. One control animal was poorly fixed and was discarded, leaving five animals per group. The mean spine density for a particular locus was similar for animals within the same group. However, the cell 232 C. H. HORNER AND OTHERS Basal Apical and oblique Control, Saline Drug Fig. 2. Camera lucida drawings of 40-50 ,um segments of basal, apical and oblique dendrites in drug- and saline-injected, and unhandled control experimental groups. to cell variability for visible spine counts at any given locus within the same animal were quite large, e.g. 28-75 spines per dendritic segment in different cells of one saline- injected animal. Similar variability was noted in data from all animals in the study. The mean spine densities, corrected for obscuration from varying dendritic diameter and spine size, for apical dendrites were 4-83 for the drug group, 4-33 for the saline- injected group and 4 05 for the unhandled control group. Basal dendrites had mean spine densities of 5-71 in the drug-treated, 5-17 in the saline-injected and 3 97 in the control groups while oblique dendrites had mean values of 6-30 for the drug animals, 5-77 for the saline animals and 3-87 for the control animals. These values and the standard error of the group means are recorded in Table 1 and displayed graphically in Figure 3. These results show basal and oblique spine densities to be higher than apical spine density except in the unhandled controls where the spine densities relate to the diameter of the dendrites, apical dendrites having the highest and oblique dendrites the lowest densities. Basal and oblique spine densities were very similar but oblique spine density was the greater in both drug and saline treatment groups. Drug- injected animals had consistently higher spine densities than saline-injected and unhandled controls while saline-treated animals had greater values than controls.
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