AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits and play important roles in synaptic transmission and plasticity. Here, we have investigated the development of AMPAR-mediated synaptic transmission in the hippocampus of the Fmr1 knock-out (KO) mouse, a widely used model of Fragile X syndrome (FXS). FXS is the leading monogenic cause of intellectual disability and autism spectrum disorders (ASD) and it is considered a neurodevelopmental disorder. For that reason, we investigated synaptic properties and dendritic development in animals from an early stage when synapses are starting to form up to adulthood. We found that hippocampal CA1 pyramidal neurons in the Fmr1-KO mouse exhibit a higher AMPAR-NMDAR ratio early in development but reverses to normal values after P13. This increase was accompanied by a larger presence of the GluA2-subunit in synaptic AMPARs that will lead to altered Ca 2+ permeability of AMPARs that could have a profound impact upon neural circuits, learning, and diseases. Following this, we found that young KO animals lack Long-term potentiation (LTP), a well-understood model of synaptic plasticity necessary for proper development of circuits, and exhibit an increased frequency of spontaneous miniature excitatory postsynaptic currents, a measure of synaptic density. Furthermore, post hoc morphological analysis of recorded neurons revealed altered dendritic branching in the KO group. Interestingly, all these anomalies are transitory and revert to normal values in older animals. Our data suggest that loss of FMRP during early development leads to temporary upregulation of the GluA2 subunit and this impacts synaptic plasticity and altering morphological dendritic branching.
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Developmental onset of enduring long‐term potentiation in mouse hippocampus
Analysis of long‐term potentiation (LTP) provides a powerful window into cellular mechanisms of learning and memory. Prior work shows late LTP (L‐LTP), lasting >3 hr, occurs abruptly at postnatal day 12 (P12) in the
- Award ID(s):
- 1707356
- NSF-PAR ID:
- 10455245
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Hippocampus
- Volume:
- 30
- Issue:
- 12
- ISSN:
- 1050-9631
- Page Range / eLocation ID:
- p. 1298-1312
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Key points Dravet syndrome mice (
Scn1a +/−) demonstrate a marked strain dependence for the severity of seizures which is correlated with GABAAreceptor α2subunit expression.The α2/α3subunit selective positive allosteric modulator (PAM) AZD7325 potentiates inhibitory postsynaptic currents (IPSCs) specifically in perisomatic synapses.
AZD7325 demonstrates stronger effects on IPSCs in the seizure resistant mouse strain, consistent with higher α2subunit expression.
AZD7325 demonstrates seizure protective effects in
Scn1a +/−mice without apparent sedative effectsin vivo .Abstract GABAAreceptor potentiators are commonly used for the treatment of epilepsy, but it is not clear whether targeting distinct GABAAreceptor subtypes will have disproportionate benefits over adverse effects. Here we demonstrate that the α2/α3selective positive allosteric modulator (PAM) AZD7325 preferentially potentiates hippocampal inhibitory responses at synapses proximal to the soma of CA1 neurons. The effect of AZD7325 on synaptic responses was more prominent in mice on the 129S6/SvEvTac background strain, which have been demonstrated to be seizure resistant in the model of Dravet syndrome (
Scn1a+/− ), and in which the α2GABAAreceptor subunits are expressed at higher levels relative to in the seizure prone C57BL/6J background strain. Consistent with this, treatment ofScn1a+/− mice with AZD7325 elevated the temperature threshold for hyperthermia‐induced seizures without apparent sedative effects. Our results in a model system indicate that selectively targeting α2is a potential therapeutic option for Dravet syndrome. -
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Summary Objective Seizures develop in 80% of patients with anti–
N ‐methyl‐d ‐aspartate receptor (NMDAR) encephalitis, and these represent a major cause of morbidity and mortality. Anti‐NMDAR antibodies have been linked to memory loss in encephalitis; however, their role in seizures has not been established. We determined whether anti‐NMDAR antibodies from autoimmune encephalitis patients are pathogenic for seizures.Methods We performed continuous intracerebroventricular infusion of cerebrospinal fluid (CSF) or purified immunoglobulin (IgG) from the CSF of patients with anti‐NMDAR encephalitis or polyclonal rabbit anti‐NMDAR IgG, in male C57BL/6 mice. Seizure status during a 2‐week treatment was assessed with video‐electroencephalography. We assessed memory, anxiety‐related behavior, and motor function at the end of treatment and assessed the extent of neuronal damage and gliosis in the CA1 region of hippocampus. We also performed whole‐cell patch recordings from the CA1 pyramidal neurons in hippocampal slices of mice with seizures.
Results Prolonged exposure to rabbit anti‐NMDAR IgG, patient CSF, or human IgG purified from the CSF of patients with encephalitis induced seizures in 33 of 36 mice. The median number of seizures recorded in 2 weeks was 13, 39, and 35 per mouse in these groups, respectively. We observed only 18 brief nonconvulsive seizures in 11 of 29 control mice (median seizure count of 0) infused with vehicle (n = 4), normal CSF obtained from patients with noninflammatory central nervous system (CNS) conditions (n = 12), polyclonal rabbit IgG (n = 7), albumin (n = 3), and normal human IgG (n = 3). We did not observe memory deficits, anxiety‐related behavior, or motor impairment measured at 2 weeks in animals treated with CSF from affected patients or rabbit IgG. Furthermore, there was no evidence of hippocampal cell loss or astrocyte proliferation in the same mice.
Significance Our findings indicate that autoantibodies can induce seizures in anti‐NMDAR encephalitis and offer a model for testing novel therapies for refractory autoimmune seizures.
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Abstract Tight regulation of immediate early gene (IEG) expression is important for synaptic plasticity, learning, and memory. Recent work has suggested that DNA double strand breaks (DSBs) may have an adaptive role in post-mitotic cells to induce IEG expression. Physiological activity in cultured neurons as well as behavioral training leads to increased DSBs and subsequent IEG expression. Additionally, infusion of etoposide—a common cancer treatment that induces DSBs—impairs trace fear memory. Here, we assessed the effects of hippocampal infusion of 60 ng of etoposide on IEG expression, learning, and memory in 3–4 month-old C57Bl/6J mice. Etoposide altered expression of the immediate early genes
cFos andArc in the hippocampus and impaired hippocampus-dependent contextual fear memory. These data add to the growing evidence that DSBs play an important role in IEG expression, learning, and memory, opening avenues for developing novel treatment strategies for memory-related disorders. -
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Abstract Despite its evident importance to learning theory and models, the manner in which the lateral perforant path (LPP) transforms signals from entorhinal cortex to hippocampus is not well understood. The present studies measured synaptic responses in the dentate gyrus (DG) of adult mouse hippocampal slices during different patterns of LPP stimulation. Theta (5 Hz) stimulation produced a modest within‐train facilitation that was markedly enhanced at the level of DG output. Gamma (50 Hz) activation resulted in a singular pattern with initial synaptic facilitation being followed by a progressively greater depression. DG output was absent after only two pulses. Reducing release probability with low extracellular calcium instated frequency facilitation to gamma stimulation while long‐term potentiation, which increases release by LPP terminals, enhanced within‐train depression. Relatedly, per terminal concentrations of VGLUT2, a vesicular glutamate transporter associated with high release probability, were much greater in the LPP than in CA3–CA1 connections. Attempts to circumvent the potent gamma filter using a series of short (three‐pulse) 50 Hz trains spaced by 200 ms were only partially successful: composite responses were substantially reduced after the first burst, an effect opposite to that recorded in field CA1. The interaction between bursts was surprisingly persistent (>1.0 s). Low calcium improved throughput during theta/gamma activation but buffering of postsynaptic calcium did not. In all, presynaptic specializations relating to release probability produce an unusual but potent type of frequency filtering in the LPP. Patterned burst input engages a different type of filter with substrates that are also likely to be located presynaptically.
image Key points The lateral perforant path (LPP)–dentate gyrus (DG) synapse operates as a low‐pass filter, where responses to a train of 50 Hz, γ frequency activation are greatly suppressed.
Activation with brief bursts of γ frequency information engages a secondary filter that persists for prolonged periods (lasting seconds).
Both forms of LPP frequency filtering are influenced by presynaptic, as opposed to postsynaptic, processes; this contrasts with other hippocampal synapses.
LPP frequency filtering is modified by the unique presynaptic long‐term potentiation at this synapse.
Computational simulations indicate that presynaptic factors associated with release probability and vesicle recycling may underlie the potent LPP–DG frequency filtering.
