Calcium (Ca
)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca
-permeable if they lack the GluA2 subunit ...or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2
) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca
-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2
mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca
-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease.
A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral ...experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca(2+)-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca(2+)-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca(2+)-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.
Abstract
Background
RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). ...Reduced Q/R site editing increases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer’s disease (AD), raising the possibility that unedited GluA2(Q)-containing AMPARs contribute to synapse loss and neurodegeneration in AD. If true, then inhibiting expression of unedited GluA2(Q), while maintaining expression of GluA2(R), may be a novel strategy of preventing synapse loss and neurodegeneration in AD.
Methods
We engineered mice with the ‘edited’ arginine codon (CGG) in place of the unedited glutamine codon (CAG) at position 607 of the
Gria2
gene. We crossbred this line with the J20 mouse model of AD and conducted anatomical, electrophysiological and behavioural assays to determine the impact of eliminating unedited GluA2(Q) expression on AD-related phenotypes.
Results
Eliminating unedited GluA2(Q) expression in AD mice prevented dendritic spine loss and hippocampal CA1 neurodegeneration as well as improved working and reference memory in the radial arm maze. These phenotypes were improved independently of Aβ pathology and ongoing seizure susceptibility. Surprisingly, our data also revealed increased spine density in non-AD mice with exonically encoded GluA2(R) as compared to their wild-type littermates, suggesting an unexpected and previously unknown role for unedited GluA2(Q) in regulating dendritic spines.
Conclusion
The Q/R editing site of the AMPA receptor subunit GluA2 may act as an epigenetic switch that regulates dendritic spines, neurodegeneration and memory deficits in AD.
Chromatic roots at 2 and the Beraha number B10 Harvey, Daniel J.; Royle, Gordon F.
Journal of graph theory,
November 2020, 2020-11-00, 20201101, Letnik:
95, Številka:
3
Journal Article
Recenzirano
Odprti dostop
By the construction of suitable graphs and the determination of their chromatic polynomials, we resolve two open questions concerning real chromatic roots. First we exhibit graphs for which the ...Beraha number B10=(5+5)∕2 is a chromatic root. As it was previously known that no other noninteger Beraha number is a chromatic root, this completes the determination of precisely which Beraha numbers can be chromatic roots. Next we construct an infinite family of 3‐connected graphs such that for any k≥1, there is a member of the family with q=2 as a chromatic root of multiplicity at least k. The former resolves a question of Salas and Sokal and the latter a question of Dong and Koh.
Tournaments and even graphs are equinumerous Royle, Gordon F.; Praeger, Cheryl E.; Glasby, S. P. ...
Journal of algebraic combinatorics,
03/2023, Letnik:
57, Številka:
2
Journal Article
Recenzirano
Odprti dostop
A graph is called
odd
if there is an orientation of its edges and an automorphism that reverses the sense of an odd number of its edges and
even
otherwise. Pontus von Brömssen (né Andersson) showed ...that the existence of such an automorphism is independent of the orientation and considered the question of counting pairwise non-isomorphic even graphs. Based on computational evidence, he made the rather surprising conjecture that the number of pairwise non-isomorphic
even graphs
on
n
vertices is equal to the number of pairwise non-isomorphic
tournaments
on
n
vertices. We prove this conjecture using a counting argument with several applications of the Cauchy–Frobenius theorem.
We describe two similar but independently-coded computations used to construct a complete catalogue of the transitive groups of degree less than 48, thereby verifying, unifying and extending the ...catalogues previously available. From this list, we construct all the vertex-transitive graphs of order less than 48. We then present a variety of summary data regarding the transitive groups and vertex-transitive graphs, focusing on properties that seem to occur most frequently in the study of groups acting on graphs. We illustrate how such catalogues can be used, first by finding a complete list of the elusive groups of order at most 47 and then by completely determining which groups of order at most 47 are CI groups.
We characterize the quartic (i.e., 4‐regular) multigraphs with the property that every edge lies in a triangle. The main result is that such graphs are either squares of cycles, line multigraphs of ...cubic multigraphs, or are obtained from these by a number of simple subgraph‐replacement operations. A corollary of this is that a simple quartic graph with every edge in a triangle is either the square of a cycle, the line graph of a cubic graph or a graph obtained from the line multigraph of a cubic multigraph by replacing triangles with copies of K1, 1, 3.
In this paper, we describe a complete computer classification of the hemisystems in the two known flock generalized quadrangles of order (5
2
, 5) and give numerous further examples of hemisystems in ...all the known flock generalized quadrangles of order (
s
2
,
s
) for
s
≤ 11. By analysing the computational data, we identify two possible new infinite families of hemisystems in the classical generalized quadrangle H(3,
s
2
).
The number and type of receptors present at the postsynaptic membrane determine the response to the neurotransmitter released from the presynaptic terminal. Because most neurons receive multiple and ...distinct synaptic inputs and contain several different subtypes of receptors stimulated by the same neurotransmitter, the assembly and trafficking of receptors in neurons is a complex process involving many levels of regulation. To investigate the mechanism that neurons use to regulate the assembly of receptor subunits, we studied a GluR2 knock-out mouse. GluR2 is a critical subunit that controls calcium permeability of AMPA receptors and is present in most native AMPA receptors. Our data indicate that in the absence of GluR2, aberrant receptor complexes composed of GluR1 and GluR3 are formed in the hippocampus, and that there is an increased number of homomeric GluR1 and GluR3 receptors. We also show that these homomeric and heteromeric receptors are less efficiently expressed at the synapse. Our results show that GluR2 plays a critical role in controlling the assembly of AMPA receptors, and that the assembly of subunits may reflect the affinity of one subunit for another or the stability of intermediates in the assembly process. Therefore, GluR1 may have a greater preference for GluR2 than it does for GluR3.
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