The hippocampus is one of the few areas of the rodent brain that continues to produce neurons postnatally. Neurogenesis reportedly persists in rats up to 11 months of age. Using bromodeoxyuridine (BrdU) labeling, the present study confirms that in the adult rat brain, neuronal progenitor cells divide at the border between the hilus and the granule cell layer (GCL). In adult rats, the progeny of these cells migrate into the GCL and express the neuronal markers NeuN and calbindin-D28k. However, neurogenesis was drastically reduced in aged rats. Six-to 27-month-old Fischer rats were injected intraperitoneally with BrdU to detect newborn cells in vivo and to follow their fate in the dentate gyrus. When killed 4-6 weeks after BrdU labeling, 12- to 27-month-old rats exhibited a significant decline in the density of BrdU-positive cells in the granule cell layer compared with 6-month-old controls. Decreased neurogenesis in aging rats was accompanied by reduced immunoreactivity for poly-sialylated neural cell adhesion molecule, a molecule that is involved in migration and process elongation of developing neurons. When animals were killed immediately (12 hr) after BrdU injection, significantly fewer labeled cells were observed in the GCL and adjacent subgranular zone of aged rats, indicative of a decrease in mitotic activity of neuronal precursor cells. The reduced proliferation was not attributable to a general aged-related metabolic impairment, because the density of BrdU-positive cells was not altered in other brain regions with known mitotic activity (e.g., hilus and lateral ventricle wall). The decline in neurogenesis that occurs throughout the lifespan of an animal can thus be related to a decreasing proliferation of granule cell precursors.

L-glutamate, the neurotransmitter of the majority of excitatory synapses in the brain, acts on three classes of ionotropic receptors: NMDA (N-methyl-D-aspartate), AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) and kainate receptors. Little is known about the physiological role of kainate receptors because in many experimental situations it is not possible to distinguish them from AMPA receptors. Mice with disrupted kainate receptor genes enable the study of the specific role of kainate receptors in synaptic transmission as well as in the neurotoxic effects of kainate. We have now generated mutant mice lacking the kainate-receptor subunit GluR6. The hippocampal neurons in the CA3 region of these mutant mice are much less sensitive to kainate. In addition, a postsynaptic kainate current evoked in CA3 neurons by a train of stimulation of the mossy fibre system is absent in the mutant. We find that GluR6-deficient mice are less susceptible to systemic administration of kainate, as judged by onset of seizures and by the activation of immediate early genes in the hippocampus. Our results indicate that kainate receptors containing the GluR6 subunit are important in synaptic transmission as well as in the epileptogenic effects of kainate.

A single case study recently documented one woman’s ability to recall accurately vast amounts of autobiographical information, spanning most of her lifetime, without the use of practiced mnemonics (Parker, Cahill, & McGaugh, 2006). The current study reports findings based on eleven participants expressing this same memory ability, now referred to as Highly Superior Autobiographical Memory (HSAM). Participants were identified and subsequently characterized based on screening for memory of public events. They were then tested for personal autobiographical memories as well as for memory assessed by laboratory memory tests. Additionally, whole-brain structural MRI scans were obtained. Results indicated that HSAM participants performed significantly better at recalling public as well as personal autobiographical events as well as the days and dates on which these events occurred. However, their performance was comparable to age- and sex-matched controls on most standard laboratory memory tests. Neuroanatomical results identified nine structures as being morphologically different from those of control participants. The study of HSAM may provide new insights into the neurobiology of autobiographical memory.

This experiment examined the effects of di- It is well known that benzodiazepines (BZDs) induce anterograde amnesia in humans (1, 2) as well as in animals trained in a variety of learning tasks (3-7). The memory-impairing effects of systemically administered BZDs appear to be due to influences on memory processes initiated during acquisition (8, 9) and not to sedation, state dependency, or motoric effects (4, 10-12). Extensive evidence suggests that the anxiolytic effects of BZDs involve influences mediated by the amygdaloid complex. Intra-amygdala injections of BZDs produce anxiolytic effects comparable to those induced by systemic injections (13,14). Furthermore, intra-amygdala injections of the BZD antagonist flumazenil attenuate the anxiolytic effects of systemically administered BZDs (15). The findings of several studies suggest that the anxiolytic effects of BZDs are mediated by the lateral (LAT)/basolateral (BL) amygdala nuclei. Injections of the BZDs chlordiazepoxide and midazolam into the LAT/BL amygdala induce anxiolytic effects, whereas injections of midazolam into the central (CE) amygdala are without effect (15-17). Such findings are consistent with evidence that BZD receptors are densely located in the LAT/BL amygdala (16,18,19).Recent findings suggest that the memory impairing effects of BZDs also involve the amygdaloid complex. Bilateral intra-amygdala injections of flumazenil and midazolam enhance and impair, respectively, retention performance ofrats trained in aversively motivated tasks (20; H.A.D.-A. and J.L.M., unpublished data). Furthermore, we recently reported that excitotoxic lesions of the amygdaloid complex block diazepam (DZP)-induced impairment of retention in an inhibitory avoidance task (21).The evidence summarized above suggests that both the anxiolytic and the amnestic effects of BZDs are mediated by the amygdala. Furthermore, findings implicating the LAT/BL amygdala nuclei in the anxiolytic effects of BZDs suggest that these nuclei might also mediate the memorymodulating effects of BZDs. To examine this implication, we investigated the effects of DZP on the acquisition and retention of an inhibitory avoidance response in rats with ibotenic acid (IBO)-induced lesions of the CE, LAT, and BL amygdala.MATERIALS AND METHODS Animals. Male Sprague-Dawley rats (200-225 g on arrival) from Charles River Laboratories were housed in a temperature-controlled (22QC) colony room and maintained on a 12-h light/12-h dark cycle (0700-1900 lights on) with food and water available ad lib. The rats were randomly assigned to one of four surgery groups: sham operated, CE lesion, LAT lesion, and BL lesion.Surgery. After arrival, the rats were maintained in the animal colony room for 1 week before surgery. They were anesthetized with sodium pentobarbital (50 mg per kg of body weight, i.p.) and given atropine sulfate (0.4 mg/kg, i.p.). The skull was fixed to a stereotaxic frame (Kopf Instruments, Tujunga, CA) and bilateral lesions of either the CE, LAT, or BL were produced by IBO (Sigma; 1 mg per...

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The physiological significance of RNA editing of transcripts that code for kainate-preferring glutamate receptor subunits is unknown, despite the fact that the functional consequences of this molecular modification have been well characterized in cloned receptor subunits. RNA editing of the codon that encodes the glutamine/arginine (Q/R) site in the second membrane domain (MD2) of glutamate receptor 5 (GluR5) and GluR6 kainate receptor subunits produces receptors with reduced calcium permeabilities and single-channel conductances. Approximately 50% of the GluR5 subunit transcripts from adult rat brain are edited at the Q/R site in MD2. To address the role of glutamate receptor mRNA editing in the brain, we have made two strains of mice with mutations at amino acid 636, the Q/R-editing site in GluR5, using embryonic stem cell-mediated transgenesis. GluR5(RloxP/RloxP) mice encode an arginine at the Q/R site of the GluR5 subunit, whereas GluR5(wt(loxP)/wt(loxP)) mice encode a glutamine at this site, similar to wild-type mice. Mutant animals do not exhibit developmental abnormalities, nor do they show deficits in the behavioral paradigms tested in this study. Kainate receptor current densities were reduced by a factor of six in acutely isolated sensory neurons of dorsal root ganglia from GluR5(RloxP/RloxP) mice compared with neurons from wild-type mice. However, the editing mutant mice did not exhibit altered responses to thermal and chemical pain stimuli. Our investigations with the GluR5-editing mutant mice have therefore defined a set of physiological processes in which editing of the GluR5 subunit is unlikely to play an important role.

Discrete BLAC lesions blocked the amnestic effect of propofol. BLAC activity appears to be a requirement for propofol-induced amnesia. This finding suggests that the BLAC is a key brain site mediating anesthetic-induced amnesia.

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