Pro- and anti-apoptotic evidence for cholinergic denervation and hippocampal sympathetic ingrowth in rat dorsal hippocampus

In rat, injection of the specific cholinotoxin, 192 IgG-saporin, into the medial septum results not only in a selective cholinergic denervation of hippocampus, but in an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion, into the hippocampus. A similar process, in which peripheral noradrenergic axons invade hippocampus, may also occur in Alzheimer's disease. Since apoptotic cell death has been demonstrated in the selective neuronal loss found in Alzheimer's disease, the aim of this study was to measure apoptotic protein expression and DNA fragmentation in hippocampal sympathetic ingrowth and cholinergic denervation. Western blot, TdT-mediated dUTP nick end labeling, and oligo ligation techniques were used. Choline acetyltransferase activity and norepinephrine concentrations were also measured. As seen in our previous results, an increase in apoptotic markers was induced by cholinergic denervation alone (medial septum lesion + ganglionectomy), while hippocampal sympathetic ingrowth (medial septum + sham ganglionectomy) reduced or normalized apoptotic effects to control group levels. A decrease in choline acetyltransferase activity was also found in the dorsal hippocampus of hippocampal sympathetic ingrowth and cholinergic denervation groups. An increase in norepinephrine concentration was found in hippocampal sympathetic ingrowth but not in cholinergic denervation group. Results of this study suggest that cholinergic denervation is responsible for most of the proapoptotic responses, while hippocampal sympathetic ingrowth produces a protective effect in the process of programmed cell death in rat dorsal hippocampus. This effect may be a secondary to an altered relationship between norepinephrine-acetylcholine.     

Interaction of neurotransmitter systems in the hippocampus: a study of some behavioral effects of hippocampal sympathetic ingrowth.

Recent research has suggested that normal learning/memory may depend upon the balance between central noradrenergic and cholinergic systems. This hypothesis has particular relevance to the study of the neuronal rearrangement that follows cholinergic denervation of hippocampus. In this, peripheral noradrenergic fibers, originating from the superior cervical ganglion, grow into the hippocampus in response to lesions of the medial septal (MS) cholinergic cell bodies. To understand further the influence of hippocampal sympathetic ingrowth (HSI) on behavior, gustatory neophobia, passive avoidance (PA) learning, and open field activity were studied. Male Sprague-Dawley rats underwent one of four surgical procedures: MS lesions and sham ganglionectomy (ingrowth group; MS/HSI group), sham MS lesions and ganglionectomy (Gx group), MS lesions and ganglionectomy (no-ingrowth group; MS/Gx group), or sham MS lesions and sham ganglionectomy (CON group). Behavioral testing began 4 weeks following surgery. The time to acquire the PA task was similar among all groups; however, the initial latency to enter the dark chamber of the PA apparatus was longer, and the number of partial reentries greatest, for MS/HSI animals. Retention testing at 24 hr revealed that MS/HSI animals were significantly impaired when compared to the CON and MS/Gx groups. The MS/Gx and the CON groups demonstrated gustatory neophobia, preferring water to saccharin solution, while gustatory neophobia was absent in the MS/HSI and Gx groups. MS/HSI animals were found to be more active in the open field than the other groups. Biochemical studies revealed the expected loss of ChAT activity in the dorsal and ventral hippocampi of lesioned animals along with elevated levels of norepinephrine (NE) in the dorsal hippocampus of MS/HSI animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pertussis toxin and galpha-protein-specific antibodies on phosphoinositide hydrolysis in rat brain membranes after cholinergic denervation and hippocampal sympathetic ingrowth

Cholinergic denervation of the hippocampal formation, via medial septal lesions, induces peripheral noradrenergic fibers, originating from the superior cervical ganglion, to grow into the hippocampus. We have previously reported that cholinergic denervation and hippocampal sympathetic ingrowth differentially affect guanosine-5'-O-(3-thiotriphosphate)- as well as guanosine-5'-O-(3-thiotriphosphate) + carbachol-stimulated polyphosphoinositide hydrolysis, suggesting an alteration in G proteins and/or the entire receptor complex. To examine the type of G protein which may be involved in these effects, rat dorsal hippocampal membranes were preincubated with pertussis toxin in the presence of guanosine-5'-O-(3-thiotriphosphate) and guanosine-5'-O-(3-thiotriphosphate) + carbachol. Pertussis toxin reduced guanosine-5'-O-(3-thiotriphosphate) in all groups, while guanosine-5'-O-(3-thiotriphosphate) + carbachol-stimulated phosphoinositide hydrolysis was reduced in controls and animals without sympathetic ingrowth but not in animals with hippocampal sympathetic ingrowth. This suggests that pertussis toxin-sensitive G proteins may be involved in the mediation of phosphoinositide hydrolysis. To confirm this hypothesis, membranes were preincubated with antibodies to Galphao and Gq/11. The Go antibody significantly decreased guanosine-5'-O-(3-thiotriphosphate) in all groups, while guanosine-5'-O-(3-thiotriphosphate) +carbachol-stimulated phosphoinositide hydrolysis was reduced only in hippocampal sympathetic ingrowth. Impairment of guanosine-5'-O-(3-thiotriphosphate) and carbachol-stimulated phosphoinositide hydrolysis was also decreased in all groups when preincubated with Gq/11 antibody. To determine whether hippocampal sympathetic ingrowth or cholinergic denervation altered the concentration of various G proteins, immunoblotting methodology was utilized. Gq/11 concentrations were found to be equivalent among groups. The density of Go1, Go2, and Go3 isoforms was significantly increased in the cholinergic denervation, while in the hippocampal sympathetic ingrowth only group Go3 was significantly increased. When assessed as total Go protein, density was increased significantly only in the cholinergic denervation group. Overall, these results suggest that hippocampal sympathetic ingrowth and cholinergic denervation induce alterations in phosphoinositide hydrolysis through both the Gq/11 and the Go proteins and that the coupling between muscarinic receptor and G protein is the possible site which affects changes in phosphoinositide turnover. Our results also suggest that cholinergic denervation and hippocampal sympathetic ingrowth may mediate phosphoinositide hydrolysis through an effect on different isoforms of the same G protein.     

Hippocampal sympathetic ingrowth and cholinergic denervation alter hippocampal muscarinic cholinergic receptors

Cholinergic denervation of the hippocampus by medial septal (MS) lesions results in the ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglia, into the hippocampus. To determine the effect of hippocampal sympathetic ingrowth (HSI) [³H]-QNB (L-quinuclidinyl [benzilic-4, 4(n)] benzilate) binding was assessed in the dorsal and ventral hippocampus four weeks after MS lesions. In dorsal hippocampus, HSI was found to signignificantly increase the number (B_max) of [³H]-QNB binding sites and to normalize the decrease in affinity found in animals with MS lesions plus ganglionectomy (i. e., no ingrowth). In ventral hippocampus, HSI was found to normalize the increased number of binding sites and decreased affinity found in animals with MS lesions without ingrowth. No effect on either K_d or B_max was found in animals that had undergone ganglionectomy with sham MS lesions. These results suggest that HSI can induce changes in hippocampal muscarinic cholinergic receptors. © 1994 Wiley-Liss, Inc.     

Hippocampal sympathetic ingrowth occurs following 192-IgG-Saporin administration

Electrolytic lesions of the medial septal region leads to an unusual neuronal reorganization in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the cholinergically denervated areas of the hippocampus. Since these lesions disrupt cells and fibers of passage which are non-cholinergic, there has been a debate whether Hippocampal Sympathetic Ingrowth is due only to cholinergic denervation of the hippocampus. Using the intraseptal administration of 192-IgG-Saporin, a specific cholinergic neurotoxin, we have found that hippocampal sympathetic ingrowth occurs in the cholinergically denervated hippocampus at 4, 8 and 12 weeks post Saporin injection. These results clearly suggest that hippocampal sympathetic ingrowth is due to the specific loss of the cholinergic projection from the medial septum.     

Effects of Pertussis Toxin and Gα-Protein-Specific Antibodies on Phosphoinositide Hydrolysis in Rat Brain Membranes after Cholinergic Denervation and Hippocampal Sympathetic Ingrowth

Cholinergic denervation of the hippocampal formation, via medial septal lesions, induces peripheral noradrenergic fibers, originating from the superior cervical ganglion, to grow into the hippocampus. We have previously reported that cholinergic denervation and hippocampal sympathetic ingrowth differentially affect guanosine-5′-O-(3-thiotriphosphate)- as well as guanosine-5′-O-(3-thiotriphosphate) + carbachol-stimulated polyphosphoinositide hydrolysis, suggesting an alteration in G proteins and/or the entire receptor complex. To examine the type of G protein which may be involved in these effects, rat dorsal hippocampal membranes were preincubated with pertussis toxin in the presence of guanosine-5′-O-(3-thiotriphosphate) and guanosine-5′-O-(3-thiotriphosphate) + carbachol. Pertussis toxin reduced guanosine-5′-O-(3-thiotriphosphate) in all groups, while guanosine-5′-O-(3-thiotriphosphate) + carbachol-stimulated phosphoinositide hydrolysis was reduced in controls and animals without sympathetic ingrowth but not in animals with hippocampal sympathetic ingrowth. This suggests that pertussis toxin-sensitive G proteins may be involved in the mediation of phosphoinositide hydrolysis. To confirm this hypothesis, membranes were preincubated with antibodies to Gαo and Gq/11. The Go antibody significantly decreased guanosine-5′-O-(3-thiotriphosphate) in all groups, while guanosine-5′-O-(3-thiotriphosphate) +carbachol-stimulated phosphoinositide hydrolysis was reduced only in hippocampal sympathetic ingrowth. Impairment of guanosine-5′-O-(3-thiotriphosphate) and carbachol-stimulated phosphoinositide hydrolysis was also decreased in all groups when preincubated with Gq/11 antibody. To determine whether hippocampal sympathetic ingrowth or cholinergic denervation altered the concentration of various G proteins, immunoblotting methodology was utilized. Gq/11 concentrations were found to be equivalent among groups. The density of Go1, Go2, and Go3 isoforms was significantly increased in the cholinergic denervation, while in the hippocampal sympathetic ingrowth only group Go3 was significantly increased. When assessed as total Go protein, density was increased significantly only in the cholinergic denervation group. Overall, these results suggest that hippocampal sympathetic ingrowth and cholinergic denervation induce alterations in phosphoinositide hydrolysis through both the Gq/11 and the Go proteins and that the coupling between muscarinic receptor and G protein is the possible site which affects changes in phosphoinositide turnover. Our results also suggest that cholinergic denervation and hippocampal sympathetic ingrowth may mediate phosphoinositide hydrolysis through an effect on different isoforms of the same G protein.     

Hippocampal sympathetic ingrowth and cholinergic denervation uniquely alter muscarinic receptor subtypes in the hippocampus

Following cholinergic denervation of the hippocampus by medial septal lesions, an unusual neoronal reorganization occurs, in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus. Previously, we have found that both hippocampal sympathetic ingrowth (HSI) and cholinergic denervation (CD), alone, altered the total number and affinity of muscarinic cholinergic receptors (mAChR). In this study, we utilized the muscarinic antagonist [³H]Pirenzepine, in combination with membrane radioligand binding techniques, to determine the effects of HSI and CD on hippocampal M₁ and M₁ + M₃ mAChR subtypes, 4 weeks after MS lesions. In both the dorsal and ventral hippocampus, HSI was found to markedly diminish the number of M₁ AChRs, while CD was found to increase the number of M₁ AChRs. Neither treatment affected the affinity of the M₁ AChR. However, when M₁ + M₃ binding was assessed, CD was found to decrease the affinity in both hippocampal regions, without altering the number of receptors. Neither affinity nor number of M₁ + M₃ receptors was altered by HSI. The results of this study suggest that both cholinergic denervation and hippocampal sympathetic ingrowth uniquely affect hippocampal muscarinic receptors.     

Role of gender in the behavioral effects of peripheral sympathetic ingrowth

Following cholinergic denervation of the hippocampal formation, peripheral sympathetic nerves originating from the superior cervical ganglia grow into the hippocampus. As gender is known to alter the anatomy of hippocampal sympathetic ingrowth, we assessed the effect of this variable on the behavioral recovery following ingrowth. Adult male or female rats were trained on a standard version of a radial-8-arm maze task until they reached a specific learning criterion. Animals from each sex then underwent one of three surgical procedures: sham surgery, medial septal lesions plus superior cervical ganglionectomy, or medial septal lesion plus sham ganglionectomy. Reacquisition of the maze was then assessed. Prior to surgery, male animals acquired the task significantly faster than female animals. Following surgery male and female rats recovered overall performance at similar rates. However, marked group differences were observed. In males, the control group recovered faster than the group with medial septal lesion plus ganglionectomy, which recovered faster than the medial septal lesion group. In females, the control group recovered faster than the medial septal lesion group, which in turn recovered faster than the medial septal ganglionectomy group. The results of this study clearly demonstrate that gender can influence the behavioral effects of hippocampal sympathetic ingrowth. We believe that this is the first report in which gender has been shown to alter the behavioral effect of a neuronal reorganization.     

Sympathetic sprouting and recovery of a spatial behavior

After lesions of the medial septum, peripheral sympathetic fibers from the superior cervical ganglion appear in the hippocampal formation. To assess the functional significance of this neuronal rearrangement, we analyzed behavior on a spatial/memory task sensitive to hippocampal dysfunction, the radial eight-arm maze. The procedure allowed evaluation of both working and reference memory. All rats were able to master the task. Half of the rats then underwent either medial septal lesions and ganglionectomy or sham neurosurgery and ganglionectomy, and the other half underwent medial septal lesions or sham neurosurgery followed by ganglionectomy after further behavioral testing. Medial septal lesions in both groups disrupted taks performance with recovery of performance occurring with time. However, the rate of recovery was significantly enhanced in rats which had septal lesions and ganglionectomies simultaneously. Removal of the ganglion after recovery produced no effects on maze performance. Our results suggest that sympathetic ingrowth retards recovery processes.     

The effect of cholinergic denervation and hippocampal sympathetic ingrowth on the internalization of muscarinic receptors in rat hippocampus

Following cholinergic denervation of the hippocampus by medial septal (MS) lesions, an unusual neuronal reorganization occurs in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the hippocampus (hippocampal sympathetic ingrowth; HSI). Previously, we have found that with MS lesions, animals with (the HSI⁽⁺⁾ group) and without (HSI⁽⁻⁾ group) ingrowth differed in carbachol stimulated PI hydrolysis, in PKC activity, and in muscarinic cholinergic receptors (mAChR). In this study, performed in hippocampal slices obtained four weeks after MS lesions, we utilized the hydrophilic muscarinic antagonist [³H] N-methylscopolamine ([³H]NMS) and hydrophobic muscarinic antagonist [³H]quinuclidinyl benzilate ([³H]QNB) in the presence of either 4-α-phorbol or phorbol 12,13-dibutyrate (PDBu) to determine the effect of MS lesions with and without ingrowth on PKC-mediated mAChR internalization. In the presence of PDBu, a group effect was observed in [³H]NMS binding, with control groups > HSI⁽⁺⁾ group > HSI⁽⁻⁾ group. However, [³H]QNB binding was similar across groups. These results suggest that the cholinergic denervation of the hippocampus enhances the internalization of mAChRs, which is modified in the presence of HSI.     

Colchicine-induced cholinergic denervation of the hippocampus elicits sympathetic ingrowth

Sympathetic neurons from the peripheral nervous system invade the hippocampus following destruction of its septal inputs. It is thought that sympathetic ingrowth is due to the loss of cholinergic innervation since damage to the medial septum-diagonal band complex (MSDB) or its major efferent bundle, the fimbria-fornix, is required to induce ingrowth. The MSDB provides the major source of cholinergic fibers projecting to the hippocampus; however, non-cholinergic (e.g. GABAergic) neurons are also present in the MSDB and project to the hippocampus. Thus, the role of cholinergic denervation in sympatho-hippocampal sprouting cannot be directly tested by non-specific lesion techniques. In the present study, colchicine, which has been demonstrated to be specifically toxic to cholinergic neurons in the medial septum, was injected into each lateral ventricle of female Sprague-Dawley rats. Following colchicine-induced degeneration of cholinergic septohippocampal neurons, coarse, branched fibers immunoreactive for dopamine-beta-hydroxylase were observed predominantly in the dentate gyrus, on both sides of the granule cell layer, with increasing density as survival time increased. These results support the hypothesis that the invasion of the hippocampal formation by sympathetic fibers results from cholinergic denervation.     

Ascending efferent projections of the gustatory parabrachial nuclei in the rabbit

Peripheral noradrenergic fibers from the superior cervical ganglion (SCG) appear in the hippocampal formation of the adult rat central nervous system following damage to the medial septal nucleus or its afferent fibers. The appearance of these fibers coincides with a significant and substantial increase in the concentration of norepinephrine in the dentate gyrus and in the ability of synaptosomes made from the dentate to take up [3H]norepinephrine (NE) in vitro. Up to 7 weeks following a medial septal lesion, dentate norepinephrine levels are significantly lower if the sympathetic preganglionic trunk has been sectioned at the time septal lesions are made. By contrast, the uptake of [3H]NE into dentate synaptosomes is not affected by the preganglionic section. Furthermore, if the sectioned preganglionic trunk is allowed to reinnervate the SCG, the dentate NE concentration rapidly returns to levels equivalent to dentates with intact sympathetic preganglionic trunks. In addition to the ingrowth of the sympathetic fibers, central noradrenergic fibers display a sprouting or 'pruning' response to medial septal lesions. These data show that afferent input regulates the neurotransmitter concentration during sympathetic ingrowth while retrograde influences from the target appear to regulate the density or extent of the growing fibers. The experimental findings are discussed in light of the hypothesis that the hippocampal formation is capable of producing a sympathetic growth factor following septal denervation.     

Functional significance of sympathohippocampal sprouting: changes in single cell spontaneous activity

The electrophysiological consequences of noradrenergic sympathohippocampal ingrowth following medial septal lesions were investigated. Spontaneous activity of single dentate neurons was recorded in anesthetized rats with and without sympathohippocampal ingrowth. In animals with medial septal lesions (ingrowth) spontaneous firing rates were not different from rates in normal animals. Medial septal lesions combined with bilateral superior cervical ganglionectomy (no ingrowth) resulted in a significant 82% increase in spontaneous activity.     

Sympathetic noradrenergic sprouting in response to central cholinergic denervation: A histochemical study of neuronal sprouting in the rat hippocampal formation

An unusual example of neuronal sprouting occurs in the rat brain. Several weeks after fimbrial transection or septal lesions, peripheral sympathetic fibers appear in the dentate and hippocampal gyri. We compared the distribution of normal cholinergic septohippocampal fibers and nerve terminals with the distribution of noradrenergic sympathetic (sympathohippocampal) fibers after septal lesions using anterograde transport of horseradish peroxidase and fluorescence histochemistry. In addition, we destroyed other afferents to the hippocampal formation and examined the effect of subtotal septal lesions on acetylcholinesterase staining and the distribution of sympathohippocampal fibers. The combined results of these experiments suggest that peripheral noradrenergic fibers sprout specifically in response to destruction of central cholinergic fibers after septal lesions. This appears to be the first model of neuronal sprouting in the central nervous system where one identified transmitter system (noradrenergic) sprouts only in response to, and perhaps to replace, another specific transmitter system (cholinergic).     

Pineal and habenula innervation altered by septal lesions

Septal lesions result in a measurable increase in sympathetic innervation of the hippocampus. The cell bodies of origin of these sympathetic fibers reside in the superior cervical ganglion (SCG), which also projects to the pineal gland and medial habenula. If the SCG neurons which project to the pineal are the same neurons which sprout into the hippocampus after septal lesions, a common cell body reaction might mediate changes in innervation of the pineal. If cholinergic denervation is the principal trigger of hippocampal sprouting, a similar response might be observed in habenula which is also innervated cholinergically from septal area neurons. Pineal and medial habenula innervation were quantified using a new microfluorometric method at 20 post-lesion intervals following septal lesions. Changes in intensity and density of innervation were correlated with time in days after the lesions. Pineal intensity, pineal density, and habenula intensity exhibited statistically significant correlations with time in days after septal lesions. These changes occurred during the growth of sympathohippocampal fibers. The data suggest that a common cell body reaction mediated the changes in pineal and the sympathetic sprouting in the hippocampus.     

Noradrenergic sprouting in response to cholinergic denervation: The sympathohabenular connection

Using anterograde transport of HRP, we confirm the presence of a septal projection to the medial habenulae of rats. After a septal lesion, peripheral sympathetic fibers appeared in the medial habenulae. The similarity of this phenomenon to the appearance of sympathetic fibers in the rat hippocampal formation after septal lesions and the presumably cholinergic nature of the septal projections to the habenulae and hippocampal formation suggest that sympathetic fibers may appear in other brain regions after cholinergic denervation.     

Hippocampal sympathetic ingrowth in rats and guinea pigs: quantitative morphometry and topographical differences

Sympathetic ingrowth is an unusual neural rearrangement in response to damage of the septohippocampal pathway in which peripheral noradrenergic nerves grow into the hippocampal formation. Hippocampal ingrowth has been extensively studied in rats and has been suggested to be regulated by the mossy fibers of the dentate granule cells, hippocampal interneurons, or glial cells. Sympathetic ingrowth was found to occur in both rats and guinea pigs; however, a discrepancy between the species was observed in the topographical distribution of sympathetic ingrowth. Ingrowth fibers were found in the dentate hilus and area CA3 of guinea pigs and rats. However, in the guinea pig fibers extended into area CA1. Quantitative estimates of fiber number confirmed these observations and identified significant differences between the species in the intrahippocampal lamellar distribution of ingrowth fibers. The topographical differences in sympathetic ingrowth could not be explained by differences in the distribution of the mossy fibers (Timms stain), cholinergic septal afferents (anterograde HRP), or in hippocampal interneurons (GAD-immunoreactive neurons). These species differences are challenging to current theories concerning the regulation of sympathetic ingrowth and may provide a useful model for testing further hypothesis about axonal guidance and target selection.     

Noradrenergic denervation facilitates the release of acetylcholine and serotonin in the hippocampus: towards a mechanism underlying upregulations described in MCI patients?

Patients with mild cognitive impairment (MCI), who are at risk for Alzheimer's disease (AD), or those with early AD, exhibit noradrenergic degeneration in the locus coeruleus. In MCI patients, upregulations of cholinergic and serotonergic functions were described in the hippocampus. To investigate the effects of selective noradrenergic denervation on hippocampal neurotransmitter functions, rats were treated with 50mg/kg (i.p.) of N-2-chlorethyl-N-ethyl-2-bromobenzylamin (DSP-4). DSP-4 treatment reduced hippocampal noradrenaline (NA) by more than 90% (vs. controls), whereas dopamine and 5-HT levels were unaffected. The accumulation and electrically-evoked release (in nCi) of [³H]-NA in hippocampal slices were strongly reduced. Accumulation of [³H]-5-HT was reduced in DSP-4 rats, whereas spontaneous and electrically-evoked release of [³H]-5-HT was significantly enhanced, probably due to a weaker effect of endogenous NA via α₂-adrenoceptors on serotonergic terminals. Accordingly, the α₂-agonist UK-14,304 [5-bromo-6-(2-imidazolin-2-ylamino)-quinoxaline] more potently inhibited the evoked 5-HT release in DSP-4 rats, whereas the α₂-antagonist idazoxan failed to exert facilitatory effects. Most surprisingly, the accumulation of [³H]-choline, and both the basal and electrically-evoked overflow of [³H] from hippocampal slices preincubated with [³H]-choline, were also significantly increased in DSP-4 rats. These observations suggest that noradrenergic damage in the locus coeruleus may facilitate cholinergic and serotonergic functions in the hippocampus. Although the current lesion model does not mimic the protracted evolution of neurodegenerative processes in MCI and AD, our data could point to an explanation for the upregulations of cholinergic and serotonergic functions described in the hippocampus of MCI patients.     

Peripheral sympathetic ingrowth can alter metabolic activity within the hippocampal formation

After cholinergic denervation of the hippocampal formation, peripheral sympathetic fibers arising from the superior cervical ganglia grow into the dentate gyrus and CA3 region; the functional significance of sympathetic ingrowth into the hippocampal formation is unknown. Utilizing electrical stimulation of the preganglionic trunk in combination with 2-deoxy-D-[3H]-glucose fine-grained autoradiograms, we demonstrated an alteration of hippocampal glucose metabolism, suggesting that this neuronal rearrangement makes functional connections within the hippocampus.     

Sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C following septohippocampal denervation of the rat hippocampus

Hippocampal sympathetic ingrowth (HSI), a form of neuronal plasticity, is induced by medial septal lesions and consists of the sprouting of peripheral sympathetic fibers, arising from the superior cervical ganglion, into the dentate gyrus and CA₃ region of the hippocampus. HSI has been previously shown to alter learned and spontaneous behaviors, phosphatidyl inositide hydrolysis, and the antagonist binding kinetics of both muscarinic cholinergic receptors and phorbol ester receptors. We now report that sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C (PKC) following septohippocampal denervation of the rat hippocampus. Further, no changes were found in α, β or γ PKC isoenzymes among experimental groups, suggesting that the group A PKC isoforms do not mediate the observed changes in activity and phorbol ester binding.