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PubMed2005

Hemodynamic infarction of the spinal cord: involvement of the gray matter plus the border-zone between the central and peripheral arteries.

OBJECTIVE: Hemodynamic infarction of the spinal cord that affected an 81-year-old female having a dissecting aortic aneurysm is presented. During the graft replacement operation, systemic hypotension occurred and the patient was subsequently complicated with paraplegia of the lower limbs. The patient died 2 weeks after the surgery due to gastrointestinal bleeding. An autopsy, which did not include the brain, was performed and the spinal cord was sampled. The aim of this report is to describe the pathologic profile of the spinal cord of the patient, and to gain insight into the pathogenesis of the lesion. METHODS: Histochemical and immunohistochemical methods were employed to study the spinal cord ranging from the lower thoracic to sacral segments. RESULTS: The whole central areas of the spinal cord showed coagulation and/or liquefaction necroses, while the white matter on the circumference of the cord remained unaffected, thus exhibiting a 'ring-like' appearance. CONCLUSION: This case is an example of hemodynamic infarction of the spinal cord involving the gray matter that is supplied by the central artery, plus the border-zone that is supplied by both the central and peripheral arteries. The former is probably associated with selective vulnerability of the gray matter to ischemia, while the latter is probably associated with intrinsic vulnerability of the border-zone to systemic hypotension or low blood-flow states.

Aged↗

PubMed2003

Electrophysiological assessment of the afferent sensory pathway in cardiac arrest survivors.

BACKGROUND: Hypoxic-ischaemic brain damage in cardiac arrest survivors is global, but postmortem histology could identify parts of the brain that are selectively vulnerable to ischaemia, comprising the thalamus and cortex. We hypothesized that hypoxic-ischaemic brain damage increases along the afferent sensory pathway with a stepwise decrease of detectable somatosensory evoked potential peaks. METHODS: Somatosensory evoked potentials were recorded within 72 h after cardiac arrest in 305 comatose patients after cardiopulmonary resuscitation. We measured the short latency SEP peaks N9, P15, N20, P25 (reflecting the peripheral-thalamo-cortical pathway) and the long latency SEP peaks N35 and N70 (reflecting complex cortico-cortical interactions). Patients with a Cerebral Performance Category score > 2 at 1 year were defined as patients with hypoxic-ischaemic brain damage. RESULTS: Patients with hypoxic-ischaemic brain damage (n = 232) showed a statistically significant decrease of detectable peaks (P < 0.05) along the thalamo-cortical afferent pathway: N13, P15, N20, P25 and N70 peaks were detectable in 99%, 63%, 59%, 55% and 44% patients, respectively. In patients without hypoxic-ischaemic brain damage (n = 73) the N13, P15, N20, P25 peaks were detectable in all, and the N35 and N70 peaks in 98%. Furthermore, in patients with hypoxic-ischaemic brain damage and detectable SEP peaks, P15, N20, P25, N35 and N70, peak latencies were prolonged (P < 0.05) and N20 and N70 amplitudes were decreased (P < 0.05) compared with patients without hypoxic-ischaemic brain damage. CONCLUSION: Extent of hypoxic-ischaemic brain damage in cardiac arrest survivors increases along the afferent sensory pathway, with pronounced vulnerability of thalamic and cortical brain regions.

Adolescent↗

PubMed1998

The Dorothy Russell Memorial Lecture. The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms.

The mechanisms underlying secondary or delayed cell death following traumatic brain injury (TBI) are poorly understood. Recent evidence from experimental models of TBI suggest that diffuse and widespread neuronal damage and loss is progressive and prolonged for months to years after the initial insult in selectively vulnerable regions of the cortex, hippocampus, thalamus, striatum, and subcortical nuclei. The development of new neuropathological and molecular techniques has generated new insights into the cellular and molecular sequelae of brain trauma. This paper will review the literature suggesting that alterations in intracellular calcium with resulting changes in gene expression, activation of reactive oxygen species (ROS), activation of intracellular proteases (calpains), expression of neurotrophic factors, and activation of cell death genes (apoptosis) may play a role in mediating delayed cell death after trauma. Recent data suggesting that TBI should be considered as both an inflammatory and/or a neurodegenerative disease is also presented. Further research concerning the complex molecular and neuropathological cascades following brain trauma should be conducted, as novel therapeutic strategies continue to be developed.

Animals↗

PubMed2003

Involvement of precerebellar nuclei in multiple system atrophy.

In this semiquantitative study based on 26 post-mortem cases, we describe the involvement of precerebellar nuclei in multiple system atrophy (MSA), a progressive degenerative disorder of the human central nervous system characterized by abnormal, argyrophilic and alpha-synuclein immunopositive intracellular inclusions within selectively vulnerable oligodendrocytes and nerve cells. The Campbell-Switzer silver-pyridine technique with alpha-synuclein immunoreactions using 100-microm thick sections is recommended over more conventional methods, thereby permitting visualization of the pertinent lesions in greater detail and facilitating post-mortem diagnosis of MSA specimens. Affected oligodendrocytes occur in specific fibre tracts and grey matters, with most pathology being observed in projections from the precerebellar nuclei to the cerebellum (ponto-cerebellar, olivo-cerebellar, reticulo-cerebellar tracts) and in descending/ascending fibre tracts of the motor system (cortico-pontine, cortico-bulbar, cortico-spinal, spino-reticular, spino-olivary, spino-cerebellar tracts). Three types of abnormal intraneuronal aggregations occur: (i) a loosely woven network within the cell nucleus; (ii) a latticework accumulating in peripheral portions of the cell body; and (iii) irregularly outlined patches of compact, intensely argyrophilic material usually located within deposits of lipofuscin granules. Counter-staining for the presence of extraneuronal lipofuscin can aid neuropathologists in the recognition of lost existent neurones in MSA. Neurones with inclusion bodies occur in the inferior olivary nuclear complex, lateral reticular nucleus, external cuneate nucleus, conterminal nucleus, interfascicular nucleus, nucleus of Roller, dorsal paramedian reticular nucleus, subventricular nucleus, arcuate nucleus, pontobulbar body and pontine grey. The lateral reticular nucleus and accessory nuclei of the inferior olive sustain the most damage and reveal prominent neuronal loss, followed by the pontobulbar body and arcuate nucleus. The uniformly bilateral damage and, in some cases, even obliteration of the nuclei studied, supply additional evidence for the pathoanatomical substrata of the cerebellar dysfunction that reportedly emerges in the clinical course of MSA.

Aged↗

PubMed2003

Pathological inclusion bodies in tauopathies contain distinct complements of tau with three or four microtubule-binding repeat domains as demonstrated by new specific monoclonal antibodies.

Pathological inclusions containing fibrillar aggregates of hyperphosphorylated tau protein are a characteristic feature in the tauopathies, which include Alzheimer's disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), progressive supranuclear palsy, corticobasal degeneration and Pick's disease. Tau isoform composition and cellular and regional distribution as well as morphology of these inclusions vary in each disorder. Recently, several pathological missense and exon 10 splice-donor site mutations of the tau gene were identified in FTDP-17. Exon 10 codes for the second of four microtubule-binding repeat domains. The splice-site mutations result in increased inclusion of exon 10 which causes a relative increase in tau isoforms containing four microtubule-binding repeat domains over those containing three repeat domains. This could be a central aetiological mechanism in FTDP-17 and, perhaps, other related tauopathies. We have investigated changes in the ratio and distribution of three-repeat and four-repeat tau in the different tauopathies as a basis of the phenotypic range of these disorders and the selective vulnerability of different subsets of neurones. In this study, we have developed two monoclonal antibodies, RD3 and RD4 that effectively distinguish these closely related tau isoforms. These new isoform-specific antibodies are useful tools for analysing tau isoform expression and distribution as well as pathological changes in the human brain.

Animals↗

PubMed2002

Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia.

RNA expression profiles in rat brain were examined 24 h after ischemic stroke, intracerebral haemorrhage, kainate-induced seizures, insulin-induced hypoglycemia, and hypoxia and compared to sham- or untouched controls. Rat oligonucleotide microarrays were used to compare expression of over 8000 transcripts from three subjects in each group (n = 27). Of the somewhat less than 4000 transcripts called 'present' in normal or treated cortex, 5-10% of these were up-regulated 24 h after ischemia (415), haemorrhage (205), kainate (187), and hypoglycemia (302) with relatively few genes induced by 6 h of moderate (8% oxygen) hypoxia (15). Of the genes induced 24 h after ischemia, haemorrhage, and hypoglycemia, approximately half were unique for each condition suggesting unique components of the responses to each of the injuries. A significant component of the responses involved immune-process related genes likely to represent responses to dying neurons, glia and vessels in ischemia; to blood elements in haemorrhage; and to the selectively vulnerable neurons that die after hypoglycemia. All of the genes induced by kainate were also induced either by ischemia, haemorrhage or hypoglycemia. This strongly supports the concept that excitotoxicity not only plays an important role in ischemia, but is an important mechanism of brain injury after intracerebral haemorrhage and hypoglycemia. In contrast, there was only a single gene that was down-regulated by all of the injury conditions suggesting there is not a common gene down-regulation response to injury.

Animals↗

PubMed2002

Impaired acquisition in the water maze and hippocampal long-term potentiation after chronic prenatal ethanol exposure in the guinea-pig.

In the hippocampus, the CA1 region is selectively vulnerable to the effects of chronic prenatal ethanol exposure. In the guinea-pig, the number of CA1 pyramidal cells is decreased after chronic prenatal ethanol exposure. We tested the hypotheses that chronic prenatal ethanol exposure (through maternal ethanol ingestion) results in impairments in spatial learning and short- and long-term plasticity in the CA1 region of the postnatal guinea-pig hippocampus. Timed, pregnant guinea-pigs were treated with ethanol (4 g/kg maternal body weight/day), isocaloric sucrose/pair-feeding, or water throughout gestation. Offspring were studied between postnatal days 40 and 80. In the Morris water maze, animals exposed to ethanol prenatally showed slower acquisition of an escape response to a hidden platform over 5 days of training. The amplitude of the field excitatory postsynaptic potential in the CA1 region in response to contralateral CA3 stimulation was decreased in offspring exposed to ethanol prenatally. Two forms of short-term plasticity (paired-pulse and frequency facilitation) were unaffected by chronic prenatal ethanol exposure. Long-term potentiation (LTP) in response to high-frequency CA3 stimulation was induced reliably and maintained over 60 min in isocaloric-sucrose and water control animals. However, LTP failed to be induced in the CA1 area of the hippocampus in prenatal ethanol-exposed offspring. These data show that chronic prenatal ethanol exposure, through maternal ethanol administration, impairs spatial performance and LTP in CA1 neurons. Hippocampal dysfunction could contribute importantly to the cognitive and behavioural deficits resulting from chronic prenatal ethanol exposure.

Alcohol-Induced Disorders, Nervous System↗

PubMed1998

Postischemic changes of

Sequential alterations of [3H]nimodipine and [3H]ryanodine binding in gerbils were investigated in selectively vulnerable regions, such as the striatum and hippocampus, 1 h to 7 days after 10 min of transient cerebral ischemia. [3H]Nimodipine binding showed no significant changes in the striatum and hippocampus up to 48 h after ischemia. Seven days after ischemia, however, a severe reduction in [3H]nimodipine binding was observed in the dorsolateral striatum, hippocampal CA1 (stratum oriens, stratum pyramidale and stratum radiatum) and hippocampal CA3 sector. On the other hand, [3H]ryanodine binding showed a significant increase in the hippocampus 1 h after ischemia. Five hours after ischemia, a significant reduction in [3H]ryanodine binding was observed only in the hippocampal CA1 sector. Thereafter, the striatum and hippocampus showed no significant alterations in [3H]ryanodine binding up to 48 h after ischemia. After 7 days, a marked reduction in [3H]ryanodine binding was observed in the striatum and hippocampus which were particularly vulnerable to ischemia. These results demonstrate that postischemic alteration in [3H]nimodipine and [3H]ryanodine binding is produced with different processes in the hippocampus. They also suggest that the mechanism for striatal cell damage caused by transient cerebral ischemia may, at least in part, differ from that for hippocampal neuronal damage. Furthermore, our findings suggest that abnormal calcium release from intracellular stores may play a pivotal role in the development of hippocampal neuronal damage. Copyright Rapid Science Ltd

Journal Article↗

PubMed1994

Might migraine damage the brain?

Recent debate concerning the interpretation of studies of regional cerebral blood flow in migraine has re-emphasized that cerebral ischaemia may occur during attacks of migraine with aura. In this article we suggest that the presence of ischaemia during attacks makes it possible that migraine with aura causes neuronal damage in the long term. We argue that damage is likely to occur in the primary visual cortex, given that a recent high-resolution rCBF study has found flow reductions confined to this area. Furthermore, we hypothesize that the extent to which rCBF is reduced in migraine with aura is sufficient to cause damage only to GABA-ergic inhibitory interneurons in layer IV of this cortex. In animal models, similar cells are known to be selectively vulnerable to damage as a result of hypoxic conditions. Evidence consistent with our hypothesis is provided by recent studies of visual function in migraine. Some clinical and pathophysiological implications of this hypothesis are discussed.

Animals↗

PubMed2000

Bcl-2, tissue transglutaminase and p53 protein expression in the apoptotic cascade in ribs of premature infants.

Apoptotic cells of the human growth plate have not previously been demonstrated in situ. We have investigated the distribution of apoptotic cells in costosternal growth plates and bone of premature infants aged 4-11 d with a gestational age of approximately 26 wk. In addition, we investigated the immunolocalisation of apoptosis-related proteins within the growth plates and associated bone. A proportion of late hypertrophic chondrocytes and osteocytes within newly formed primary spongiosa showed evidence of highly fragmented DNA. The incidence of osteocyte apoptosis decreased as the distance from the chondroosseous junction increased. Tissue transglutaminase (tTG) expression was associated with apoptosis of osteocytes and hypertrophic chondrocytes. In contrast the presence of tTG was demonstrated in osteoblasts and bone lining cells but it did not colocalise with evidence of apoptosis. The anti-apoptotic gene product Bcl-2 was absent from the growth plate but was present in osteocytes. Visual assessment indicated a greater occurrence of the protein in cells occupying regions of low apoptosis. P53 was not demonstrated in the growth plate or bone. These findings would indicate that human growth plate chondrocytes appear to show little provision for ensuring cell longevity. In contrast osteocyte apoptosis appears negatively correlated with the skeletal distribution of Bcl-2 protein in the human infant, implying a potential selective vulnerability in individual cells. Lack of Bcl-2 and the high incidence of osteocyte apoptosis in the more rapidly remodelling bone of the human infant suggest a potential role of osteocyte apoptosis in the remodelling process.

Apoptosis↗

PubMed1999

In situ detection of neuronal DNA strand breaks using the Klenow fragment of DNA polymerase I reveals different mechanisms of neuron death after global cerebral ischemia.

Ischemic cell injury in the brain may involve a cascade of programmed cell death. DNA damage may be either a catalyst or a consequence of this cascade. Therefore, the induction of DNA strand breaks in the rat brain following transient global ischemia was examined using (a) the Klenow labeling assay, identifying DNA single-strand breaks (SSBs) or double-strand breaks (DSBs) with protruding 5' termini, and (b) terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL), detecting DNA DSBs with protruding 3' termini or blunt ends. Klenow-positive staining occurred within 2 h of reperfusion and increased with increasing durations of reperfusion. DNA damage detected with the Klenow labeling assay preceded that of TUNEL expression in the caudate putamen, reticular thalamus, thalamus, and cortex. However, in CA1, DNA SSBs were not detected until 72 h of reperfusion and occurred simultaneously with DSBs. Thus, the time course and fragmentation characteristics of DNA damage differ between the hippocampal CA1 and other selectively vulnerable brain regions. This distinct pattern suggests that the delayed neuronal death in CA1 following transient global ischemia may occur via an apoptotic mechanism different from that of other brain regions.

Animals↗

PubMed1999

Subtype-specific enhancement of NMDA receptor currents by mutant huntingtin.

Evidence suggests that NMDA receptor-mediated neurotoxicity plays a role in the selective neurodegeneration underlying Huntington's disease (HD). The gene mutation that causes HD encodes an expanded polyglutamine tract of >35 in huntingtin, a protein of unknown function. Both huntingtin and NMDA receptors interact with cytoskeletal proteins, and, for NMDA receptors, such interactions regulate surface expression and channel activity. To determine whether mutant huntingtin alters NMDA receptor expression or function, we coexpressed mutant or normal huntingtin, containing 138 or 15 glutamine repeats, respectively, with NMDA receptors in a cell line and then assessed receptor channel function by patch-clamp recording and surface expression by western blot analysis. It is interesting that receptors composed of NR1 and NR2B subunits exhibited significantly larger currents when coexpressed with mutant compared with normal huntingtin. Moreover, this effect was selective for NR1/NR2B, as NR1/NR2A showed similar currents when coexpressed with mutant versus normal huntingtin. However, ion channel properties and total surface expression of the NR1 subunit were unchanged in cells cotransfected with NR1/NR2B and mutant huntingtin. Our results suggest that mutant huntingtin may increase numbers of functional NR1/NR2B-type receptors at the cell surface. Because NR1/NR2B is the predominant NMDA receptor subtype expressed in medium spiny neostriatal neurons, our findings may help explain the selective vulnerability of these neurons in HD.

Cell Line↗

PubMed1999

Relationship between seizure-induced transcription of the DNA damage-inducible gene GADD45, DNA fragmentation, and neuronal death in focally evoked limbic epilepsy.

We investigated the temporal and spatial profile of mRNA transcription for the growth arrest and DNA damage-inducible gene GADD45, DNA fragmentation, and neuronal death in rat brain following focally evoked limbic seizures. GADD45 mRNA was detected by in situ hybridization, whereas fragmented DNA was detected using in situ nick end-labeling by the large (Klenow) fragment of DNA polymerase I. Kainic acid (0.1 microg) was injected into the right amygdala of rats to induce seizures for 45 min, after which diazepam (30 mg/kg) was administered. GADD45 mRNA, DNA fragmentation, and cell death were quantified bilaterally within six limbic brain regions 0-96 h following seizure cessation. All animals underwent seizures of equivalent severity and duration as determined electrographically. In situ hybridization detected bilateral up-regulation of GADD45 mRNA throughout the CA1, CA3, and dentate gyrus of the hippocampus, the piriform and retrosplenial cortices, and the thalamus within 1 h of seizure termination. GADD45 mRNA levels remained elevated for up to 6 h, declining to baseline within all structures by 16 h. Klenow-positive cells were only found within the CA3 pyramidal layer of the ipsilateral hippocampus and appeared 16-72 h following seizure cessation. Morphologic cell death was also restricted to the CA3 subfield. These data demonstrate that focally evoked limbic seizures trigger early bihemispheric GADD45 mRNA transcription within connected limbic structures, whereas subsequent DNA fragmentation and cell death are restricted to selectively vulnerable brain regions.

Amygdala↗

PubMed1999

Peroxynitrite- and nitrite-induced oxidation of dopamine: implications for nitric oxide in dopaminergic cell loss.

Increased nitric oxide (NO) production has been implicated in many examples of neuronal injury such as the selective neurotoxicity of methamphetamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to dopaminergic cells, presumably through the generation of the potent oxidant peroxynitrite (ONOO). Dopamine (DA) is a reactive molecule that, when oxidized to DA quinone, can bind to and inactivate proteins through the sulfhydryl group of the amino acid cysteine. In this study, we sought to determine if ONOO could oxidize DA and participate in this process of protein modification. We measured the oxidation of the catecholamine by following the binding of [3H]DA to the sulfhydryl-rich protein alcohol dehydrogenase. Results showed that ONOO oxidized DA in a concentration- and pH-dependent manner. We confirmed that the resulting DA-protein conjugates were predominantly 5-cysteinyl-DA residues. In addition, it was observed that ONOO decomposition products such as nitrite were also effective at oxidizing DA. These data suggest that the generation of NO and subsequent formation of ONOO or nitrite may contribute to the selective vulnerability of dopaminergic neurons through the oxidation of DA and modification of protein.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2000

Expression of 15 glutamate receptor subunits and various splice variants in tissue slices and single neurons of brainstem nuclei and potential functional implications.

Brainstem nuclei serve a diverse array of functions in many of which ionotropic glutamate receptors are known to be involved. However, little detailed information is available on the expression of different glutamate receptor subunits in specific nuclei. We used RT-PCR in mice to analyze the glutamate receptor subunit composition of the pre-Bötzinger complex, the hypoglossal nucleus, the nucleus of the solitary tract, and the inferior olive. Analyzing 15 receptor subunits and five variants, we found all four alpha-amino-3-hydroxy-5-methyl-4-propionic acid (AMPA) and six NMDA receptor (NR) subunits as well as three of five kainate (KA) receptors (GluR5, GluR6, and KA1) to be expressed in all nuclei. However, some distinct differences were observed: The inferior olive preferentially expresses flop variants of AMPA receptors, GluR7 is more abundant in the pre-Bötzinger complex than in the other nuclei, and NR2C is most prominent in the nucleus of the solitary tract. In single hypoglossal motoneurons and interneurons of the pre-Bötzinger complex investigation of GluR2 editing revealed strong expression of the GluR2-R editing variant, suggesting low Ca2+ permeability of AMPA receptors. Thus, Ca2+-permeable AMPA receptors are unlikely to be the cause for the reported selective vulnerability of hypoglossal motoneurons during excitotoxic events.

Alternative Splicing↗

PubMed2001

Bax kappa, a novel Bax splice variant from ischemic rat brain lacking an ART domain, promotes neuronal cell death.

Bax is a pro-apoptotic Bcl-2 family protein that regulates programmed cell death through homodimerization and through heterodimerization with Bcl-2. Bax alpha is encoded by six exons and undergoes alternative splicing. Bax kappa, a splice variant of Bax with conserved BH1, BH2 and BH3 binding domains and a C-terminal transmembrane domain (TM), but with an extra 446-bp insert between exons 1 and 2 leading to loss of an N-terminal ART domain, was identified from an ischemic rat brain cDNA library. Expression of Bax kappa mRNA and protein was up-regulated in hippocampus after cerebral ischemic injury. The increased Bax kappa mRNA was distributed mainly in selectively vulnerable hippocampal CA1 neurons that are destined to die after global ischemia. Overexpression of Bax kappa protein in HN33 mouse hippocampal neuronal cells induced cell death, which was partially abrogated by co-overexpression of Bcl-2. Moreover, co-overexpression of Bax kappa and Bax alpha increased HN33 cell death. The results suggest that the Bax kappa may have a role in ischemic neuronal death.

Alternative Splicing↗

PubMed2001

Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases.

Oxidative stress generated by dopamine (DA) oxidation could be one of the factors underlying the selective vulnerability of nigral dopaminergic neurons in Parkinson's diseases. Here we show that DA induces apoptosis in SH-SY5Y neuroblastoma cells demonstrated by activation of caspase-9 and caspase-3, cleavage of poly(ADP-ribose) polymerase as well as nuclear condensation. We also show that p38 mitogen-activated protein kinase is activated within 10 min of DA treatment, which precedes the onset of apoptosis because the potent p38 kinase inhibitor SB203580 protects against DA-induced cell death as well as against caspase-9 and caspase-3 activation. In addition, the antioxidant N-acetyl-L-cysteine (NAC) effectively blocks DA-induced p38 kinase activation, caspase-9 and caspase-3 cleavage and subsequent apoptosis, indicating that DA triggers apoptosis via a signaling pathway that is initiated by the generation of reactive oxygen species (ROS). Dopamine exerts its toxicity principally intracellularly as the DA uptake inhibitor, nomifensine significantly reduces DA-induced cell death as well as activation of p38 kinase and caspase-3. Furthermore, DA induces mitochondrial cytochrome c release, which is dependent on p38 kinase activation and precedes the cleavage of caspases. These observations indicate that DA induces apoptosis primarily by generating ROS, p38 kinase activation, cytochrome c release followed by caspase-9 and caspase-3 activation.

Acetylcysteine↗

PubMed2003

Rat hippocampal GABAergic molecular markers are differentially affected by ageing.

We previously reported that the pharmacological properties of the hippocampal GABAA receptor and the expression of several subunits are modified during normal ageing. However, correlation between these post-synaptic modifications and pre-synaptic deficits were not determined. To address this issue, we have analysed the mRNA levels of several GABAergic molecular markers in young and old rat hippocampus, including glutamic acid decarboxylase enzymes, parvalbumin, calretinin, somatostatin, neuropeptide Y and vasoactive intestinal peptide (VIP). There was a differential age-related decrease in these interneuronal mRNAs that was inversely correlated with up-regulation of the alpha1 GABA receptor subunit. Somatostatin and neuropeptide Y mRNAs were most frequently affected (75% of the animals), then calretinin and VIP mRNAs (50% of the animals), and parvalbumin mRNA (25% of the animals) in the aged hippocampus. This selective vulnerability was well correlated at the protein/cellular level as analysed by immunocytochemistry. Somatostatin interneurones, which mostly innervate principal cell distal dendrites, were more vulnerable than calretinin interneurones, which target other interneurones. Parvalbumin interneurones, which mostly innervate perisomatic domains of principal cells, were preserved. This age-dependent differential reduction of specific hippocampal inteneuronal subpopulations might produce functional alterations in the GABAergic tone which might be compensated, at the post-synaptic level, by up-regulation of the expression of the alpha1 GABAA receptor subunit.

Aging↗