Synaptic Spine Density Research Articles

Cranial irradiation compromises neuronal architecture in the hippocampus

Cranial irradiation is used routinely for the treatment of nearly all brain tumors, but may lead to progressive and debilitating impairments of cognitive function. Changes in synaptic plasticity underlie many neurodegenerative conditions that correlate to specific structural alterations in neurons that are believed to be morphologic determinants of learning and memory. To determine whether changes in dendritic architecture might underlie the neurocognitive sequelae found after irradiation, we investigated the impact of cranial irradiation (1 and 10 Gy) on a range of micromorphometric parameters in mice 10 and 30 d following exposure. Our data revealed significant reductions in dendritic complexity, where dendritic branching, length, and area were routinely reduced (>50%) in a dose-dependent manner. At these same doses and times we found significant reductions in the number (20-35%) and density (40-70%) of dendritic spines on hippocampal neurons of the dentate gyrus. Interestingly, immature filopodia showed the greatest sensitivity to irradiation compared with more mature spine morphologies, with reductions of 43% and 73% found 30 d after 1 and 10 Gy, respectively. Analysis of granule-cell neurons spanning the subfields of the dentate gyrus revealed significant reductions in synaptophysin expression at presynaptic sites in the dentate hilus, and significant increases in postsynaptic density protein (PSD-95) were found along dendrites in the granule cell and molecular layers. These findings are unique in demonstrating dose-responsive changes in dendritic complexity, synaptic protein levels, spine density and morphology, alterations induced in hippocampal neurons by irradiation that persist for at least 1 mo, and that resemble similar types of changes found in many neurodegenerative conditions.

Stress-Induced Grey Matter Loss Determined by MRI Is Primarily Due to Loss of Dendrites and Their Synapses

Stress, unaccompanied by signs of post-traumatic stress disorder, is known to decrease grey matter volume (GMV) in the anterior cingulate cortex (ACC) and hippocampus but not the amygdala in humans. We sought to determine if this was the case in stressed mice using high-resolution magnetic resonance imaging (MRI) and to identify the cellular constituents of the grey matter that quantitatively give rise to such changes. Stressed mice showed grey matter losses of 10 and 15% in the ACC and hippocampus, respectively but not in the amygdala or the retrosplenial granular area (RSG). Concurrently, no changes in the number or volumes of the somas of neurons, astrocytes or oligodendrocytes were detected. A loss of synaptic spine density of up to 60% occurred on different-order dendrites in the ACC and hippocampus (CA1) but not in the amygdala or RSG. The loss of spines was accompanied by decreases in cumulative dendritic length of neurons of over 40% in the ACC and hippocampus (CA1) giving rise to decreases in volume of dendrites of 2.6mm(3) for the former and 0.6mm(3) for the latter, with no change in the amygdala or RSG. These values are similar to the MRI-determined loss of GMV following stress of 3.0 and 0.8mm(3) in ACC and hippocampus, respectively, with no changes in the amygdala or RSG. This quantitative study is the first to relate GMV changes in the cortex measured with MRI to volume changes in cellular constituents of the grey matter.

NGL-2 Regulates Input-Specific Synapse Development in CA1 Pyramidal Neurons

An important organizing feature of the CNS is that individual neurons receive input from many different sources. Independent regulation of synaptic input is critical for the function and adaptive responses of thenervous system, but the underlying molecular mechanisms are not well understood. We identify the leucine-rich repeat (LRR)-containing protein NGL-2 (Lrrc4) as a key regulator of input-specific synapse development in the hippocampus. Using genetic deletion and shRNA-mediated knockdown, we demonstrate a role for NGL-2 in regulating the strength of synaptic transmission and spine density specifically at Schaffer collateral synapses in the stratum radiatum (SR) in CA1. NGL-2 protein is restricted to SR and spine regulation requires NGL-2's LRR and PDZ-binding domains. Finally, loss of NGL-2 disrupts cooperative interactions between distal and proximal synapses in CA1 pyramidal cells. These results demonstrate that NGL-2 is critical for pathway-specific synapse development and functional integration of distinct inputs.

Prolyl Endopeptidase-Deficient Mice Have Reduced Synaptic Spine Density in the CA1 Region of the Hippocampus, Impaired LTP, and Spatial Learning and Memory

Prolyl endopeptidase (PREP) is a phylogenetically conserved serine protease and, in humans and rodents, is highly expressed in the brain. Several neuropeptides associated with learning and memory and neurodegenerative disorders have been proposed to be the substrates for PREP, suggesting a possible role for PREP in these processes. However, its physiological function remains elusive. Combining genetic, anatomical, electrophysiological, and behavioral approaches, we show that PREP genetrap mice have decreased synaptic spine density in the CA1 region of the hippocampus, reduced hippocampal long-term potentiation, impaired hippocampal-mediated learning and memory, and reduced growth-associated protein-43 levels when compared with wild-type controls. These observations reveal a role for PREP in mediating hippocampal plasticity and spatial memory formation, with implications for its pharmacological manipulation in diseases related to cognitive impairment.

Delayed reduction of hippocampal synaptic transmission and spines following exposure to repeated subclinical doses of organophosphorus pesticide in adult mice.

Agricultural and household organophosphorus (OP) pesticides inhibit acetylcholinesterase (AchE), resulting in increased acetylcholine (Ach) in the central nervous system. In adults, acute and prolonged exposure to high doses of AchE inhibitors causes severe, clinically apparent symptoms, followed by lasting memory impairments and cognitive dysfunction. The neurotoxicity of repeated environmental exposure to lower, subclinical doses of OP pesticides in adults is not as well studied. However, repeated exposure to acetylcholinesterase inhibitors, such as chlorpyrifos (CPF), pyridostigmine, and sarin nerve agent, has been epidemiologically linked to delayed onset symptoms in Gulf War Illness and may be relevant to environmental exposure in farm workers among others. We treated adult mice with a subclinical dose (5 mg/kg) of CPF for 5 consecutive days and investigated hippocampal synaptic transmission and spine density early (2-7 days) and late (3 months) after CPF administration. No signs of cholinergic toxicity were observed at any time during or after treatment. At 2-7 days after the last injection, we found increased synaptic transmission in the CA3-CA1 region of the hippocampus of CPF-treated mice compared with controls. In contrast, at 3 months after CPF administration, we observed a 50% reduction in synaptic transmission likely due to a corresponding 50% decrease in CA1 pyramidal neuron synaptic spine density. This study is the first to identify a biphasic progression of synaptic abnormalities following repeated OP exposure and suggests that even in the absence of acute cholinergic toxicity, repeated exposure to CPF causes delayed persistent damage to the adult brain in vivo.

Extraordinary neoteny of synaptic spines in the human prefrontal cortex

The major mechanism for generating diversity of neuronal connections beyond their genetic determination is the activity-dependent stabilization and selective elimination of the initially overproduced synapses [Changeux JP, Danchin A (1976) Nature 264:705-712]. The largest number of supranumerary synapses has been recorded in the cerebral cortex of human and nonhuman primates. It is generally accepted that synaptic pruning in the cerebral cortex, including prefrontal areas, occurs at puberty and is completed during early adolescence [Huttenlocher PR, et al. (1979) Brain Res 163:195-205]. In the present study we analyzed synaptic spine density on the dendrites of layer IIIC cortico-cortical and layer V cortico-subcortical projecting pyramidal neurons in a large sample of human prefrontal cortices in subjects ranging in age from newborn to 91 y. We confirm that dendritic spine density in childhood exceeds adult values by two- to threefold and begins to decrease during puberty. However, we also obtained evidence that overproduction and developmental remodeling, including substantial elimination of synaptic spines, continues beyond adolescence and throughout the third decade of life before stabilizing at the adult level. Such an extraordinarily long phase of developmental reorganization of cortical neuronal circuitry has implications for understanding the effect of environmental impact on the development of human cognitive and emotional capacities as well as the late onset of human-specific neuropsychiatric disorders.

DGKι regulates presynaptic release during mGluR-dependent LTD

Diacylglycerol (DAG) is an important lipid second messenger. DAG signalling is terminated by conversion of DAG to phosphatidic acid (PA) by diacylglycerol kinases (DGKs). The neuronal synapse is a major site of DAG production and action; however, how DGKs are targeted to subcellular sites of DAG generation is largely unknown. We report here that postsynaptic density (PSD)-95 family proteins interact with and promote synaptic localization of DGKι. In addition, we establish that DGKι acts presynaptically, a function that contrasts with the known postsynaptic function of DGKζ, a close relative of DGKι. Deficiency of DGKι in mice does not affect dendritic spines, but leads to a small increase in presynaptic release probability. In addition, DGKι-/- synapses show a reduction in metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) at neonatal (∼2 weeks) stages that involve suppression of a decrease in presynaptic release probability. Inhibition of protein kinase C normalizes presynaptic release probability and mGluR-LTD at DGKι-/- synapses. These results suggest that DGKι requires PSD-95 family proteins for synaptic localization and regulates presynaptic DAG signalling and neurotransmitter release during mGluR-LTD.

Duration of estrogen deprivation, not chronological age, prevents estrogen's ability to enhance hippocampal synaptic physiology

Whether estrogen replacement is beneficial to cognitive health is controversial. Some studies have shown that estrogen replacement therapy (ERT) relieves memory impairment associated with menopause in women, whereas others suggest that estrogen not only is incapable of providing a benefit, but actually can be detrimental. One possible explanation for this discrepancy in study findings could be the varying time after menopause at which ERT is initiated. It has been proposed that a critical period exists during which ERT must be administered to enhance cognitive function. This idea has yet to be tested directly using functional synaptic studies, however. Here we investigated whether prolonged hormone deprivation caused by ovariectomy (OVX) in young adult rats prevents the ability of estrogen replacement to increase synaptic function in the hippocampus to a degree necessary for estrogen-induced improvement in learning and memory. Remarkably, estrogen replacement was found to increase long-term potentiation, the current mediated by NR2B-containing NMDA receptors, and the dendritic spine density at CA3-CA1 synapses up to 15 months post-OVX. However, by 19 months post-OVX, the same estrogen replacement was unable to induce these changes. Importantly, this loss of estrogen's effectiveness was seen to be a consequence of the duration of deprivation. In female rats aged with their ovaries intact and examined at the same chronological age as the 19-month post-OVX group, estrogen replacement significantly increased synaptic function and spine density. These data clearly demonstrate that a critical period exists during which ERT must be administered, and that once this period passes, the beneficial effects are lost.

Generation and Therapeutic Efficacy of Highly Oligomer-Specific β-Amyloid Antibodies

Oligomers of the beta-amyloid (Abeta) peptide have been indicated in early neuropathologic changes in Alzheimer's disease. Here, we present a synthetic Abeta(20-42) oligomer (named globulomer) with a different conformation to monomeric and fibrillar Abeta peptide, enabling the generation of highly Abeta oligomer-specific monoclonal antibodies. The globulomer-derived antibodies specifically detect oligomeric but not monomeric or fibrillar Abeta in various Abeta preparations. The globulomer-specific antibody A-887755 was able to prevent Abeta oligomer binding and dynamin cleavage in primary hippocampal neurons and to reverse globulomer-induced reduced synaptic transmission. In amyloid precursor protein (APP) transgenic mice, vaccination with Abeta globulomer and treatment with A-887755 improved novel object recognition. The cognitive improvement is likely attributable to reversing a deficit in hippocampal synaptic spine density in APP transgenic mice as observed after treatment with A-887755. Our findings demonstrate that selective reduction of Abeta oligomers by immunotherapy is sufficient to normalize cognitive behavior and synaptic deficits in APP transgenic mice.

Synapse Regression in Depression: The Role of 5-HT Receptors in Modulating NMDA Receptor Function and Synaptic Plasticity

Depression is accompanied by an increase in activity in the amygdala and a decrease in the rostral anterior cingulate cortex (rACC), with the former attributed to a failure of the latter to exert its normal inhibitory influence. This failure is likely due to regression of synaptic connections between the rACC and the amygdala, a process reversed in part by selective serotonin reuptake inhibitors (SSRIs). The present work presents a hypothesis as to how SSRIs might bring about this process and hence normalization of activity, at least in patients that are responsive to SSRIs. Serotonin receptors of the excitatory 5-HT(2A)R class increase N-methyl-D-aspartate receptor (NMDAR) efficacy, while those of the inhibitory 5-HT(1A)R class decrease NMDAR efficacy. A decrease of 5-HT transporter (5-HTT) efficacy, either during human development through functional polymorphisms, or in animals through 5-HTT transgenic knockouts, is accompanied by a decrease in 5-HT(1A)R and hence an increase in excitability and NMDAR efficacy which drives an increase in synaptic spines in the amygdala. As the limbic region of the brain normally possesses high levels of 5-HT(1A)R the effect of loss of these is to increase excitation in this region, as is observed. Changes in the level of extracellular 5-HT in adult animals also modulates the density of synaptic spines, with these increasing with an increase in 5-HT, possibly as a consequence of increases in 5-HT(2A)R activity over that of 5-HT(1A)R. Increasing extracellular levels of 5-HT with SSRIs would then lead to an increase in excitability and in synaptic spines for afferents in the dorsal rostral anterior cingulate cortex but not in the ventral regions such as the amygdala that have few 5-HT(2A)R. This allows dorsal regions to once more exert their inhibitory influence over ventral regions. In this way, SSRIs may exert their effect in normalizing dorsal hypometabolism and ventral hypermetabolism in those suffering from depression.

Genetically Increased Cell-Intrinsic Excitability Enhances Neuronal Integration into Adult Brain Circuits

New neurons are added to the adult brain throughout life, but only half ultimately integrate into existing circuits. Sensory experience is an important regulator of the selection of new neurons but it remains unknown whether experience provides specific patterns of synaptic input or simply a minimum level of overall membrane depolarization critical for integration. To investigate this issue, we genetically modified intrinsic electrical properties of adult-generated neurons in the mammalian olfactory bulb. First, we observed that suppressing levels of cell-intrinsic neuronal activity via expression of ESKir2.1 potassium channels decreases, whereas enhancing activity via expression of NaChBac sodium channels increases survival of new neurons. Neither of these modulations affects synaptic formation. Furthermore, even when neurons are induced to fire dramatically altered patterns of action potentials, increased levels of cell-intrinsic activity completely blocks cell death triggered by NMDA receptor deletion. These findings demonstrate that overall levels of cell-intrinsic activity govern survival of new neurons and precise firing patterns are not essential for neuronal integration into existing brain circuits.

Chronic treatment with oestradiol does not alter in vitro LTP in subfield CA1 of the female rat hippocampus

Population excitatory post-synaptic potentials (pEPSPs) were recorded in vitro from subfield CA1 of the hippocampus of female rats which had been ovariectomized and treated for 14 days with either oil or 17 β-oestradiol (10 μg/day). The currents applied to the Schaffer collateral-commissural input necessary to induce threshold, maximum and 50% maximum pEPSP responses did not differ between groups. Application of trains of pulses (0.1–1 s; 100 Hz) evoked post-tetanic and long-term (>60 min) potentiation of pEPSP responses, the magnitude of which was related to stimulus duration in both groups. However, the degree of potentiation induced by near-threshold (0.1, 0.15 and 0.2 s) and saturating (1 s) stimuli did not differ between groups. Thus, despite reports that oestradiol can modulate synaptic spine density and glutamatergic and GABAergic components of the inputs to CA1, these data suggest that chronic oestradiol treatment has no effect on either the excitability or induction of LTP in the Schaffer collateral-commissural-CA1 pathway.

Effects of neonatal serotonin depletion on the development of rat dentate granule cells

The appearance of serotonergic (5-HT) neurons and projections early in central nervous system (CNS) development has resulted in the hypothesis that 5-HT is an important factor in neuronal differentiation and synaptogenesis. Studies of the effects of 5-HT on the development of molluscan and mammalian neurons in vitro support this hypothesis, but mammalian in vivo studies have produced equivocal results. The present study reinvestigated the role of 5-HT in CNS development using the dentate granule cell as a model. Dentate granule cells were chosen for this study of the effects of 5-HT depletion on neuronal development because they are generated in the early postnatal period. Thus, 5-HT depletion could be effected by the treatment of rat pups with either parachloroamphetamine (PCA) or 5,7-dihydroxytryptamine (5,7-DHT) thereby avoiding problems inherent in maternal treatment paradigms. The morphology of Neurobiotin-filled granule cells was studied on P14, P21, P60 and P120 (PO = day of birth). The parameters measured were total dendritic length, number of dendritic segments and dendritic spine density (number of spines/50 μm dendritic length). Granule cells from vehicle-treated controls were similar to those previously reported in studies of normal granule cell development in all respects. In particular, the decrease in dendritic spine density from P14 to P120 observed in Golgi preparations was verified in our population of intracellularly filled granule cells. Transient depletion of 5-HT by neonatal PCA treatment resulted in a decrease dendritic length that was not statistically different from control values. However, dendritic spine density was reduced by about 27% at all ages studied. 5,7-DHT treatment produces a permanent, severe depletion of 5-HT. Spine densities in granule cells from 5,7-DHT-treated pups were also about 38% lower than controls. Total dendritic length in cells from 5,7-DHT-treated rats was reduced to a degree comparable to that observed in PCA-treated pups. The number of granule cell dendritic segments was also less than that observed in control and PCA-treated rats but this difference was not statistically significant. These observations suggest that reduction of 5-HT in the early postnatal period can result in changes in the morphology of dentate granule cells, particularly at the level of the synapse as reflected by the permanent reduction in synaptic spine density. The comparison of results from cases with permanent and transient reduction of 5-HT indicates that the developmental influence of 5-HT is most important during the first three postnatal weeks.

Subtle re-location of dendritic spine branches containing membrane with fast spiking mechanisms can alter synaptic efficacy

The potential physiological impact of morphological changes in the active dendritic spines, which are believed to be associated with altered synaptic efficacy, was investigated in a computer simulation study using the NEURON package [1]. A compartmental model of a simplified neuron was built, which included 30 complex spines (neck, head, and active zone) and accommodating AMPA-type synaptic inputs with alpha-function conductances. Hodgkin-Huxley type excitable membranes were inserted into the spine heads. It was shown that arranging spines in dense clusters, as opposed to a uniformly random spine distribution, has a negligible effect on the synaptic signal transfer (other model conditions, including synaptic input and spine density, remained unchanged). However, if a proportion (e.g., 3–20%) of the spines partly fuse with their neighbors forming branched spines, this could increase dramatically the cell response to the unchanged synaptic input. Results of this pilot study provide the basis for a more detailed investigation of the relationship between the spine arrangement and synaptic function, considering dual-component synaptic currents and mechanisms controlling ion fluxes in the dendritic compartments.

Prenatal alcohol exposure and the effects of environmental enrichment on hippocampal dendritic spine density

The effects of environmental enrichment on synaptic spine density in hippocampal area CAI were examined in rats exposed prenatally to alcohol. Pregnant dams were given ethanol via intragastric intubation (6 g/kg/day) from gestational days 8 through 19, or given isocaloric sucrose. An untreated control group was also used. After weaning, offspring from the three groups were then reared for 10 weeks in either isolated (caged alone, not handled) or enriched (group housed with “toys,” handled) conditions. Animals were then sacrificed, the brains Golgi impregnated, and CA1 pyramidal cell apical and basilar spine densities quantified. Among isolated animals there were no significant differences between control and alcohol-exposed groups. In general, environmental enrichment increased apical or basilar spine densities in untreated and sucrose controls. However, in prenatal alcohol-exposed animals, environmental enrichment did not increase spine densities. Because the environmental enrichment acted postnatally, these findings suggest that the effects of prenatal alcohol exposure include decreased neural plasticity enduring into early adulthood. Such a reduction in neuroanatomical plasticity in Hppocampus may be associated with cognitive impairments found following prenatal alcohol exposure.

Effects of prenatal malnutrition and postnatal nutritional rehabilitation on CA3 hippocampal pyramidal cells in rats of four ages

The effects of prenatal protein malnutrition and postnatal nutritional rehabilitation on CA3 hippocampal pyramidal cells were investigated in rats of 15, 30, 90 and 220 days of age. Female rats week fed either 6% or 25% casein diet 5 weeks before conception. Following delivery, litters born the same day to 6% and 25% casein diet rats were randomly cross-fostered to 25% casein diet dams and maintained on that diet until sacrificed. In 288 rapid-Golgi impregnated cells, we measured somal size, length of the longest apical dendrite, number of apical and basal dendrites intersecting 10 concentric rings 38 μm apart, synaptic spine density in three 50 μm segments of the largest apical dendrite and the thorny excrescence area. Prenatal protein malnutrition produced differential morphological changes on CA3 pyramidal cells. We observed significant decreases of somal size (at 90 and 220 days of age), of length of apical dendrites (at 15 days old), of apical (in 15 day animals) and basal (in 15, 90 and 220 day animals) dendritic branching and of spine density (in 30, 90 and 220 day animals). We also found significant increases of apical dendritic branching in 90 and 220 day old rats. These results indicate that prenatal protein malnutrition affects normal development and produces long-term effects on CA3 pyramidal cells.

Effect of protein malnutrition on CA3 hippocampal pyramidal cells in rats of three ages

Prenatal and postnatal protein deprivation effect on CA3 hippocamapal pyramidal pyramidal cells were investigated in 30-, and 90- and 220-day old rats Female rats were fed either a 6% or a 25% casein diet 5 wk before conception and the litters were maintained on their respective diet until sacrificed. In 216 rapid Golgi-impregnatd cells, we measured somal size, length and diameter of apical dendrite, number of apical dendrites intersecting 10 concentric rings 38 μm apart, thorny excrescence area and length, head diameter and density of synaptic spines on 50-μm segments of apical dendrite. The present experiments showed that malnutrition produced significant reductions of somal size in animals at 220 days of age. There were significant reductions of apical dendrite diameters in animals of 30 and 90 days, and of density and head diameter of synaptic spines at the three ages studied, and significant decrease of the thorny excrescence area at 220 days of age. At this latter age, dendritic branching was significantly decreased in the last four rings representing the area into which the perforant pathway projects. In 30-day malnourished rats, dendritic branching showed a significant increase in rings 4–6 representing the area in which the Schaffer collaterals synapse. The location of the deficit spines corresponds to the sites where mossy fibers synapse on the apical dendrites of CA3 neurons. Age-related changes normally observed in control rats (e.g., the 30-day-old control group showed the smallest somal size and 220-day-old controls the largest size) failed to occur in the malnourished rats. The deficits in spine density and dendritic branching (in animals of 220 days old) were similar to those found in our previous studies on fascia dentata.

Effects of prenatal protein deprivation on postnatal development of granule cells in the fascia dentata

The effect of prenatal protein deprivation on the postnatal development of granule cells in the fascia dentata in the rat was studied at 15, 30, 90, and 220 days of age. The granule cells showed a significant reduction in cell size, decreased number of synaptic spines throughout their dendritic extent, and reduced complexity of dendritic branching in the outer two-thirds of the molecular layer. All of these deficits were present at 15 days and persisted throughout the study (220 days). The least deficits in synaptic spine density occurred at 90 days and in dendritic branching at 30 days. Partial restitution of earlier, more severe deficits was associated primarily with maturational events occurring in the protein deprived rats, whereas later increases in deficits were related primarily to a failure of the protein deprived rats to keep pace with neuronal development occurring in the controls. The present results are similar to those noted in our previous study in this journal of the effect of a low protein diet (8% casein) on these neurons that extended from pregnancy until the time of sacrifice at 30, 90, and 220 days of age (Cintra et al., '90; 532:271-277). Taken together, these two studies suggest that the postnatal adaptation of the granule cells to prenatal protein deprivation is primarily due to events that occur during pregnancy and that the site of predilection for the deficit is their dendrites in the outer two-thirds of the molecular layer of the fascia dentata.

Effect of a low protein diet on the anatomical development of subcortical formations

KEMPER, T. L., D. A. PASQUIER AND S. DRAZEN. Effect of a low protein diet on the anatomical development of subcortical formations. BRAIN RES. BULL. 3(5) 443–450, 1978.—The effects of a low protein diet during gestation, lactation, and after weaning on the anatomical development of a subcortical nucleate formation, the neostriatum, and a reticulate formation, the diagonal band of Broca, were studied. At 10, 30, and 90 days the volume of the neostriatum was decreased in the experimental rats. However, the percent of the brain volume that was neostriatum was unaffected at each of these ages. In a rapid Golgi study of individual neurons at 90 days of age there was no significant effect of the low protein diet on the dendritic length of three different types of neurons within the neostriatum. However, its heavily spined dominant neuron showed a significant decrease in synaptic spine density. In the reticular formation, there was also no significant effect on dendritic length. A minute, apparently axonless cell corresponding to the neurogliaform cell of Ramón y Cajal, showed a decrease in extent of its cell processes only in the neostriatum. When compared to cortical formations, these phylogenetically more conservative neuronal substrates appear to be more resistant to the effects of undernutrition.

The effect of a low protein diet on the anatomical development of the rat brain

Albino rats were conceived and suckled by mothers maintained on a 8% or an isocaloric 25% casein diet. After weaning, pups were maintained on their respective diets ad libitum. By most parameters of CNS maturation, rats on the low protein diet closely resembled their age-matched controls. only by the parameter of the ratio of brain weight to body weight did they resemble rats of a younger age. Camera lucida drawings of comparable Rapid Golgi-impregnated cortical neurons of 10-day-old control and experimental rats were nearly identical to each other. A similar finding was also noted in 30-day-old rats. However, with quantitative studies, the 30-day-old experimental animals showed a decrease in synaptic spine density and reduced dendritic length for some but not all dendritic processes. At all ages, experimental animals closely resembled age matched controls in the proportion of their brain weight that was neocortex, archicortex, and cerebellum. In these results we concur with Dobbing and Sands that developmental timetables for the brain are not affected by undernutrition, though extent of development may be.