A distinct impact of repeated morphine exposure on synaptic plasticity at Schaffer collateral-CA1, temporoammonic-CA1, and perforant pathway-dentate gyrus synapses along the longitudinal axis of the hippocampus

We aimed to study how morphine affects synaptic transmission in the dentate gyrus and CA1 regions along the hippocampal long axis. For this, recording and measuring of field excitatory postsynaptic potentials (fEPSPs) were utilized to test the effects of repeated morphine exposure on paired-pulse evoked responses and long-term potentiation (LTP) at Schaffer collateral-CA1 (Sch-CA1), temporoammonic-CA1 (TA-CA1) and perforant pathway-dentate gyrus (PP-DG) synapses in transverse slices from the dorsal (DH), intermediate (IH), and ventral (VH) hippocampus in adult male rats. After repeated morphine exposure, the expression of opioid receptors and the α1 and α5 GABA_A subunits were also examined. We found that repeated morphine exposure blunt the difference between the DH and the VH in their basal levels of synaptic transmission at Sch-CA1 synapses that were seen in the control groups. Significant paired-pulse facilitation of excitatory synaptic transmission was observed at Sch-CA1 synapses in slices taken from all three hippocampal segments as well as at PP-DG synapses in slices taken from the VH segment in the morphine-treated groups as compared to the control groups. Interestingly, significant paired-pulse inhibition of excitatory synaptic transmission was observed at TA-CA1 synapses in the DH slices from the morphine-treated group as compared to the control group. While primed-burst stimulation (a protocol reflecting normal neuronal firing) induced a robust LTP in hippocampal subfields in all control groups, resulting in a decaying LTP at TA-CA1 synapses in the VH slices and at PP-DG synapses in both the IH and VH slices taken from the morphine-treated rats. In the DH of morphine-treated rats, we found increased levels of the mRNAs encoding the α1 and α5 GABA_A subunits as compared to the control group. Taken together, these findings suggest the potential mechanisms through which repeated morphine exposure causes differential changes in circuit excitability and synaptic plasticity in the dentate gyrus and CA1 regions along the hippocampal long axis.     

The sorting receptor SorCS3 is a stronger regulator of glutamate receptor functions compared to GABAergic mechanisms in the hippocampus

Correct function of glutamate receptors in the postsynaptic density is crucial to synaptic function and plasticity. SorCS3 (sortilin‐related receptor CNS expressed 3) is a sorting receptor which previously has been shown to interact with the key postsynaptic proteins; PSD‐95 and PICK1. In this study, we employed electrophysiological analyses of acute brain slices combined with immunohistochemistry to define the role of SorCS3 in hippocampal synapses in CA1 and the dentate gyrus. We analyzed a juvenile (P17‐21) and a young adult (P55‐65) group of animals from a Sorcs3 knockout mouse model. We show that the basal synaptic transmission is severely affected in SorCS3‐deficient neurons in CA1, while only slightly reduced in the dentate gyrus. Specifically, input/output curves of CA1 synapses revealed a 20% reduction of fEPSP (field excitatory postsynaptic potential) slopes at the highest stimulation intensity in knockouts of the juvenile group, which developed to a 33% decrease in young adult animals. These impairments may be a result of changes in the postsynaptic AMPA receptors. Interestingly, repetitive afferent stimulation demonstrated that SorCS3‐deficient slices respond with an enhanced synaptic facilitation and reduced synaptic depression. These changes also developed with age. A molecular mechanism underlying this relative increase during repetitive stimulations is compatible with enhanced mobility of postsynaptic AMPA receptors resulting in faster exchange of desensitized receptors in the postsynaptic density. The altered response during repetitive stimulation was characteristic for CA1 but not the dentate gyrus. Immunohistochemical analyses of parvalbumin positive neurons combined with paired‐pulse tests of network inhibition and patch‐clamp recordings only showed minute inhibitory changes in SorCS3‐deficient slices. Our results suggest that SorCS3 serves an important role in the postsynaptic protein network, which is more pronounced in CA1 compared to the dentate gyrus. These data support a role for SorCS3 in controlling proper positioning and mobility of glutamate receptors in the postsynaptic density. © 2016 Wiley Periodicals, Inc.     

单侧液压脑损伤对大鼠双侧海马GFAP表达和CA1区突触传递的影响

目的研究单侧液压脑损伤(FPI)对大鼠双侧海马区胶质纤维酸性蛋白(GFAP)表达和CA1区突触传递的影响。方法建立大鼠单侧液压脑损伤模型,脑标本分为对照组(包括正常对照和假手术对照)、FPI损伤同侧组和FPI损伤对侧组。免疫组化法检测海马水平切片GFAP表达,对海马CA1区锥体神经元进行细胞内记录。结果FPI大鼠双侧海马齿状回门区和CA1区GFAP表达均比对照组明显增强。FPI损伤同侧组兴奋性输入-输出关系曲线的斜率比其他两组显著增大(P<0.05);FPI损伤同侧组和对侧组双脉冲易化(PPF)比值和抑制性突触后电位(IPSP)幅值均比对照组显著减小(P<0.05);FPI损伤同侧组和对侧组双脉冲抑制(PPD)比值均比对照组显著增大(P<0.05)。结论大鼠单侧液压脑损伤对双侧海马均可产生影响,导致双侧海马CA1区兴奋性突触传递增强,抑制性突触传递减弱。     

Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism

Transient reductions in thyroid hormone during critical periods of brain development can have devastating and irreversible effects on neurological function. The hippocampus is a brain region sensitive to thyroid hormones and is a necessary substrate for some forms of learning and memory. Subregions within the hippocampus display distinct ontogenetic profiles and have shown differential vulnerability to some indices of thyrotoxic insult. Synaptic function can be readily assessed in the hippocampus, yet little information exists on the consequences of early thyroid hormone insufficiency on the neurophysiological integrity of this structure. Previous work has examined the long-term consequences of perinatal hypothyroidism on neurophysiology of the dentate gyrus of the hippocampal formation. The current study reveals that alterations in synaptic function also exist in area CA1, and some differences in the pattern of effects are evident between the two hippocampal subfields. Developing rats were transiently exposed to the thyrotoxicant, propylthiouracil (PTU; 0 or 15 ppm), through the drinking water of pregnant dams beginning on gestational day 18. This regimen markedly reduced circulating levels of thyroid hormones and stunted pup growth. PTU exposure was terminated on postnatal day (PN) 21 and electrophysiological assessments were conducted by recording field potentials in area CA1 of hippocampal slices derived from adult male offspring. Synaptic transmission, short-term, and long-term synaptic plasticity were assessed. Consistent with observations in the dentate gyrus, somatic population spike amplitudes were reduced in assessments of baseline synaptic transmission of slices from PTU-exposed animals. No differences were identified in excitatory postsynaptic potentials (EPSP). Short-term plasticity of the EPSP as indexed by paired pulse facilitation was markedly impaired by PTU exposure. Long-term potentiation (LTP) of the population spike was enhanced, consistent with findings in dentate gyrus, but no change in EPSP LTP was detected. Perturbations in synaptic function in the hippocampus of adult rats transiently exposed to a period of hormone insufficiency during the perinatal period are likely to contribute to cognitive deficits associated with developmental hypothyroidism.     

Long-term increases in the evoked population spike in the CA1 region of rat hippocampus induced by beta-adrenergic receptor activation.

The effects of the selective beta-adrenergic receptor agonist isoproterenol (ISO) were characterized in the CA1 region of the rat hippocampal slice preparation. As has been previously described, 500 nM ISO increased the amplitude of the evoked population spike response without having any effect upon field EPSP (fEPSP) responses. However, the increase in the population spike response was quite persistent and was not reversed by greater than 30 min of washout in the majority of the slices tested; we have termed this prolonged increase beta-adrenergic potentiation (BAP). As with the acute effect of ISO, BAP is confined to an increase in the population spike response and not the fEPSP. In input-output curves, this was clearly observed as a persistent leftward shift in the EPSP-population spike relationship. Similar long-term increases in the population spike could also be elicited by superfusion of the slices for 10 min with 20-25 microM norepinephrine (NE). Although both the acute and the long-term effects of ISO were blocked by pretreatment with timolol, a beta-adrenergic antagonist, the long-term effects were not reversed by superfusion with timolol following ISO treatment, demonstrating that the prolonged effects were not due to slow washout of ISO from the tissue. BAP was not blocked by pretreatment with 50 microM 2-amino-5-phosphonovaleric acid, an NMDA receptor antagonist that blocks hippocampal long-term potentiation and the long-lasting changes in synaptic responses induced in the dentate gyrus by NE and ISO.(ABSTRACT TRUNCATED AT 250 WORDS)     

Kynurenic acid inhibits synaptic and acidic amino acid-induced responses in the rat hippocampus and spinal cord

Kynurenic acid, a tryptophan metabolite, inhibits excitatory synaptic transmission in the rat hippocampal slice and the isolated immature rat spinal cord, but does not affect membrane potential or input resistance of hippocampal CA1 pyramidal cells. Kynurenic acid also antagonizes responses induced in the dentate gyrus by excitatory amino acids, particularly N-methyl-DL-aspartate and the endogenous excitant quinolinic acid. These results indicate that kynurenic acid antagonizes synaptic transmission probably by blocking postsynaptic transmitter receptors at putative amino acid mediated synapses.     

Kindling induces transient fast inhibition in the dentate gyrus--CA3 projection

The granule cells of the dentate gyrus (DG) send a strong glutamatergic projection, the mossy fibre tract, toward the hippocampal CA3 field, where it excites pyramidal cells and neighbouring inhibitory interneurons. Despite their excitatory nature, granule cells contain small amounts of GAD (glutamate decarboxylase), the main synthetic enzyme for the inhibitory transmitter GABA. Chronic temporal lobe epilepsy results in transient upregulation of GAD and GABA in granule cells, giving rise to the speculation that following overexcitation, mossy fibres exert an inhibitory effect by release of GABA. We therefore stimulated the DG and recorded synaptic potentials from CA3 pyramidal cells in brain slices from kindled and control rats. In both preparations, DG stimulation caused excitatory postsynaptic potential (EPSP)/inhibitory postsynaptic potential (IPSP) sequences. These potentials could be completely blocked by glutamate receptor antagonists in control rats, while in the kindled rats, a bicuculline-sensitive fast IPSP remained, with an onset latency similar to that of the control EPSP. Interestingly, this IPSP disappeared 1 month after the last seizure. When synaptic responses were evoked by high-frequency stimulation, EPSPs in normal rats readily summate to evoke action potentials. In slices from kindled rats, a summation of IPSPs overrides that of the EPSPs and reduces the probability of evoking action potentials. Our data show for the first time that kindling induces functionally relevant activity-dependent expression of fast inhibition onto pyramidal cells, coming from the DG, that can limit CA3 excitation in a frequency-dependent manner.     

The action of norepinephrine in the dentate gyrus: Beta-mediated facilitation of evoked potentials in vitro

The effects of superfusion of norepinephrine (NE) on perforant path (PP) evoked potentials in the dentate gyrus were evaluated in the rat hippocampal slice preparation. Superfusion of NE (10 microM) produced a facilitation of the PP evoked responses. Facilitation of the synaptically-evoked responses was expressed in the field potential as an increase in extracellular excitatory postsynaptic potential (EPSP) (117% of control), a decrease in population spike onset latency (94% of control) and an increase in population spike amplitude (131% of control). In 24% of the slices the facilitation of the population spike amplitude lasted longer than 30 min. Isoproterenol, a beta-agonist, mimicked NE effects while timolol, a beta-antagonist, blocked them. Facilitation of the population spike amplitude by NE could not be accounted for solely by the increase in EPSP slope also produced by NE. Superfusion of NE did not produce facilitation of the antidromically evoked field potentials, but in 4 of 8 slices produced a small decrease. NE effects were activity-independent, since the subsequently evoked PP responses were facilitated even when the PP was not concurrently stimulated during superfusion with NE.     

Nitric Oxide Signalling is Required for the Generation of Anoxia-induced Long-term Potentiation in the Hippocampus

The involvement of nitric oxide in anoxia-induced long-term potentiation (anoxic LTP) of synaptic transmission was investigated in CA1 neurons of rat hippocampal slices using intracellular recording techniques in vitro . In response to superfusion of an anoxic artificial cerebral spinal fluid saturated with 95% N₂-_-5% CO₂, the excitatory postsynaptic potential (EPSP) generated in hippocampal CA1 neurons by stimulation of the Schaffer collateral/commissural afferent pathway was completely abolished within 10 min of anoxia. On return to reoxygenated medium, the EPSP returned to the control value within 10 min and was subsequently and progressively potentiated to reach a plateau 15–20 min after return to oxygen. This anoxia-induced persistent increase in synaptic transmission lasted for more than 1 h. Application of the nitric oxide synthase inhibitors 7-nitroindazole (7-NI) or l- N ^G-nitroarginine (NOARG) produced no effects on the baseline EPSP amplitude, but effectively attenuated the anoxic LTP. The inhibitory effects of both 7-NI and NOARG on the anoxic LTP were blocked by l-arginine, a substrate for nitric oxide synthase. These results suggest that nitric oxide is required for the generation of anoxia-induced LTP of glutamatergic synaptic transmission in the CA1 region of the rat hippocampus.     

Enhanced long-term potentiation in the hippocampus of rats expressing mutant presenillin-1 is age related

Electrophysiological recordings were made from Fischer rats engineered to express the human presenilin 1 gene carrying the M146V mutation. Extracellular recordings of field excitatory post-synaptic potential (EPSPs) were made to investigate EPSP properties, paired pulse responses, posttetanic potentiation, and long-term potentiation in the stratum radiatum and dentate gyrus of hippocampal slices maintained in vitro. Transgenic rats aged approximately 6 months showed no differences from their wild-type littermates in any of these properties. However, at 18 months, long-term potentiation in the CA1 was facilitated in the transgenic rats with a different pattern of synaptic enhancement. No changes were observed in paired pulse facilitation (PPF) or post-tetanic potentiation (PPT) and no changes were seen in the dentate gyrus. Field potential amplitudes were significantly greater and PPF was enhanced in the CA1 of all older rats. Intracellular recordings from CA1 pyramidal cells of the older group of rats revealed no differences in the passive or active membrane properties of cells in the two groups, but intracellularly recorded EPSPs were significantly longer.     

Expression of synapsin III in nerve terminals and neurogenic regions of the adult brain

We have examined the distribution of synapsin III in the adult mouse brain. Expression of synapsin III was observed in puncta throughout the brain, but demonstrated greater regional variation than that of synapsins I or II. This punctate staining is typical for synaptic vesicle proteins located at nerve terminals. These findings are also consistent with the well-established role for synapsins in regulating neurotransmitter release. However, unexpectedly, synapsin III was also highly expressed in the cell body and processes of immature neurons in neurogenic regions of the adult brain, such as the hippocampal dentate gyrus, rostral migratory stream, and olfactory bulb. Many synapsin III-positive neurons also reacted with an antibody directed toward polysialylated-neuronal cell adhesion molecule, a marker of immature, migrating neurons. These results suggest that synapsin III may also play a role in adult neurogenesis.     

Vasopressin induction of long-lasting potentiation of synaptic transmission in the dentate gyrus

Vasopressin receptors are present in both the developing and mature dentate gyrus of the rat brain and are of the V₁ vasopressor type. Because vasopressin has been shown to influence memory function when injected into the dentate gyrus, the influence of this peptide on an electrophysiological model of learning and memory using the field excitatory postsynaptic potential (EPSP) of the dentate gyrus was investigated. Results of these studies showed that nanomolar concentrations of [Arg⁸]-vasopressin induced a prolonged increase in the amplitude and slope of the evoked population response in the presence of 1.5 mM calcium. Moreover, the expression of the vasopressin-induced potentiation of the EPSP persisted following removal of vasopressin from the perfusion medium. The vasopressin-induced sustained increase has been termed long-term vasopressin potentiation (LTVP). The closely related neuropeptide oxytocin had no effect upon the EPSP of the dentate gyrus. Preincubation of hippocampal slices in a selective V₁ antagonist blocked the expression of LTVP. The ability of the V₁ antagonist to block LTVP demonstrates that the potentiation induced by vasopressin is receptor-specific. In the presence of 2.5 mM calcium, the effect of vasopressin was opposite to that observed in 1.5 mM calcium. Under the conditions of 2.5 calcium, vasopressin induced a prolonged depression in the amplitude and slope of the EPSP. Expression of both potentiation and depression appeared within 5 minutes of application and persisted for the length of the observation, 60 minutes. These experiments demonstrate that vasopressin can induce long-lasting changes in the excitability of dentate gyrus neurons that are both calcium-dependent and receptor-specific.     

Chronic unpredictable stress impairs long-term potentiation in rat hippocampal CA1 area and dentate gyrus in vitro

Rises in corticosteroid levels, e.g. after acute stress, impair synaptic plasticity in the rat hippocampus when compared with the situation where levels are basal, i.e. under rest. We here addressed the question whether basal and raised levels of corticosterone affect synaptic plasticity similarly in animals that experienced chronic stress prior to corticosterone application. To this end, rats were exposed to a 21-day variable stress paradigm. Synaptic plasticity was examined in vitro in the dentate gyrus and CA1 hippocampal region, 24 h after exposure to the last stressor, i.e. when corticosterone levels are basal (low). First we observed that long-term potentiation was greatly impaired in both CA1 and dentate gyrus after 3 weeks of exposure to variable stress, when recorded under conditions where plasma corticosterone levels are low. Second, administration of 100 nm corticosterone in vitro reduced synaptic plasticity in CA1 of control rats, but induced no further impairment of synaptic plasticity in chronically stressed rats. Third, in the dentate gyrus, corticosterone incubation did not affect synaptic plasticity in slices from both control and stressed animals. We conclude that: (i) exposure to chronic variable stress per se reduces synaptic plasticity both in CA1 and dentate gyrus; and (ii) acute rises in corticosterone level induce no additional impairment of synaptic plasticity in the CA1 region of chronically stressed rats. It is tempting to speculate that the stress-induced reduction of hippocampal efficacy provides a cellular substrate for cognitive deficits in hippocampus-dependent learning tasks seen after prolonged exposure to stressful events.     

Postischemic synaptic physiology in area CA1 of the gerbil hippocampus studied in vitro

After transient forebrain ischemia in the Mongolian gerbil, CA1b hippocampal pyramidal cells degenerate during a period of 2-4 d. We tested the hypothesis that this delayed neuronal death is preceded by excessive synaptic excitation. Hippocampal slices were prepared from gerbils that had been subjected to a 5 min occlusion of both common carotid arteries. Input/output curves demonstrated enhancement of the initial slope of the Schaffer collateral-commissural focally recorded EPSP at all stimulus currents between 5 and 10 hr after the ischemic insult. The duration of the focally recorded EPSP also increased. At the same time, the excitability of the CA1b pyramidal cells decreased. Thus, the EPSP brought fewer pyramidal cells to threshold than the same size EPSP in control slices. During the first 14 hr after ischemia, the antidromic population spike remained unaffected. By 24 hr after ischemia, however, the focally recorded EPSP and both orthodromic and antidromic population spikes were markedly depressed, and they declined further over the next 2 d. No recovery was detected. In the same slices, transient ischemia only mildly and reversibly affected the response of dentate granule cells to perforant path stimulation and did not affect their response to antidromic stimulation. Hippocampal slices adjacent to those used for electrophysiological recording were analyzed histologically. Examination of somatic argyrophilia confirmed that CA1b pyramidal cells suffered delayed neuronal death, whereas dentate granule cells remained intact. Pyramidal cell argyrophilia was, however, not detected until 2 d after these neurons had become virtually inexcitable. We conclude that CA1b pyramidal cells begin to lose electrophysiological function well before definite morphological signs of degeneration become visible. The observation of enhanced excitatory transmission 5-10 hr after reperfusion is consistent with the idea that delayed ischemic neuronal death results, at least in part, from excessive excitation.     

Decreases in excitatory synaptic transmission and increases in recurrent inhibition in the rat dentate gyrus after transient cerebral ischemia

Excitatory transmission along the perforant path from the entorhinal cortex to the granule cells of the dentate gyrus was evaluated two days after 10 min of transient cerebral ischemia in the rat. The amplitude of the population spike, and the amplitude and the initial slope of the population excitatory postsynaptic potential (EPSP) evoked by the perforant path stimulation were measured across a range of stimulus intensities, and were compared with control values. Inhibitory interactions were evaluated using the paradigm of paired pulse stimulation, comparing the amplitude of the population spike evoked by the second pulse of a pair to the initial spike. The maximal values of the initial slope of the population EPSP and the population spike were reduced in the ischemic group. Also, the extent of paired pulse inhibition was greater in the ischemic group. These results suggest that: (1) excitatory synaptic transmission along the perforant path is impaired in the postischemic period, (2) inhibition of the dentate granule cells is enhanced in this period. These results are not consistent with the hypothesis that there is a hyperactivation of the tri-synaptic circuit in the chronic postischemic period that accounts for the excitotoxic death of CA1 neurons.     

The effects of chronic lead exposure on long-term depression in area CA1 and dentate gyrus of rat hippocampus in vitro

Long-term potentiation (LTP) and long-term depression (LTD), two forms of synaptic plasticity, are believed to underlie the mechanisms of learning and memory. Previous studies have demonstrated that low-level lead exposure can impair the induction and maintenance of LTP in vivo and in vitro. The present study was carried out to investigate whether the low-level lead exposure affected the induction and maintenance of LTD. Neonatal Wistar rats were exposed to lead from parturition to weaning via milk of dams drinking 0.2% lead acetate solution. Field excitatory postsynaptic potentials (EPSPs) were recorded in hippocampal slices in adult rats (50–65 days) to study the alterations of LTD in area CA1 and dentate gyrus (DG) of hippocampus following chronic lead exposure. The input–output (I/O) curves before conditioning in both areas showed no evident alterations in basic synaptic transmission between the control and lead exposure groups. In area CA1, the mean amplitude of EPSP slope in control rats (61±11%, n=15) decreased significantly greater than that in lead-exposed rats (78±8%, n=8, P<0.05) following low frequency stimulation (LFS, 1 Hz, 15 min), which lasted at least 45 min. In area DG, with application of the same LFS, the LTD was induced in control rats (72±22%, n=8), while the LFS failed to induce LTD in lead-exposed rats (100±26%, n=8). These results showed that chronic lead exposure affected the induction of LTD in both area CA1 and DG. The effect of lead on synaptic plasticity in area CA1 was also investigated. The alteration of the amplitude of LTP in hippocampal slices caused by lead was reexamined in order to compare with that on LTD (control: 189±23, n=5; lead-exposed: 122±12, n=10). The result demonstrated that low-level lead exposure could reduce the range of synaptic plasticity, which might underlie the dysfunction of learning and memory caused by chronic lead exposure.     

Development of synapsin I and synapsin II in intraocular hippocampal transplants.

Previous studies have indicated that the appearance of synaptic vesicle-associated proteins known as the synapsins is one indicator of synapse formation. In this study, the levels and morphological distribution of synapsin I and synapsin IIa and IIb were studied in intraocular hippocampal transplants and in situ in the intact hippocampus. No detectable levels of either synapsin I or synapsin II were found in the fetal brain. The in situ levels of the synapsins exhibited parallel increases rapidly after birth, reaching peak levels at 8 weeks, after which a slight decline was noted in synapsin I and synapsin IIb. In hippocampal transplants, a comparable increase in the synapsins was seen during the first 8 weeks in oculo. It is likely that the synapse formation in the hippocampal transplants represents synapses from neurons within the transplant, as well as from various peripheral ganglia that send collaterals into the graft. Peripheral and central synapses express different synapsin I: synapsin IIa and IIb ratios. When the ratios of the synapsin proteins in hippocampal transplants were examined ratios essentially identical to those seen in the normal hippocampus were found, despite the numerous peripheral neurites innervating the grafts. Immunohistochemical studies supported the immunoblot data, showing no detectable immunofluorescence with synapsin antibodies in fetal or newborn hippocampal formation. The density of immunoreactive profiles increased substantially both in transplants and in the hippocampal formation in situ during the first 2 postnatal months. In conclusion, the present data demonstrate that hippocampal transplants in oculo can develop significant levels of the synapsins and that there is no time lag in development in these levels compared to the hippocampal formation in situ.     

Cysteamine potentiates entorhinal activation of dentate gyrus granule cells in rats

A dense plexus of somatostatin-positive fibers and varicosities is observed in the outer two-thirds of the dentate gyrus molecular layer where the glutamatergic perforant path afferents from the entorhinal cortex terminate. To test for a functional interaction between these two pathways, we examined the effects of Cysteamine, which enhances somatostatin release for a few hours after administration but produces subsequent depletion of somatostatin lasting several days, on perforant path evoked potentials recorded in the dentate gyrus. Cysteamine (50–400 mg/kg, IP) increased the population spike dose-dependently both in anesthetized and in awake rats, but the slope of the population excitatory postsynaptic potential (EPSP) was left unchanged or even decreased. The antidromic population spike evoked by mossy fiber stimulation was not changed by cysteamine. The change is thought to be due to the increase in slope of the EPSP-spike relationship. In the hippocampal slice preparation, a similar effect of the drug (1–5 mM) on dentate evoked potentials was observed, suggesting that cysteamine acts through its effects on somatostatin in the hippocampus itself. In chronically implanted awake animals, the perforant path population spike was increased 1 h after cysteamine but returned to the predrug level by 24 h when somatostatin seemed to be depleted. These results suggest that hippocampal somatostatin released by cysteamine potentiates the response of dentate granule cells to perforant path input, without directly affecting synaptic transmission or general cell excitability.     

Age-related impairments of synaptic plasticity in the lateral perforant path input to the dentate gyrus of galanin overexpressing mice

In the present study, electrophysiological recordings were made from hippocampal slices obtained from mice overexpressing galanin under the promoter for the platelet-derived growth factor-B (GalOE mice). In these mice, a particularly strong galanin expression is seen in the granule cell layer/mossy fibers. Paired-pulse facilitation (PPF) of excitatory postsynaptic field potentials (fEPSPs) at the lateral perforant path (LPP)-dentate gyrus synapses was elicited in the dentate gyrus after stimulation with different interpulse intervals. Slices from young adult wild-type (WT) animals showed significant PPF of the 2nd EPSP evoked with paired-pulse stimuli, while PPF was reduced in slices from young adult GalOE mice, as well as aged WT mice, but were not observed at all in slices from aged GalOE animals. Application of the putative galanin antagonist M35 increased PPF in slices from aged WT mice as well as from adult and aged GalOE mice, but had no effect in slices taken from young adult WT mice. These data indicate that galanin is involved in hippocampal synaptic plasticity, in particular in age-related reduction of synaptic plasticity in the LPP input to the dentate gyrus. Galaninergic mechanisms may therefore represent therapeutic targets for treatment of age-related memory deficits and Alzheimer's disease.