Loss of synapses in the dentate gyrus of the senescent rat

Synapses were counted in electron micrographs of the middle third of the molecular layer of the dentate gyrus of Fischer 344 rats, 3 months and 25 months of age. A 27% decrease in the number of synapses was found in senescent animals compared with young adults. This loss of synapses could not be correlated with changes in synaptic size, tissue volume or number of postsynaptic granule cells.     

Oral choline alfoscerate counteracts age-dependent loss of mossy fibres in the rat hippocampus.

Mossy fibres represent a major intrahippocampal associative pathway. They consist of axons of granule cells of the dentate gyrus and show an age-dependent loss as do the granule cells of the dentate gyrus. The present study was designed to assess whether long-term treatment of rats with choline alfoscerate in their drinking water would be effective in countering the loss of mossy fibres and of granule cells occurring with aging. Choline alfoscerate is a precursor in the biosynthesis of brain phospholipids and increases the bioavailability of choline in nervous tissue. Male Sprague-Dawley rats of 18 months of age were divided into two groups. One group received a daily dose of 100 mg/kg choline alfoscerate for 6 months; the other group was used as an untreated control. Twelve-month-old untreated animals were used as a reference group. The area occupied by mossy fibres, as well as their density, was significantly reduced in 24-month-old control rats in comparison with 12-month-old rats. The same is true for the density granule cells of the dentate gyrus which was decreased by about 20% in the oldest animals. In choline alfoscerate-treated rats both the area occupied by mossy fibres and their density were significantly higher than in age-matched controls. Moreover, the number of granule neurons of the hippocampus was higher by about 7% in choline alfoscerate-treated than in control 24-month-old rats. The above data suggest that choline alfoscerate treatment counteracts some anatomical changes of the rat hippocampus occurring in old age.     

Effect of adrenalectomy on membrane properties and synaptic potentials in rat dentate granule cells

Adrenalectomy is known to accelerate both neurogenesis and cell death of granule cells located in the suprapyramidal blade of the rat dentate gyrus. Three days after adrenalectomy, some granule cells have already died by apoptosis while newly formed cells are not yet incorporated in the cell layer, resulting in a temporary loss of granule cells. Concomitantly, the field response to stimulation of perforant path afferents is reduced. While the temporary cell loss is likely to attenuate synaptic field responses, adrenalectomy-induced changes in properties of the surviving cells may also contribute to the reduction in field response amplitude. To address this possibility, we here investigated the membrane properties and synaptic responses of dentate granule cells, 3 days after adrenalectomy. We found that passive and most of the active membrane properties of granule cells in adrenalectomized rats were not significantly different from the cell properties in sham-operated controls. However, intracellularly recorded synaptic responses from surviving granule cells were markedly reduced after adrenalectomy. The N-methyl-D-aspartate (NMDA)- and the non-NMDA receptor-mediated components were reduced to a similar extent, suggesting that the attenuation of synaptic transmission after adrenalectomy could be partly of presynaptic origin. The data indicate that the earlier observed attenuation of synaptic field responses after adrenalectomy may be partly due to a diminished glutamatergic input to the dentate gyrus and not exclusively to a loss of granule cells participating in the synaptic circuit.     

Re-structuring of synapses 24 hours after induction of long-term potentiation in the dentate gyrus of the rat hippocampus in vivo

In male rats, long-term potentiation was induced unilaterally in the dentate gyrus, either by high frequency (200Hz) or theta rhythm stimulation. Structural synaptic changes were examined 24h after induction using quantitative electron microscopy. A disector technique was employed in order to estimate the density of synapses (using 70-80-nm sections) and of granule cell nuclei (using 2-microm sections) in the middle, and inner molecular layer in both hemispheres. Synaptic height and total lateral areas of synaptic active zones per unit tissue volume were assessed via assumption-free stereological techniques coupled with image analysis. The results obtained indicated that both synaptic density and number (corrected per neuron) of axo-spinous, but not axo-dendritic, synapses were approximately 40% higher in the middle, but not inner molecular layer of the potentiated hemisphere compared to the contralateral (control hemisphere). No significant inter-hemispheric difference was found in the volume densities of lateral areas of active zones.These data suggest that 24h after long-term potentiation induction, active zones of existing axo-spinous synapses either split forming separate contacts, or decrease in size while new synapses are formed.     

Decrease in the number of synapses in the senescent brain: a quantitative electron microscopic analysis of the dentate gyrus molecular layer in the rat.

Axo-dendritic synapses were counted in electron micrographs taken from the middle third of the dentate gyrus molecular layer of young adult and senescent Fischer 344 rats. A significant decrease in the number of synapses was found in senescent animals relative to young ones. This loss of synapses, which involved all the morphological varieties of axo-dendritic synaptic contacts in the dentate gyrus molecular layer, appeared to be unrelated to changes in dimensions of synapses, tissue volume or number of postsynaptic granule cells. It is proposed that the age-related loss of synaptic contacts might be attributed to a reduced capacity of senescent brains for synaptic regeneration and remodelling.     

Sex differences in the stereological parameters of the hippocampal dentate gyrus of the guinea-pig before puberty

Studies in rats and mice have shown several sex-dependent functional and structural differences in the hippocampal region, a brain structure playing a key role in learning and memory. The aim of the present study was to establish whether sex differences exist prior to puberty in the stereological parameters of the dentate gyrus in the guinea-pig, a long-gestation rodent, whose brain is at a more advanced stage of maturation at birth than the rat and mouse. The number of granule cells and volumes of the granule cell layer, molecular layer and hilus were evaluated in Nissl-stained brains of neonatal (15-16 days old) and peripubescent (45-46 days old) guinea-pigs. Based on a pilot study, the optical disector method was preferred to the optical fractionator method to estimate cell number. For volume (Vref) estimation with the Cavalieri principle, contour tracing was preferred to the point counting method, as the latter appeared to underestimate volumes. The results showed that neonatal males had more granule cells than females in both the dorsal and ventral dentate gyrus and a larger volume in all layers. Peripubescent males had a larger volume of the granule cell layer than females in both the dorsal and ventral dentate gyrus, more granule cells in the ventral dentate gyrus, a larger volume of the hilus in both the dorsal and ventral dentate gyrus and a larger volume of the molecular layer in the ventral dentate gyrus. The results show that sex differences are present in the guinea-pig dentate gyrus prior to puberty and go in the same direction at both investigated ages, with males exhibiting more granule cells and larger volumes than females. The widespread distribution of these sex differences suggests that in the guinea-pig, similarly to other rodents, hippocampus-dependent functions may be sexually dimorphic.     

Compensatory loss of axosomatic synapses in the dentate gyrus of the senescent rat

A portentous reorganization of the dentate gyrus occurs characteristically in senescent rats. This reorganization includes atrophy of dendrites, hypertrophy of astrocytes and a 27% loss of axodendritic synapses in the molecular layer of the dentate gyrus.A coincident loss of axosomatic synapses is now reported. These synapses on granule cell somata were counted in electron micrographs of representative coronal sections through the dentate gyri of five 3-month-old and five 25-month-old Fischer-344 male rats. A 15% decrease in the number of axosomatic synapses per 100 μm length of granule cell plasma membrane and a 22% decrease in the amount of neuronal surface covered by synapses were found in the senescent, as compared with the young adult, animals. These differences were statistically significant.As synapses on granule cell somata are inhibitory terminals of GABAergic interneurons it is suggested that their loss in senescence may be compensatory for the loss of axodendritic synapses, which are excitatory. By means of a compensatory loss of synapses it may be possible for the aging animal to maintain a reasonably adaptive level of function in spite of ongoing changes in the level of granule cell excitation resulting from the reorganization of the dentate gyrus in senescence.     

Postnatal development of rat dentate gyrus: effects of methylazoxymethanol administration.

In order to investigate the role of postnatal neurogenesis in granule cell number control in the rat dentate gyrus, we administered Methylazoxymethanol (MAM), a drug able to prevent cells from dividing, on P3, P5, P7, P9, when the most granule cells are produced. The effect of MAM on the number of proliferating precursors and of granule cells was examined at P16 and P90. We used 5-bromo-2'-deoxyuridine administration to label proliferating cells and immunohistochemistry to characterize the cell phenotype using neuron markers TUC 4, PSA-NCAM, Calbindin D28K and glial marker GFAP. At 16 days of age in MAM-treated rats we observed a significant decrease of BrdU-positive cells. Consistently, a decrease in density and number of granule cells was found compared to the controls. At 90 days the dentate gyrus of treated rats showed a complete recovery: no differences in the density, total number of neurons, the BrdU- and TUC 4-positive cells were revealed with respect to the controls. No deficits were evident in performance on the water maze in MAM-treated rats. These data suggest that the dentate gyrus is able to re-establish the proliferative zone and to rebuild the granule cell layer following neonatal MAM administration.     

Synaptic loss is accompanied by an increase in synaptic area in the dentate gyrus of aged human apolipoprotein E4 transgenic mice

To investigate the relationship between the three isoforms of apolipoprotein E (E2, E3 and E4) and the integrity of the synaptic circuitry in the dentate gyrus of the hippocampus, we have estimated the synapse per neuron ratio and mean apposition zone area per synapse at the electron microscope level in the dentate gyrus of apolipoprotein E knockout and human apolipoprotein E transgenic mice aged six to 24months. During ageing, only in human apolipoprotein E4 mice was there a decrease in synapse per neuron ratio, accompanied by an increase in synaptic size. When these mice were compared with human apolipoprotein E2, apolipoprotein E knockout and wild-type mice at old age, they displayed the lowest synapse per neuron ratio, but similar apposition zone area. In contrast, as in our previous study, aged apolipoprotein E knockout mice did not show any sign of synaptic degeneration.The functional consequences of such morphological changes remain to be determined. However, if such age-related loss of synapses occurred in the brain of Alzheimer apolipoprotein E4 patients, they might be additive to pathological processes and could contribute to greater cognitive impairment.     

Synaptic connections from multiple subfields contribute to granule cell hyperexcitability in hippocampal slice cultures

Limbic status epilepticus and preparation of hippocampal slice cultures both produce cell loss and denervation. This commonality led us to hypothesize that morphological and physiological alterations in hippocampal slice cultures may be similar to those observed in human limbic epilepsy and animal models. To test this hypothesis, we performed electrophysiological and morphological analyses in long-term (postnatal day 11; 40-60 days in vitro) organotypic hippocampal slice cultures. Electrophysiological analyses of dentate granule cell excitability revealed that granule cells in slice cultures were hyperexcitable compared with acute slices from normal rats. In physiological buffer, spontaneous electrographic granule cell seizures were seen in 22% of cultures; in the presence of a GABA(A) receptor antagonist, seizures were documented in 75% of cultures. Hilar stimulation evoked postsynaptic potentials (PSPs) and multiple population spikes in the granule cell layer, which were eliminated by glutamate receptor antagonists, demonstrating the requirement for excitatory synaptic transmission. By contrast, under identical recording conditions, acute hippocampal slices isolated from normal rats exhibited a lack of seizures, and hilar stimulation evoked an isolated population spike without PSPs. To examine the possibility that newly formed excitatory synaptic connections to the dentate gyrus contribute to granule cell hyperexcitability in slice cultures, anatomical labeling and electrophysiological recordings following knife cuts were performed. Anatomical labeling of individual dentate granule, CA3 and CA1 pyramidal cells with neurobiotin illustrated the presence of axonal projections that may provide reciprocal excitatory synaptic connections among these regions and contribute to granule cell hyperexcitability. Knife cuts severing connections between CA1 and the dentate gyrus/CA3c region reduced but did not abolish hilar-evoked excitatory PSPs, suggesting the presence of newly formed, functional synaptic connections to the granule cells from CA1 and CA3 as well as from neurons intrinsic to the dentate gyrus. Many of the electrophysiological and morphological abnormalities reported here for long-term hippocampal slice cultures bear striking similarities to both human and in vivo models, making this in vitro model a simple, powerful system to begin to elucidate the molecular and cellular mechanisms underlying synaptic rearrangements and epileptogenesis.     

Sex differences in the hippocampal dentate gyrus of the guinea-pig before puberty

The aim of the present research was to ascertain the presence of sex differences in the hippocampal dentate gyrus of the guinea-pig, a long-gestation rodent which gives birth to mature young and whose brain is at a more advanced stage of maturation at birth than that of the rat and mouse. The brains of neonatal (15-16 days old) and prepubescent (45-46 days old) male and female guinea pigs were Golgi-Cox stained. Granule cells were sampled from the upper (suprapyramidal) and lower (infrapyramidal) blade of the septal dentate gyrus and their dendritic tree and soma were measured. The analysis was conducted separately on granule cells with soma in the superficial (superficial granule cells) and deep (deep granule cells) half of the granule cell layer. Numerous sex differences were found in the upper blade of the dentate gyrus. Neonatal males had more dendritic branches than females in the innermost dendritic tree of both superficial and deep granule cells, but females had more branches over the middle/outer dendritic tree and a longer dendritic length. In prepubescent animals, the sex difference in the middle dendritic tree of the superficial granule cells changed direction, with males having more branches than females. In the deep granule cells, the sex differences were similar to those in neonatal animals. In both granule cell types, the dendritic length was similar in the two sexes. While no sex differences were found in dendritic spine density in neonatal animals, in prepubescent animals spine density was greater in females. In the lower blade the granule cells showed very few sex differences in both neonatal and prepubescent animals. This study shows wide dynamically changing sex differences in the granule cells located in the upper blade of the septal dentate gyrus, but almost no differences in the lower blade. These results demonstrate that sex differences are not ubiquitous in the dentate gyrus and suggest that the lower blade, unlike the upper blade, might be involved in non-sexually dimorphic behaviors.     

Cell formation in the human hippocampal formation from mid-gestation to the late postnatal period

In the present study cell formation was studied in the human hippocampal formation from the 24th gestational week until the end of the first postnatal year. Proliferating cells were detected with the monoclonal antibody MIB-1.The cytoarchitectonic layers of Ammon's horn are formed before the 24th gestational week. In harmony with this observation, cell proliferation in the hippocampal ventricular zone is minimal after the 24th week. In addition, local cell multiplication in Ammon's horn is occasional and the proliferating cells are glial or endothelial cells. In contrast, cell formation continues in the hilar region of the dentate gyrus even after birth. Immature cells accumulate in the hilus, and at the border between the hilus and the granule cell layer throughout the first eight postnatal months. The subgranular zone of the dentate gyrus becomes a cell sparse area at about the 11th postnatal month, indicating that immature cells from the hilus have already migrated to the granule cell layer and differentiated into granule cells. There is an increase in glial cell proliferation both in Ammon's horn and the dentate gyrus at the 11.5th postnatal month suggesting the onset of myelination by the end of the first year.Our findings indicate that most pyramidal neurons of Ammon's horn are generated in the first half of pregnancy and no pyramidal neurons are formed after the 24th gestational week. In contrast, granule cells of the dentate gyrus proliferate in a decreasing rate during the second half of pregnancy and after birth. Proliferating neuronal precursors occur in a low percentage in the dentate gyrus of 3-, 5- and 11.5-month-old children.     

Sexual dimorphism in the mossy fiber synapses of the rat hippocampus

Summary The presence of sexual dimorphism in the hippocampal formation has long been recognized. Differences between male and female rats have been detected with respect to the number of dentate granule cells and branching patterns of dentate granule and hippocampal pyramidal cell dendrites. Groups of 6 male and 6 female Sprague-Dawley rats were studied at 180 days of age. Based on light microscopical Timm-staining and Golgi-impregnation and electron microscopy, and applying morphometric techniques, we now report that the total number of synapses between mossy fibers and the apical dendritic excrescences of CA3 pyramidal cells is the same in male and female rats, despite a higher numerical density in the latter. Moreover, the volume of the mossy fiber system was found to be smaller in females. Because the number of dentate granule cells is smaller in females than in males, the increased numerical density of synapses may be thought of as a compensatory mechanism to equalize the number of synaptic contacts between dentate granule and CA3 pyramidal cells in the two sexes. We demonstrate that an increase in the number of mossy fiber boutons in female rats is a determining factor for the sexual differences found.     

Altered synaptic transmission in dentate gyrus of rats reared in complex environments: evidence from hippocampal slices maintained in vitro

Pre- and postsynaptic responses to activation of medial perforant path (MPP) axons were examined in hippocampal slices taken from rats reared for 3-4 wk in relatively complex (EC) or individual cage (IC) environments. Three types of extracellular field potentials were recorded in the infrapyramidal blade of the dentate gyrus: 1) granule cell population spikes (PSs), which reflect the number and synchrony of discharging granule cells (2), 2) population excitatory postsynaptic potentials (EPSPs), which reflect the amount of excitatory synaptic current flow into dendrites (28), and 3) presynaptic fiber volleys (FVs), which reflect the number of activated axons (28). Stimulation of the MPP evoked significantly larger PSs in slices taken from EC rats. There was no significant effect of rearing environment on PS/EPSP relationships. The slopes of EPSPs recorded at the site of synaptic activation in the dentate molecular layer and at the major current source in the dentate granule cell layer were significantly greater in slices taken from EC rats. The presynaptic FV was recorded at the site of synaptic activation in the molecular layer. FV amplitude did not differ significantly as a function of rearing environment. To examine possible differences in tissue impedance, granule cells were activated by stimulating granule cell axons in the dentate hilus and recording the antidromic PS in the granule cell layer. Antidromic PS amplitude was not significantly affected by rearing environment. The relative permanence of the experience-dependent alterations in synaptic transmission was assessed by comparing slices taken from rats that had been reared for 4 wk in complex environments followed by 3-4 wk in individual cages with those from rats reared for 7-8 wk in individual cages. There were no significant differences in MPP synaptic transmission between these groups of animals. The results suggest that experience in a relatively complex environment is associated with greater MPP synaptic transmission arising from an increased synaptic input to granule cells; the greater MPP synaptic transmission associated with behavioral experience can occur independent of behavioral state, influences from extrahippocampal brain regions and intrahippocampal inhibitory activity; and the experience-dependent synaptic alterations in the dentate gyrus are transient, in contrast to experience-dependent morphological alterations described in occipital cortex. The possible relationship of these alterations to the phenomenon of long-term enhancement is discussed.     

人胎儿海马发育的初步观察

取4—10个月的人胎儿海马中段,作沿长轴横切片,Nissl法染色后,观察其发育过程中锥体细胞最的锥体细胞和齿状回的颗粒细胞的变化。结果发现随着海马的发育,细胞的密度变小,体积变大,并且这种变化有快慢交替的情况。     

Recurrent excitatory connectivity in the dentate gyrus of kindled and kainic acid-treated rats

Repeated seizures induce mossy fiber axon sprouting, which reorganizes synaptic connectivity in the dentate gyrus. To examine the possibility that sprouted mossy fiber axons may form recurrent excitatory circuits, connectivity between granule cells in the dentate gyrus was examined in transverse hippocampal slices from normal rats and epileptic rats that experienced seizures induced by kindling and kainic acid. The experiments were designed to functionally assess seizure-induced development of recurrent circuitry by exploiting information available about the time course of seizure-induced synaptic reorganization in the kindling model and detailed anatomic characterization of sprouted fibers in the kainic acid model. When recurrent inhibitory circuits were blocked by the GABA(A) receptor antagonist bicuculline, focal application of glutamate microdrops at locations in the granule cell layer remote from the recorded granule cell evoked trains of excitatory postsynaptic potentials (EPSPs) and population burst discharges in epileptic rats, which were never observed in slices from normal rats. The EPSPs and burst discharges were blocked by bath application of 1 microM tetrodotoxin and were therefore dependent on network-driven synaptic events. Excitatory connections were detected between blades of the dentate gyrus in hippocampal slices from rats that experienced kainic acid-induced status epilepticus. Trains of EPSPs and burst discharges were also evoked in granule cells from kindled rats obtained after > or = 1 wk of kindled seizures, but were not evoked in slices examined 24 h after a single afterdischarge, before the development of sprouting. Excitatory connectivity between blades of the dentate gyrus was also assessed in slices deafferented by transection of the perforant path, and bathed in artificial cerebrospinal fluid (ACSF) containing bicuculline to block GABA(A) receptor-dependent recurrent inhibitory circuits and 10 mM [Ca(2+)](o) to suppress polysynaptic activity. Low-intensity electrical stimulation of the infrapyramidal blade under these conditions failed to evoke a response in suprapyramidal granule cells from normal rats (n = 15), but in slices from epileptic rats evoked an EPSP at a short latency (2.59 +/- 0.36 ms) in 5 of 18 suprapyramidal granule cells. The results are consistent with formation of monosynaptic excitatory connections between blades of the dentate gyrus. Recurrent excitatory circuits developed in the dentate gyrus of epileptic rats in a time course that corresponded to the development of mossy fiber sprouting and demonstrated patterns of functional connectivity corresponding to anatomic features of the sprouted mossy fiber pathway.     

Alcohol withdrawal does not impede hippocampal granule cell progressive loss in chronic alcohol-fed rats

Using the unbiased disector method we have shown that chronic alcohol consumption induces a significant decrease of dentate gyrus granule cell density in alcohol-fed rats for 18 months. A still more dramatic reduction was observed in a group of age-matched rats alcohol-fed for 12 months and switched to water for 6 months (recovery group). These results indicate that a progressive neuronal loss of the hippocampal granule cells in not impeded after cessation of alcohol intake. It is thus suggested that once the mechanisms underlying the alcohol-induced neuronal degeneration are triggered, they continue to act even after withdrawal.     

Functional consequences of the lack of amyloid precursor protein in the mouse dentate gyrus in vivo

The amyloid precursor protein (APP) plays a crucial role in the pathogenesis of Alzheimer's disease. Here, we studied whether the lack of APP affects the synaptic properties in the dentate gyrus by measuring granule cell field potentials evoked by perforant path stimulation in anesthetized 9-11-month-old APP-deficient mice in vivo. We found decreased paired-pulse facilitation, indicating altered presynaptic short-term plasticity in the APP-deficient dentate gyrus. In contrast, excitatory synaptic strength and granule cell firing were unchanged in APP knockout mice. Likewise, long-term potentiation (LTP) induced by a theta-burst stimulation protocol was not impaired in the absence of APP. These findings suggest that the deletion of APP may affect presynaptic plasticity of synaptic transmission at the perforant path-granule cell synapse but leaves synaptic efficacy intact and LTP preserved, possibly due to functional redundancy within the APP gene family.     

Newborn granule cells in the ageing dentate gyrus

The dentate gyrus of the hippocampus generates neurons throughout life, but adult neurogenesis exhibits a marked age-dependent decline. Although the decrease in the rate of neurogenesis has been extensively documented in the ageing hippocampus, the specific characteristics of dentate granule cells born in such a continuously changing environment have received little attention. We have used retroviral labelling of neural progenitor cells of the adult mouse dentate gyrus to study morphological properties of neurons born at different ages. Dendritic spine density was measured to estimate glutamatergic afferent connectivity. Fully mature neurons born at the age of 2 months display ∼2.3 spines μm⁻¹ and maintain their overall morphology and spine density in 1-year-old mice. Surprisingly, granule cells born in 10-month-old mice, at which time the rate of neurogenesis has decreased by ∼40-fold, reach a density of dendritic spines similar to that of neurons born in young adulthood. Therefore, in spite of the sharp decline in cell proliferation, differentiation and overall neuronal number, the ageing hippocampus presents a suitable environment for new surviving neurons to reach a high level of complexity, comparable to that of all other dentate granule cells.     

Differential regulation of Ca(2+)-calmodulin stimulated and Ca(2+)-insensitive adenylyl cyclase messenger RNA in intact and denervated mouse hippocampus

The Ca(2+)-calmodulin stimulated AC1 and Ca(2+)-insensitive AC2 are major isoforms of adenylyl cyclase, playing an important role in synaptic plasticity in the mammalian brain. We studied the pattern of expression of AC1 and AC2 genes in the hippocampus of C57BL/6 mice. We found that there were differences in their patterns of distribution in the dentate gyrus. AC1 messenger RNA was detected both in the dentate granule cell bodies and the corresponding molecular field whereas AC2 messenger RNA was preferentially distributed in the dentate granule cell layer, suggesting that AC1 and AC2 messenger RNA are differentially regulated in the dentate gyrus. In order to examine the regulation of AC1 and AC2 expression in response to synaptic deafferentation and reinnervation, the distribution patterns of the two AC messenger RNA in the hippocampal fields and the parietal cortex were analysed 2, 5, 9 and 30 days following an unilateral entorhinal cortex lesion. Interestingly, we found significantly reduced levels of AC1 hybridization signal following the lesion whereas the level of AC2 messenger RNA remained unaffected in all lesioned groups. The changes in AC1 messenger RNA were transient, with a maximal reduction at five days postlesion, and were restricted to the granule cell bodies and stratum moleculare of the deafferented dentate gyrus. No significant change in AC1 messenger RNA levels was detected in other hippocampal fields nor for any other postlesion times studied.These findings suggest that, at least in the dentate gyrus, messenger RNA for AC1 and AC2 might be differentially compartmentalized in cell bodies and dendritic fields. The activity-dependent regulation of AC1 messenger RNA levels by afferent synapses may provide an elegant mechanism for achieving a selective local regulation of AC1 protein, close to its site of action.