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1.
bioRxiv ; 2024 May 15.
Article in English | MEDLINE | ID: mdl-38798487

ABSTRACT

Tau reduction is a promising therapeutic strategy for Alzheimer's disease. In numerous models, tau reduction via genetic knockout is beneficial, at least in part due to protection against hyperexcitability and seizures, but the underlying mechanisms are unclear. Here we describe the generation and initial study of a new conditional Tau flox model to address these mechanisms. Given the protective effects of tau reduction against hyperexcitability, we compared the effects of selective tau reduction in excitatory or inhibitory neurons. Tau reduction in excitatory neurons mimicked the protective effects of global tau reduction, while tau reduction in inhibitory neurons had the opposite effect and increased seizure susceptibility. Since most prior studies used knockout mice lacking tau throughout development, we crossed Tau flox mice with inducible Cre mice and found beneficial effects of tau reduction in adulthood. Our findings support the effectiveness of tau reduction in adulthood and indicate that excitatory neurons may be a key site for its excitoprotective effects. SUMMARY: A new conditional tau knockout model was generated to study the protective effects of tau reduction against hyperexcitability. Conditional tau reduction in excitatory, but not inhibitory, neurons was excitoprotective, and induced tau reduction in adulthood was excitoprotective without adverse effects.

2.
Epilepsy Curr ; 23(5): 315-317, 2023.
Article in English | MEDLINE | ID: mdl-37901783
3.
Neurobiol Dis ; 186: 106263, 2023 10 01.
Article in English | MEDLINE | ID: mdl-37591465

ABSTRACT

The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimer's disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-ß sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.


Subject(s)
Alzheimer Disease , Humans , Animals , Mice , Alzheimer Disease/genetics , Alleles , Seizures , Amyloid beta-Peptides , Disease Models, Animal , Plaque, Amyloid , Synapses , Membrane Glycoproteins/genetics , Receptors, Immunologic/genetics
4.
Epilepsia ; 64(10): e214-e221, 2023 10.
Article in English | MEDLINE | ID: mdl-37501613

ABSTRACT

The solute carrier family 6 member 1 (SLC6A1) gene encodes GAT-1, a γ-aminobutyric acid transporter expressed on astrocytes and inhibitory neurons. Mutations in SLC6A1 are associated with epilepsy and developmental disorders, including motor and social impairments, but variant-specific animal models are needed to elucidate mechanisms. Here, we report electrocorticographic (ECoG) recordings and clinical data from a patient with a variant in SLC6A1 that encodes GAT-1 with a serine-to-leucine substitution at amino acid 295 (S295L), who was diagnosed with childhood absence epilepsy. Next, we show that mice bearing the S295L mutation (GAT-1S295L/+ ) have spike-and-wave discharges with motor arrest consistent with absence-type seizures, similar to GAT-1+/- mice. GAT-1S295L/+ and GAT-1+/- mice follow the same pattern of pharmacosensitivity, being bidirectionally modulated by ethosuximide (200 mg/kg ip) and the GAT-1 antagonist NO-711 (10 mg/kg ip). By contrast, GAT-1-/- mice were insensitive to both ethosuximide and NO-711 at the doses tested. In conclusion, ECoG findings in GAT-1S295L/+ mice phenocopy GAT-1 haploinsufficiency and provide a useful preclinical model for drug screening and gene therapy investigations.


Subject(s)
Epilepsy, Absence , Ethosuximide , Humans , Mice , Animals , Child , Ethosuximide/therapeutic use , Haploinsufficiency/genetics , Nipecotic Acids/therapeutic use , Epilepsy, Absence/drug therapy , GABA Plasma Membrane Transport Proteins/genetics , GABA Plasma Membrane Transport Proteins/metabolism
5.
Acta Neuropathol Commun ; 11(1): 70, 2023 04 28.
Article in English | MEDLINE | ID: mdl-37118844

ABSTRACT

Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick's disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick's disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD subtypes.


Subject(s)
Frontotemporal Dementia , Frontotemporal Lobar Degeneration , Pick Disease of the Brain , Mice , Animals , Frontotemporal Dementia/genetics , Frontotemporal Dementia/pathology , Pick Disease of the Brain/pathology , Progranulins/genetics , Cathepsin D/genetics , Frontotemporal Lobar Degeneration/pathology , Mutation/genetics , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Mice, Transgenic
6.
Neurobiol Dis ; 181: 106094, 2023 06 01.
Article in English | MEDLINE | ID: mdl-36990364

ABSTRACT

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.


Subject(s)
Epilepsy, Absence , Epilepsy, Generalized , Epilepsy, Generalized/therapy , Humans , Seizures , Thalamus
7.
Sci Transl Med ; 14(652): eabj4310, 2022 07 06.
Article in English | MEDLINE | ID: mdl-35857628

ABSTRACT

Inflammatory processes induced by brain injury are important for recovery; however, when uncontrolled, inflammation can be deleterious, likely explaining why most anti-inflammatory treatments have failed to improve neurological outcomes after brain injury in clinical trials. In the thalamus, chronic activation of glial cells, a proxy of inflammation, has been suggested as an indicator of increased seizure risk and cognitive deficits that develop after cortical injury. Furthermore, lesions in the thalamus, more than other brain regions, have been reported in patients with viral infections associated with neurological deficits, such as SARS-CoV-2. However, the extent to which thalamic inflammation is a driver or by-product of neurological deficits remains unknown. Here, we found that thalamic inflammation in mice was sufficient to phenocopy the cellular and circuit hyperexcitability, enhanced seizure risk, and disruptions in cortical rhythms that develop after cortical injury. In our model, down-regulation of the GABA transporter GAT-3 in thalamic astrocytes mediated this neurological dysfunction. In addition, GAT-3 was decreased in regions of thalamic reactive astrocytes in mouse models of cortical injury. Enhancing GAT-3 in thalamic astrocytes prevented seizure risk, restored cortical states, and was protective against severe chemoconvulsant-induced seizures and mortality in a mouse model of traumatic brain injury, emphasizing the potential of therapeutically targeting this pathway. Together, our results identified a potential therapeutic target for reducing negative outcomes after brain injury.


Subject(s)
Brain Injuries , COVID-19 , Animals , Astrocytes/metabolism , Disease Models, Animal , GABA Plasma Membrane Transport Proteins/metabolism , Inflammation/pathology , Mice , Polymers , Rodentia/metabolism , SARS-CoV-2 , Seizures , Thalamus/metabolism , Thalamus/pathology
8.
Neurobiol Aging ; 106: 207-222, 2021 10.
Article in English | MEDLINE | ID: mdl-34303222

ABSTRACT

The hippocampus is vulnerable to deterioration in Alzheimer's disease (AD). It is, however, a heterogeneous structure, which may contribute to the differential volumetric changes along its septotemporal axis during AD progression. Here, we investigated amyloid plaque deposition along the dorsoventral axis in two strains of transgenic AD (ADTg) mouse models. We also used patch-clamp physiology in these mice to probe for functional consequences of AD pathogenesis in ventral hippocampus, which we found bears significantly higher plaque burden in the aged ADTg group compared to corresponding dorsal regions. Despite dorsoventral differences in amyloid load, ventral CA1 pyramidal neurons of aged ADTg mice exhibited subthreshold physiological changes similar to those previously reported in dorsal neurons, indicative of an HCN channelopathy, but lacked exacerbated suprathreshold accommodation. Additionally, HCN channel function could be rescued by pharmacological manipulation of the endoplasmic reticulum. These observations suggest that an AD-linked HCN channelopathy emerges in both dorsal and ventral CA1 pyramidal neurons, but that the former encounter an additional integrative obstacle in the form of reduced intrinsic excitability.


Subject(s)
Aging/metabolism , Alzheimer Disease/etiology , Alzheimer Disease/metabolism , CA1 Region, Hippocampal/cytology , CA1 Region, Hippocampal/metabolism , Plaque, Amyloid/metabolism , Pyramidal Cells/metabolism , Signal Transduction , Animals , Disease Models, Animal , Disease Progression , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels , Mice, Transgenic , Organ Size , Patch-Clamp Techniques
9.
PLoS Genet ; 17(1): e1009195, 2021 01.
Article in English | MEDLINE | ID: mdl-33411788

ABSTRACT

Dravet syndrome (DS) is a developmental and epileptic encephalopathy that results from mutations in the Nav1.1 sodium channel encoded by SCN1A. Most known DS-causing mutations are in coding regions of SCN1A, but we recently identified several disease-associated SCN1A mutations in intron 20 that are within or near to a cryptic and evolutionarily conserved "poison" exon, 20N, whose inclusion is predicted to lead to transcript degradation. However, it is not clear how these intron 20 variants alter SCN1A expression or DS pathophysiology in an organismal context, nor is it clear how exon 20N is regulated in a tissue-specific and developmental context. We address those questions here by generating an animal model of our index case, NM_006920.4(SCN1A):c.3969+2451G>C, using gene editing to create the orthologous mutation in laboratory mice. Scn1a heterozygous knock-in (+/KI) mice exhibited an ~50% reduction in brain Scn1a mRNA and Nav1.1 protein levels, together with characteristics observed in other DS mouse models, including premature mortality, seizures, and hyperactivity. In brain tissue from adult Scn1a +/+ animals, quantitative RT-PCR assays indicated that ~1% of Scn1a mRNA included exon 20N, while brain tissue from Scn1a +/KI mice exhibited an ~5-fold increase in the extent of exon 20N inclusion. We investigated the extent of exon 20N inclusion in brain during normal fetal development in RNA-seq data and discovered that levels of inclusion were ~70% at E14.5, declining progressively to ~10% postnatally. A similar pattern exists for the homologous sodium channel Nav1.6, encoded by Scn8a. For both genes, there is an inverse relationship between the level of functional transcript and the extent of poison exon inclusion. Taken together, our findings suggest that poison exon usage by Scn1a and Scn8a is a strategy to regulate channel expression during normal brain development, and that mutations recapitulating a fetal-like pattern of splicing cause reduced channel expression and epileptic encephalopathy.


Subject(s)
Epilepsies, Myoclonic/genetics , NAV1.1 Voltage-Gated Sodium Channel/genetics , NAV1.6 Voltage-Gated Sodium Channel/genetics , Animals , Brain/metabolism , Brain/pathology , Disease Models, Animal , Epilepsies, Myoclonic/pathology , Exons/genetics , Gene Expression Regulation/genetics , Gene Knock-In Techniques , Humans , Introns/genetics , Mice , Mutation/genetics , Organ Specificity/genetics , RNA-Seq
10.
Elife ; 92020 07 13.
Article in English | MEDLINE | ID: mdl-32657270

ABSTRACT

Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer's disease (AD). One limitation in understanding BIN1's contribution to AD is its unknown function in the brain. AD-associated BIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured rat hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1-LVGCC interactions were modulated by Tau in rat hippocampal neurons and mouse brain. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1's neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Alzheimer Disease/genetics , Hippocampus/metabolism , Neurons/metabolism , Nuclear Proteins/genetics , Tumor Suppressor Proteins/genetics , tau Proteins/metabolism , Adaptor Proteins, Signal Transducing/metabolism , Alzheimer Disease/metabolism , Animals , Cell Line , Cells, Cultured , Humans , Nuclear Proteins/metabolism , Rats , Rats, Sprague-Dawley , Tumor Suppressor Proteins/metabolism
11.
Neurobiol Learn Mem ; 154: 141-157, 2018 10.
Article in English | MEDLINE | ID: mdl-29906573

ABSTRACT

Voltage-gated ion channels are critical for neuronal integration. Some of these channels, however, are misregulated in several neurological disorders, causing both gain- and loss-of-function channelopathies in neurons. Using several transgenic mouse models of Alzheimer's disease (AD), we find that sub-threshold voltage signals strongly influenced by hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels progressively deteriorate over chronological aging in hippocampal CA1 pyramidal neurons. The degraded signaling via HCN channels in the transgenic mice is accompanied by an age-related global loss of their non-uniform dendritic expression. Both the aberrant signaling via HCN channels and their mislocalization could be restored using a variety of pharmacological agents that target the endoplasmic reticulum (ER). Our rescue of the HCN channelopathy helps provide molecular details into the favorable outcomes of ER-targeting drugs on the pathogenesis and synaptic/cognitive deficits in AD mouse models, and implies that they might have beneficial effects on neurological disorders linked to HCN channelopathies.


Subject(s)
Alzheimer Disease/physiopathology , CA1 Region, Hippocampal/physiology , Channelopathies/physiopathology , Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/physiology , Neuronal Plasticity , Pyramidal Cells/physiology , Action Potentials , Aging , Animals , CA1 Region, Hippocampal/ultrastructure , Disease Models, Animal , Endoplasmic Reticulum/physiology , Female , Male , Mice, Transgenic , Pyramidal Cells/ultrastructure
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