Short-term synaptic plasticity in the dentate gyrus of monkeys

The hippocampus plays an important role in learning and memory. Synaptic plasticity in the hippocampus, short-term and long-term, is postulated to be a neural substrate of memory trace. Paired-pulse stimulation is a standard technique for evaluating a form of short-term synaptic plasticity in rodents. However, evidence is lacking for paired-pulse responses in the primate hippocampus. In the present study, we recorded paired-pulse responses in the dentate gyrus of monkeys while stimulating to the medial part of the perforant path at several inter-pulse intervals (IPIs) using low and high stimulus intensities. When the stimulus intensity was low, the first pulse produced early strong depression (at IPIs of 10-30 ms) and late slight depression (at IPIs of 100-1000 ms) of field excitatory postsynaptic potentials (fEPSPs) generated by the second pulse, interposing no depression IPIs (50-70 ms). When the stimulus intensity was high, fEPSPs generated by the second pulse were depressed by the first pulse at all IPIs except for the longest one (2000 ms). Population spikes (PSs) generated by the second pulse were completely blocked or strongly depressed at shorter IPIs (10-100 or 200 ms, respectively), while no depression or slight facilitation occurred at longer IPIs (500-2000 ms). Administration of diazepam slightly increased fEPSPs, while it decreased PSs produced by the first pulse. It also enhanced the facilitation of PSs produced by the second stimulation at longer IPIs. The present results, in comparison with previous studies using rodents, indicate that paired-pulse responses of fEPSPs in the monkey are basically similar to those of rodents, although paired-pulse responses of PSs in the monkey are more delayed than those in rodents and have a different sensitivity to diazepam.     

Amino acids and the synaptic pharmacology of granule cells in the dentate gyrus of the rat

Granule cells in the dentate gyrus in the hippocampi of anaesthetized rats were excited by stimulation of the contralateral hippocampus (the commissural input) and the ipsilateral entorhinal cortex (the perforant path). The cells were also activated by the electrophoretic administration of various amino acids. A selective antagonism of glutamate and perforant path excitations was obtained with glutamic acid diethylester, and of aspartate and other amino acid induced and commissural excitations with D- or DL-alpha-aminoadipate. An excitatory effect of alpha-aminoadipate which was sometimes observed was prevented by the gamma-aminobutyric acid antagonist bicuculline, and may be a disinhibitory phenomenon. The results lend support to the proposition that the transmitter of the perforant path is glutamate while that of the commissural fibres is aspartate.     

Multipotent progenitor cells in the adult dentate gyrus

Neurogenesis persists in the adult dentate gyrus of rodents throughout the life of the organism. The factors regulating proliferation, survival, migration, and differentiation of neuronal progenitors are now being elucidated. Cells from the adult hippocampus can be propagated, cloned in vitro, and induced to differentiate into neurons and glial cells. Cells cultured from the adult rodent hippocampus can be genetically marked and transplanted back to the adult brain, where they survive and differentiate into mature neurons and glial cells. Although multipotent stem cells exist in the adult rodent dentate gyrus, their biological significance remains elusive. © 1998 John Wiley & Sons, Inc. J Neurobiol 36: 249–266, 1998.     

The complement inhibitor CD59 is required for GABAergic synaptic transmission in the dentate gyrus

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(-)-Clausenamide potentiates synaptic transmission in the dentate gyrus of rats

The effect of clausenamide on synaptic transmission in the dentate gyrus of rats in vivo and its possible mechanism of action were investigated in this study. Four of 16 enantiomers showed potentiating effects on basal synaptic transmission in anesthetized animals. By comparing one pair of enantiomers, (-)-clausenamide and (+)-clausenamide, we can report three primary findings: (1) (-)-clausenamide potentiated synaptic transmission in both anesthetized and freely moving animals while (+)-clausenamide showed no or little effect; (2) (-)-clausenamide increased the magnitude of long-term potentiation (LTP) induced by high-frequency stimulation (HFS) in anesthetized animals whereas (+)-clausenamide had no effect; (3) voltage-dependent calcium channels (VDCCs) calcineurin and calpain are involved in (-)-clausenamide-induced potentiation of synaptic transmission. Because hippocampal LTP is thought to reflect a cellular mechanism involved in learning and memory, our findings may provide the pharmacological basis for understanding the nootropic mechanisms of (-)-clausenamide, which is the first chiral nootropic agent developed in China.     

Enigmas of the dentate gyrus

We are rapidly approaching a better understanding of the mechanisms that allow our brains to form distinct representations for similar events or episodes. McHugh et al. have brought that goal one step closer by showing that NMDA receptor-dependent synaptic plasticity in the dentate gyrus is necessary for immediate differentiation between environments with similar features.     

Adolescent development of neuron structure in dentate gyrus granule cells of male Syrian hamsters

Hippocampal function, including spatial cognition and stress responses, matures during adolescence. In addition, hippocampal neuron structure is modified by gonadal steroid hormones, which increase dramatically at this time. This study investigated pubertal changes in dendritic complexity of dentate gyrus neurons. Dendrites, spines, and cell bodies of Golgi-impregnated neurons from the granule cell layer were traced in pre-, mid-, and late-pubertal male Syrian hamsters (21, 35, and 49 days of age). Sholl analysis determined the number of intersections and total dendritic length contained in concentric spheres set at 25-microm increments from the soma. Spine densities were quantified separately in proximal and distal segments of a subset of neurons used for the Sholl analysis. We found that the structure of neurons in the lower, but not upper, blade of the dentate gyrus changed during adolescence. The lower, infrapyramidal blade showed pruning of dendrites close to the cell body and increases in distal dendritic spine densities across adolescence. These data demonstrate that dentate gyrus neurons undergo substantial structural remodeling during adolescence and that patterns of maturation are region specific. Furthermore, these changes in dendrite structure, which alter the electrophysiological properties of granule cells, are likely related to the adolescent development of hippocampal-dependent cognitive functions such as learning and memory, as well as hippocampus-mediated stress responsivity.     

Moderate traumatic brain injury causes acute dendritic and synaptic degeneration in the hippocampal dentate gyrus

Hippocampal injury-associated learning and memory deficits are frequent hallmarks of brain trauma and are the most enduring and devastating consequences following traumatic brain injury (TBI). Several reports, including our recent paper, showed that TBI brought on by a moderate level of controlled cortical impact (CCI) induces immature newborn neuron death in the hippocampal dentate gyrus. In contrast, the majority of mature neurons are spared. Less research has been focused on these spared neurons, which may also be injured or compromised by TBI. Here we examined the dendrite morphologies, dendritic spines, and synaptic structures using a genetic approach in combination with immunohistochemistry and Golgi staining. We found that although most of the mature granular neurons were spared following TBI at a moderate level of impact, they exhibited dramatic dendritic beading and fragmentation, decreased number of dendritic branches, and a lower density of dendritic spines, particularly the mushroom-shaped mature spines. Further studies showed that the density of synapses in the molecular layer of the hippocampal dentate gyrus was significantly reduced. The electrophysiological activity of neurons was impaired as well. These results indicate that TBI not only induces cell death in immature granular neurons, it also causes significant dendritic and synaptic degeneration in pathohistology. TBI also impairs the function of the spared mature granular neurons in the hippocampal dentate gyrus. These observations point to a potential anatomic substrate to explain, in part, the development of posttraumatic memory deficits. They also indicate that dendritic damage in the hippocampal dentate gyrus may serve as a therapeutic target following TBI.     

Borna disease virus infection alters synaptic input of neurons in rat dentate gyrus

Granule cells are major targets of entorhinal afferents terminating in a laminar fashion in the outer molecular layer of the dentate gyrus. Since Borna disease virus (BDV) infection of newborn rats causes a progressive loss of granule cells in the dentate gyrus, entorhinal fibres become disjoined from their main targets. We have investigated the extent to which entorhinal axons react to this loss of granule cells. Unexpectedly, anterograde DiI tracing has shown a prominent layered termination of the entorhinal projection, despite an almost complete loss of granule cells at 9 weeks after infection. Combined light- and electron-microscopic analysis of dendrites at the outer molecular layer of the dentate gyrus at 6 and 9 weeks post-infection has revealed a transient increase in the synaptic density of calbindin-positive granule cells and parvalbuminergic neurons after 6 weeks. In contrast, synaptic density reaches values similar to those of uninfected controls 9 weeks post-infection. These findings indicate that, after BDV infection, synaptic reorganization processes occur at peripheral dendrites of the remaining granule cells and parvalbuminergic neurons, including the unexpected persistence of entorhinal axons in the absence of their main targets.     

Radiation effects on neural precursor cells in the dentate gyrus

Ionizing irradiation is an effective treatment for intracranial tumors but is limited by the potential adverse effects induced in surrounding normal brain. These effects can include cognitive impairments, and whereas the pathogenesis of such injury has not yet been definitively established, it may involve injury to the neurogenic cell population that exists in the dentate subgranular zone (SGZ) of the hippocampus. Understanding the issues surrounding this topic could have a major impact in the management of specific sequelae associated with cranial irradiation. Although radiation is now becoming a useful tool in investigations into the biology of neurogenesis, the perspective of this review is directed more toward the potential relevance of studying radiation and the stem/precursor cell response. This work was supported in part by NIH grant R01 NS46051, NASA grant NNJ04HC90G, and NCI Contract 22xs026a.     

Priming of associative long-term depression in the dentate gyrus by theta frequency synaptic activity.

Associative long-term synaptic depression (LTD) was investigated utilizing negatively correlated activity patterns in the medial and lateral perforant path inputs to the dentate gyrus in anesthetized rats. Normally only nonassociative, or heterosynaptic, LTD is elicited in naive pathways. We report here, however, that associative LTD in the lateral path is readily induced after being "primed" by a brief period of lateral path synaptic activity at a theta rhythm frequency (5 Hz). Priming of associative LTD lasts at least 2 hr and is not seen following priming activity at non-theta frequencies (1 and 15 Hz). N-methyl-D-aspartate receptor activation is critical for establishing the priming effect, but not for the subsequent induction of the associative LTD. These data suggest that theta rhythm activity in the dentate gyrus may predispose the system to a specific form of synaptic plasticity, associative LTD.     

Postnatal development of the dentate gyrus: a karyometric and topographic study.

We have analysed the postnatal development of the nuclear sizes of the granular cells of the dentate gyrus in 5- to 190-day-old male mice. The study was performed in three topographic levels: rostral, intermediate and caudal. Three subdivisions were analysed in each level: suprapyramidal blade, infrapyramidal blade and the transition between them, the angular zone. Additionally, each of these subdivisions was measured in its external and internal layer, separately. Three gradients of postnatal karyometric development can be described: external-to-internal, suprapyramidal-to-infrapyramidal, and caudal-to-rostral, indicating that the external, suprapyramidal and caudal cells show higher karyometric sizes than the other subdivisions. These gradients are related to the ontogenetic gradients of these neurons.     

The mechanism of rate remapping in the dentate gyrus

Rate remapping is a recently revealed neural code in which sensory information modulates the firing rate of hippocampal place cells. The mechanism underlying rate remapping is unknown. Its characteristic modulation, however, must arise from the interaction of the two major inputs to the hippocampus, the medial entorhinal cortex (MEC), in which grid cells represent the spatial position of the rat, and the lateral entorhinal cortex (LEC), in which cells represent the sensory properties of the environment. We have used computational methods to elucidate the mechanism by which this interaction produces rate remapping. We show that the convergence of LEC and MEC inputs, in conjunction with a competitive network process mediated by feedback inhibition, can account quantitatively for this phenomenon. The same principle accounts for why different place fields of the same cell vary independently as sensory information is altered. Our results show that rate remapping can be explained in terms of known mechanisms.     

The chemokine BRAK/CXCL14 regulates synaptic transmission in the adult mouse dentate gyrus stem cell niche

The chemokine BRAK/CXCL14 is an ancient member of the chemokine family whose functions in the brain are completely unknown. We examined the distribution of CXCL14 in the nervous system during development and in the adult. Generally speaking, CXCL14 was not expressed in the nervous system prior to birth, but it was expressed in the developing whisker follicles (E14.5) and subsequently in the hair follicles and skin. Postnatally, CXCL14 was also highly expressed in many regions of the brain, including the cortex, basal ganglia, septum and hippocampus. CXCL14 was also highly expressed in the dorsal root ganglia. We observed that in the hippocampal dentate gyrus (DG) CXCL14 was expressed by GABAergic interneurons. We demonstrated that CXCL14 inhibited GABAergic transmission to nestin-EGFP-expressing neural stem/progenitor cells in the adult DG. CXCL14 inhibited both the tonic and phasic effects of synaptically released GABA. In contrast CXCL12 enhanced the effects of GABA at these same synapses. CXCL14 increased [Ca(2+)](i) in neural stem cells cultured from the postnatal brain indicating that they expressed the CXCL14 receptor. These observations are consistent with the view that CXCL12 and CXCL14 may normally act as positive and negative regulators of the effects of GABA in the adult DG stem cell niche.     

Neurogenin 2 has an essential role in development of the dentate gyrus

The dentate gyrus (DG) of the hippocampus has a central role in learning and memory in adult rodents. The DG is generated soon after birth, although new neurons continue to be generated in the DG throughout life. The proneural factors Mash1 (Ascl1) and neurogenin 2 (Ngn2) are expressed during formation of the DG but their role in the development of this structure has not yet been addressed. Here, we show that Ngn2 is essential for the development of the DG. Ngn2 mutant mice have fewer DG progenitors and these cells present defects in neuronal differentiation. By contrast, the DG is normal in Mash1 mutant mice at birth, and loss of both Mash1 and Ngn2 does not aggravate the defect observed in Ngn2 single mutants. These data establish a unique role of Ngn2 in DG neurogenesis during development and raise the possibility that Ngn2 has a similar function in adult neurogenesis.     

Flexible encoding of objects and space in single cells of the dentate gyrus

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