GABA(B) receptor GTP-binding is decreased in the prefrontal cortex but not the hippocampus of aged rats

Gamma aminobutyric acid (GABA)(B) receptors (GABA(B)Rs) have been linked to a wide range of physiological and cognitive processes and are of interest for treating a number of neurodegenerative and psychiatric disorders. As many of these diseases are associated with advanced age, it is important to understand how the normal aging process impacts GABA(B)R expression and signaling. Thus, we investigated GABA(B)R expression and function in the prefrontal cortex (PFC) and hippocampus of young and aged rats characterized in a spatial learning task. Baclofen-stimulated GTP-binding and GABA(B)R1 and GABA(B)R2 proteins were reduced in the prefrontal cortex of aged rats but these reductions were not associated with spatial learning abilities. In contrast, hippocampal GTP-binding was comparable between young and aged rats but reduced hippocampal GABA(B)R1 expression was observed in aged rats with spatial learning impairment. These data demonstrate marked regional differences in GABA(B)R complexes in the adult and aged brain and could have implications for both understanding the role of GABAergic processes in normal brain function and the development of putative interventions that target this system.     

Involvement of GABA(B) receptors of the dorsal hippocampus on the acquisition and expression of morphine-induced place preference in rats

In the present study, effects of intra-hippocampal CA1 (intra-CA1) injections of GABA(B) receptor agonist and antagonist on the acquisition and expression of morphine-induced place preference in male Wistar rats have been investigated. Subcutaneous administration of different doses of morphine sulphate (0.5-6 mg/kg) produced a dose-dependent conditioned place preference (CPP). Using a 3-day schedule of conditioning, it was found that the GABA(B) receptor agonist, baclofen (0.5-2 microg/rat; intra-CA1), or the GABA(B) receptor antagonist, phaclofen (1-3 microg/rat; intra-CA1), did not produce a significant place preference or place aversion. Intra-CA1 administration of baclofen (1 and 2 microg/rat; intra-CA1) decreased the acquisition of CPP induced by morphine (3 mg/kg; s.c.). On the other hand, intra-CA1 injection of phaclofen (1 and 2 microg/rat; intra-CA1) in combination with a lower dose of morphine (1 mg/kg) elicited a significant CPP. The response of baclofen (2 microg/rat; intra-CA1) was reversed by phaclofen (4 and 6 microg/rat; intra-CA1). Furthermore, intra-CA1 administration of baclofen but not phaclofen before testing significantly decreased the expression of morphine (3 mg/kg; s.c.)-induced place preference. Baclofen or phaclofen injections had no effects on locomotor activity on the testing sessions. It is concluded that the GABA(B) receptors in dorsal hippocampus may play an active role in morphine reward.     

The role of the GABA(B) receptor and calcium channels in a Drosophila model of Parkinson's Disease

Transgenic Drosophila melanogaster carrying the human gene for alpha synuclein is an animal model for the study of Parkinson's Disease. Climbing activity in these flies is reduced as a result of the effect of this protein on the locomotor activity of the transgenic fly. L-DOPA and gamma amino butyric acid (GABA) reverse the loss of this activity when placed in the food fed to these flies. While muscimol, a GABA(A) receptor agonist has no effect in this system, baclofen and the allosteric agonists CG 7930 and GS 39783 which affect the GABA(B) receptor reverse this activity. This latter effect is eliminated when these compounds are fed in conjunction with the GABA(B) receptor antagonist 2-hydroxysaclofen. In addition, fendiline which is a Ca(++) receptor blocker also reverses the loss of climbing ability. Because there is a calcium channel close to the GABA(B) receptor on the cell surface, these data are indicative of a relationship between the roles of the GABA(B) receptor, the calcium channel and the effect of alpha-synuclein on the motor activity of the transgenic fly.     

Association analysis of exonic variants of the GABA(B)-receptor gene and alpha electroencephalogram voltage in normal subjects and alcohol-dependent patients

Based on pharmacologic evidence, it has been suggested that GABA_B receptors may play a crucial role in the generation of alpha-electroencephalogram (EEG) oscillations. We tested whether three exonic variants of the gene encoding the human GABA_B receptor (GABA_BR1) modify scalp-recorded alpha-EEG voltage. One hundred twenty-eight patients suffering from alcoholism and 114 normal subjects were investigated. Alcohol-dependent patients were included because evidence exists that the frequently observed alpha low voltage in these subjects is at least partly a trait variable. Logistic regression analyses revealed no associations between alpha-EEG voltage and polymorphic variations in exon 1a1 or exon 11. A significant interaction was observed for an exon 7 substitution polymorphism and diagnosis (P = 0.009). Post hoc analyses showed an association between EEG phenotype and exon 7 genotype in normal subjects only. It is concluded that this particular association may only be observable under physiologic conditions and that alpha low voltage in alcohol-dependent subjects is under the control of either different genes or that it is related to the disease process.     

Subregional analysis of GABA(A) receptor subunit mRNAs in the hippocampus of older persons with and without cognitive impairment

We employed in situ hybridization and quantitative densitometry techniques to examine hippocampal mRNA expression of GABA(A) receptor subunits alpha1 and alpha5 in human subjects with progressing cognitive impairment. Included in this study were 17 participants of the Religious Order Study (ROS), who were categorized into three groups based upon degree of cognitive impairment: no cognitive impairment (n = 6); moderate cognitive impairment (n = 5); and probable Alzheimer's disease (AD) (n = 6). While the levels of each specific subunit mRNA were relatively homogeneously distributed throughout the five hippocampal subregions analyzed (CA1-4, and the granule cell layer of the dentate gyrus), mRNA expression of the alpha1 receptor subunit was found to be 20% reduced in the moderate cognitive impairment group as compared to the no cognitive impairment group. In addition, alpha1 mRNA expression was 25% reduced in the probable Alzheimer's disease group compared to the group with no cognitive impairment. Similarly, alpha5 subunit mRNA was reduced 32% between no cognitive impairment and moderate cognitive impairment groups, and 35% between no cognitive impairment and probable Alzheimer's disease groups. No significant reductions were found between moderate cognitive impairment and probable Alzheimer's disease groups for either subunit. Collectively, our data provide evidence for modest reductions in GABA(A) receptor subunit mRNAs, and suggest these changes occur very early in the progression of Alzheimer's disease cognitive impairment.     

Genetic deletion or antagonism of kinin B(1) and B(2) receptors improves cognitive deficits in a mouse model of Alzheimer's disease

Increased brain deposition of amyloid beta protein (Abeta) and cognitive deficits are classical signs of Alzheimer's disease (AD) that have been widely associated to inflammatory response. We have recently shown that a single i.c.v. injection of aggregated beta-amyloid peptide-(1-40) (Abeta(1-40)) (400 pmol/mouse) results in marked deficits of learning and memory in mice which are related to oxidative stress and synaptic dysfunction. In the present study, we investigated by means of genetic or pharmacological approaches the role of kinin system in the Abeta(1-40) cognitive effects on the water maze paradigm. Spatial learning and memory deficits observed at 7 days following Abeta(1-40) treatment were significantly reduced by the i.c.v. administration of the selective kinin B(2) receptor antagonist d-Arg-[Hyp(3),Thi(5),D-Tic(7),Oic(8)]-BK (Hoe 140). A similar effect was found in mice lacking kinin B(2) receptor. On the other hand, genetic deletion of the inducible kinin B(1) receptor or its blockage by i.c.v. injection of des-Arg(9)-[Leu(8)]-BK antagonist attenuated only the long-term (30 days after treatment) cognitive deficits induced by Abeta(1-40). Moreover, treatment with Abeta(1-40) resulted in a sustained increase in the expression of the kinin B(1) receptor in the hippocampus and prefrontal cortex of mice, while it did not alter the expression of the kinin B(2) receptor in these brain areas. These findings provide convincing evidence that kinins acting via activation of B(1) and B(2) receptors in the CNS exert a critical role in the spatial learning and memory deficits induced by Abeta peptide in mice. Therefore, selective kinin receptor antagonists, especially the new orally active non-peptide antagonists, might represent drugs of potential interest for the treatment of AD.     

mRNA expression and RNA editing (2451 C-to-U) of IL-12 receptor beta2 in adult atopic patients

Interleukin (IL)-12 activates T helper (Th) 1 cells to produce interferon (IFN)-gamma which inhibits atopic inflammation. IL-12 acts through interaction with its receptor, especially beta(2) subunit. In several studies, the low production of IFN-gamma in peripheral mononuclear cells of atopic patients on response to IL-12 stimulation has been reported. Therefore we investigated the IL-12 receptor beta(2) (IL-12R beta(2)) mRNA expression and RNA editing, nucleotide 2451 C-to-U conversion, to find the cause of low responsiveness to IL-12 in atopy. Quantitative real time PCR for mRNA expression and sequence analysis for RNA editing were performed in 80 atopic patients and 54 healthy controls. The expression of IL-12R beta(2) mRNA was significantly lower in atopic patients than healthy controls (p<0.05). In sequence analysis, RNA editing on nucleotide 2451 was not found from either atopic patients or healthy controls. In additional evaluation, there was no relationship between expression of IL-12R beta(2) mRNA and serum total IgE or blood eosinophil count. Reduced IL-12R beta(2) mRNA expression in atopic patients indicate the reduced capacity to respond to IL-12 which induce IFN-gamma production and this may contribute to Th2-skewed immune response in atopy.     

Membrane lipid interactions in intestinal ischemia/reperfusion-induced Injury

Ischemia, lack of blood flow, and reperfusion, return of blood flow, are a common phenomenon affecting millions of Americans each year. Roughly 30,000 Americans per year experience intestinal ischemia-reperfusion (IR), which is associated with a high mortality rate. Previous studies of the intestine established a role for neutrophils, eicosanoids, the complement system and naturally occurring antibodies in IR-induced pathology. Furthermore, data indicate involvement of a lipid or lipid-like moiety in mediating IR-induced damage. It has been proposed that antibodies recognize exposure of neo-antigens, triggering action of the complement cascade. While it is evident that the pathophysiology of IR-induced injury is complex and multi-factorial, we focus this review on the involvement of eicosanoids, phospholipids and neo-antigens in the early pathogenesis. Lipid changes occurring in response to IR, neo-antigens exposed and the role of a phospholipid transporter, phospholipid scramblase 1 will be discussed.     

Glycine and glycine receptor signaling in hippocampal neurons: Diversity,function and regulation

Glycine is a primary inhibitory neurotransmitter in the spinal cord and brainstem. It acts at glycine receptor (GlyR)-chloride channels, as well as a co-agonist of NMDA receptors (NMDARs). In the hippocampus, the study of GlyRs has largely been under-appreciated due to the apparent absence of glycinergic synaptic transmission. Emerging evidence has shown the presence of extrasynaptic GlyRs in the hippocampus, which exert a tonic inhibitory role, and can be highly regulated under many pathophysiological conditions. On the other hand, besides d-serine, glycine has also been shown to modulate NMDAR function in the hippocampus. The simultaneous activation of excitatory NMDARs and inhibitory GlyRs may provide a homeostatic regulation of hippocampal network function. Furthermore, glycine can regulate hippocampal neuronal activity through GlyR-mediated cross-inhibition of GABAergic inhibition, or through the glycine binding site-dependent internalization of NMDARs. Therefore, hippocampal glycine and its receptors may operate in concert to finely regulate hippocampus-dependent high brain function such as learning and memory. Finally, dysfunction of hippocampal glycine signaling is associated with neuropsychiatric disorders. We speculate that further studies of hippocampal glycine-mediated regulation may help develop novel glycine-based approaches for therapeutic developments.     

Stoichiometric analysis of the TM2 6' phenylalanine mutation on desensitization in alpha1beta2 and alpha1beta2gamma2 GABA A receptors

The presence of phenylalanine (F) at the 6' position of transmembrane domain 2 (TM2) in the alpha4 subunit of alpha4beta2 nicotinic receptors enhances desensitization. As the GABA A receptor affords the ability to study the influence of as few as one and as many as five Fs at this position, we have used it to investigate potential subunit- and stoichiometry-dependent effects of the TM2 6'F mutation on desensitization. Whereas the presence of one F at this position decreased extent of desensitization, desensitization was increased in all configurations that included two or more Fs at the TM2 6' position; desensitization was particularly rapid with 3 or 4 F residues present. Our results demonstrate the ability of F residues at the TM2 6' position to modulate desensitization is likely conserved in the cys-loop family of ligand-gated ion channels. Moreover, our findings demonstrate both stoichiometric- and subunit-dependent effects of the ability of this mutation to regulate desensitization in GABA A receptors.     

Synaptic activity-induced Ca(2+) signaling in avian cochlear nucleus magnocellularis neurons

Neurons of the avian cochlear nucleus magnocellularis (NM) receive glutamatergic inputs from the spiral ganglion cells via the auditory nerve and feedback GABAergic inputs primarily from the superior olivary nucleus. We investigated regulation of Ca²⁺ signaling in NM neurons with ratiometric Ca²⁺ imaging in chicken brain slices. Application of exogenous glutamate or GABA increased the intracellular Ca²⁺ concentration ([Ca²⁺]_i) in NM neurons. Interestingly, GABA-induced Ca²⁺ responses persisted into neuronal maturation, in both standard and energy substrate enriched artificial cerebrospinal fluid. More importantly, we found that electrical stimulation applied to the glutamatergic and GABAergic afferent fibers innervating the NM was able to elicit transient [Ca²⁺]_i increases in NM neurons, and the amplitude of the Ca²⁺ responses increased with increasing frequency and duration of the electrical stimulation. Antagonists for ionotropic glutamate receptors significantly blocked these [Ca²⁺]_i increases, whereas blocking GABA_A receptors did not affect the Ca²⁺ responses, suggesting that synaptically released glutamate but not GABA induced the Ca²⁺ signaling in vitro. Furthermore, activation of GABA_A receptors with exogenous agonists inhibited synaptic activity-induced [Ca²⁺]_i increases in NM neurons, suggesting a role of GABA_A receptors in the regulation of Ca²⁺ homeostasis in the avian cochlear nucleus neurons.     

A subpopulation of serotonin1B receptors colocalize with the AMPA receptor subunit GluR2 in the hippocampal dentate gyrus

The serotonin_1B receptor (5-HT_1BR) plays a role in cognitive processes that also involve glutamatergic neurotransmission via amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptors. Accumulating experimental evidence also highlights the involvement of 5-HT_1BRs in several neurological disorders. Consequently, the 5-HT_1BR is increasingly implicated as a potential therapeutic target for intervention in cognitive dysfunction. Within the hippocampus, a brain region critical to cognitive processing, populations of pre- and post-synaptic 5-HT_1BRs have been identified. Thus, 5-HT_1BRs could have a role in the modulation of hippocampal pre- and post-synaptic conductance. Previously, we demonstrated colocalization of 5-HT_1BRs with the N-methyl-d-aspartate (NMDA) receptor subunit NR1 in a subpopulation of granule cell dendrites (Peddie et al. [53]). In this study, we have examined the cellular and subcellular distribution of 5-HT_1BRs with the AMPA receptor subunit GluR2. Of 5-HT_1BR positive profiles, 28% displayed colocalization with GluR2. Of these, 87% were dendrites, corresponding to 41% and 10% of all 5-HT_1BR labeled or GluR2 labeled dendrites, respectively. Dendritic labeling was both cytoplasmic and membranous but was not usually associated with synaptic sites. Colocalization within dendritic spines and axons was comparatively rare. These findings indicate that within the dentate gyrus molecular layer, dendritic 5-HT_1BRs are expressed predominantly on GluR2 negative granule cell processes. However, a subpopulation of 5-HT_1BRs is expressed on GluR2 positive dendrites. Here, it is suggested that activation of the 5-HT_1BR may play a role in the modulation of AMPA receptor mediated conductance, further supporting the notion that the 5-HT_1BR represents an interesting therapeutic target for modulation of cognitive function.     

B type CpG-DNA suppresses poly(I:C)-induced BLyS expression and production in human tonsillar fibroblasts

Although B lymphocyte stimulator (BLyS) has potent costimulatory effects on B cells, the details of BLyS-expression in tonsillar fibroblasts remain unexplored. We examined the effect of the Toll-like receptor (TLR) ligands on BLyS-expression in human tonsillar fibroblasts as well as the crosstalk that occurs among different TLR ligands. The expression of BLyS mRNA by tonsillar fibroblasts was strongly induced in the presence of polyinosinic–polycytidylic acid (poly(I:C)) that is a ligand, of TLR3. We also revealed that DNA containing CpG motifs (CpG-DNA), coding for a TLR9 ligand, markedly suppressed the poly(I:C)-induced mRNA expression and protein production of BLyS. B type CpG-DNA decreased the poly(I:C)-induced phosphorylation of inhibitor kappa B alpha (IκBα) and its degradation. Pre-incubation with nuclear factor kappa B (NF-κB) signaling inhibitors reduced the poly(I:C)-induced BLyS-expression. These results indicate that human tonsillar fibroblasts strongly induce BLyS-expression and production that can be inhibited by CpG-DNA and regulated through NF-κB signaling.     

Cytoplasmic localization of p27 (cyclin-dependent kinase inhibitor 1B/KIP1) in colorectal cancer: inverse correlations with nuclear p27 loss, microsatellite instability, and CpG island methylator phenotype

Cytoplasmic mislocalization of p27 (CDKN1B/KIP1) is caused by activated AKT1 and has been associated with poor prognosis in various cancers. CIMP in colorectal cancer is characterized by extensive promoter methylation and is associated with MSI-MSI-H and BRAF mutations. We have recently shown a positive correlation between MSI/CIMP and loss of nuclear p27. However, no study has examined cytoplasmic p27 mislocalization in relation to CIMP and MSI in colorectal cancer. Using MethyLight assays, we quantified DNA methylation in 8 CIMP-specific gene promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) in 853 colorectal cancer samples obtained from 2 large prospective cohorts. We assessed expressions of nuclear and cytoplasmic p27 and nuclear p53 by immunohistochemistry. Cytoplasmic p27 expression was inversely associated with loss of nuclear p27 (P < .0001), CIMP-high (P < .0001), MSI-H (P < .0001), and BRAF mutations (P < .0001). The inverse association of cytoplasmic p27 with CIMP-high (or MSI-H) was independent of MSI (or CIMP) status. In addition, the inverse association of cytoplasmic p27 with CIMP-high was independent of KRAS/BRAF status. BRAF and CDKN2A (p16) methylation were not correlated with cytoplasmic p27 after stratification by CIMP status. The inverse associations of cytoplasmic p27 with MSI-H and CIMP-high were much more pronounced in p53-negative than p53-positive tumors. In conclusion, cytoplasmic p27 expression is inversely associated with MSI-H and CIMP-high, particularly in p53-negative tumors, suggesting interplay of functional losses of p27 and p53 in the development of various molecular subtypes of colorectal cancer.     

Differential distribution of γ-aminobutyric acidA, receptor subunit (α1, α2, α3, α5 and β2+3) immunoreactivity in the medial prefrontal cortex of the rat

A detailed mapping of the γ-aminobutyric acid (GABA)_A receptor subunits (α₁, α₂, α₃ and β₂₊₃) in the infralimbic/ventral prelimbic region (IL/vPL) of the rat frontal cortex was carried out using subunit-specific antibodies. The α₁ and β₂₊₃ subunit antibodies immunostained all layers of the IL/vPL region. Layers II and III displayed immunostaining of cell bodies whereas I, V and VI showed predominantly neuropil staining. The size of the α₁-positive cell bodies corresponded to that of small interneurons (range, 20–55 μm²; mean ± SEM, 37 ± 5.5 μm²) as well as pyramidal cells or large interneurons (range, 87–135 μm²; mean ± SEM, 103.4 ± 9.7 μm²). However, β₂₊₃ antibody immunostained only small cell bodies. Immunoreactivity for α₂ was restricted to layers I and II, whereas α₃ and α₅ subunit expression was seen only in layer VI. The antibody to the α₂ subunit immunostained small cell bodies (range, 29–63 μm²; mean ± SEM, 32 ± 4.5 μm²) in layer II, resembling interneurons. Conversely, both α₃ and α₅ antibodies immunostained large cell bodies (range, 94–151 gmm²; mean ± SEM, 115.7 ± 13.4 μm²), consistent with pyramidal cell labelling in layer VI.     

Defining the anatomical localisation of subsets of the murine mononuclear phagocyte system using integrin alpha X (Itgax, CD11c) and colony stimulating factor 1 receptor (Csf1r, CD115) expression fails to discriminate dendritic cells from macrophages

The murine mononuclear phagocyte (MNP) system comprises a diverse population of cells, including monocytes, dendritic cells (DC) and macrophages. Derived from the myeloid haematopoietic lineage, this group of cells express a variety of well characterized surface markers. Expression of the integrin alpha X (Itgax, CD11c) is commonly used to identify classical DC, and similarly expression of colony stimulating factor 1 receptor (Csf1r, CD115) to identify macrophages. We have characterized the expression of these markers using a variety of transgenic mouse models. We confirmed previous observations of Itgax expression in anatomically defined subsets of MNPs in secondary lymphoid organs, including all MNPs identified within the germinal centres. The majority of MNPs in the intestinal lamina propria and lung express Itgax. All mucosal Itgax expressing cells also express Csf1r suggesting Csf1-dependent haematopoietic derivation. This double-positive population included germinal centre MNPs. These data reveal that Itgax expression alone does not specifically define classical DC. These results suggest more cautious interpretation of Itgax-dependent experimentation and direct equation with uniquely DC-mediated activities, particularly in the functioning of non-lymphoid MNPs within the intestinal lamina propria.     

The serotonergic system in ageing and Alzheimer's disease

Alzheimer's disease (AD) is one of the major neurodegenerative diseases that deteriorates cognitive functions and primarily affects associated brain regions involved in learning and memory, such as the neocortex and the hippocampus. Following the discovery and establishment of its role as a neurotransmitter, serotonin (5-HT), was found to be involved in a multitude of neurophysiological processes including mnesic function, through its dedicated pathways and interaction with cholinergic, glutamatergic, GABAergic and dopaminergic transmission systems. Abnormal 5-HT neurotransmission contributes to the deterioration of cognitive processes in ageing, AD and other neuropathologies, including schizophrenia, stress, mood disorders and depression. Numerous studies have confirmed the pathophysiological role of the 5-HT system in AD and that several drugs enhancing 5-HT neurotransmission are effective in treating the AD-related cognitive and behavioural deficits. Here we present a comprehensive overview of the role of serotonergic neurotransmission in brain development, maturation and ageing, discuss its role in higher brain function and provide an in depth account of pathological modifications of serotonergic transmission in neurological diseases and AD.     

Repeated Baclofen treatment ameliorates motor dysfunction,suppresses reflex activity and decreases the expression of signaling proteins in reticular nuclei and lumbar motoneurons after spinal trauma in rats

The interruption of supraspinal input to the spinal cord leads to motor dysfunction and the development of spasticity. Clinical studies have shown that Baclofen (a GABA_B agonist), while effective in modulating spasticity is associated with side-effects and the development of tolerance. The aim of the present study was to assess if discontinued Baclofen treatment and its repeated application leads antispasticity effects, and whether such changes affect neuronal nitric oxide synthase (nNOS) in the brainstem, nNOS and parvalbumin (PV) in lumbar α-motoneurons and glial fibrillary acidic protein in the ventral horn of the spinal cord. Adult male Wistar rats were exposed to Th9 spinal cord transection. Baclofen (30 mg/b.w.) diluted in drinking water, was administered for 6 days, starting at week 1 after injury and then repeated till week 4 after injury. The behavior of the animals was tested (tail-flick test, BBB locomotor score) from 1 to 8 weeks. Our results clearly indicate the role of nitric oxide, produced by nNOS in the initiation and the maintenance of spasticity states 1, 6 and 8 weeks after spinal trauma. A considerable decrease of nNOS staining after Baclofen treatment correlates with improvement of motor dysfunction. The findings also show that parvalbumin and astrocytes participate in the regulation of ion concentrations in the sub-acute phase after the injury.     

Reconsolidation of memory: A decade of debate

Memory consolidation refers to a slow process that stabilises a memory trace after initial acquisition of novel events. The consolidation theory posits that once a memory is stored in the brain, it remains fixed for the lifetime of the memory. However, compelling evidence has suggested that upon recall, memories can re-enter a state of transient instability, requiring further stabilisation to be available once again for recall. Since its rehabilitation in the past ten years, this process of reconsolidation of memory after recall stimulated intense debates in the field of cognitive neuroscience. In this review we compile this plentiful literature with a particular emphasis on some of the key questions that have emerged from the reconsolidation theory. We focus on tracing the characterisation of the boundary conditions that constrain the occurrence of memory reconsolidation. We also discuss accumulating evidence supporting the idea that reconsolidation, as implied by its definition, is not a mere repetition of consolidation. We review seminal studies that uncovered specific mechanisms recruited during reconsolidation that are not always crucially involved in consolidation. We next address the physiological significance of reconsolidation since several lines of evidence support the idea that reconsolidation, as opposed to consolidation, may offer a unique opportunity to update memories. We finally discuss recent evidence for or against the potential that the process of memory reconsolidation offers for ongoing efforts to develop novel strategies to combat pathogenic memories.     

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

Reelin is a conserved extracellular glycoprotein crucial for neurodevelopment. In adulthood, Reelin is an important modulator of NMDA receptor-mediated neurotransmission, required for synaptic plasticity, learning and memory. Consequently, abnormal Reelin-mediated signaling has been associated with many human brain disorders involving directly or indirectly altered NMDA receptor function. For most neurological and neuropsychiatric disorders, abnormalities during brain development appear central in the disease etiology. However, a similar causative relationship for neurodegenerative diseases, like Alzheimer's disease (AD), has not been investigated yet.