Analysis Tools
mortality/aging
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• most severely affected homozygotes die around weaning, with only ~40% of mice surviving to 1 month of age
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• homozygotes show a further progressive decline in survival after ~2 months of age, with only a few mice surviving at 5-6 months as a result of epileptic seizures
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• homozygotes are born at normal Mendelian ratios but show a ~20% reduction in survival at ~3 weeks of age
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growth/size/body
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• at 2 months of age, homozygotes show a 26% reduction in body weight
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• homozygotes lag behind in growth soon after birth
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behavior/neurological
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• adult homozygotes show a significant increase in the number of open arm visits and % of time spent on the open arms in the elevated plus-maze, indicating decreased anxiety-related behavior
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• adult homozygotes show increased explorative behavior with a significantly increased number of approaches to a novel object and time spent at a novel object relative to wild-type controls
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• adult homozygotes show a significant increase in the number of hind limb claspings and the time spent in clasping during 30 s of tail suspension relative to wild-type controls
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• adult homozygotes show a significant increase in the distance traveled and number of wall rearings in an open field assay
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• after 24 hr of single housing, adult homozygotes fail to organize provided paper towel into a nest, unlike wild-type controls
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• >30% of adult homozygotes display spontaneous epileptic seizures with tonic-clonic convulsions
• most seizures are mild; however, instances of fatal seizures with unresolved tonic extensions are observed
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nervous system
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• adult homozygotes show normal gross brain morphology and synapse number in the proximal CA1 stratum radiatum region of the hippocampus
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• >30% of adult homozygotes display spontaneous epileptic seizures with tonic-clonic convulsions
• most seizures are mild; however, instances of fatal seizures with unresolved tonic extensions are observed
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• excitatory terminals (spine synapses in CA1 stratum radiatum) exhibit significantly enlarged synaptic vesicles (SVs) and accumulate endosome-like vacuoles (ELVs) to a lesser extent than inhibitory terminals
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• inhibitory terminals (perisomatic synapses formed on CA1 pyramidal cells) exhibit elongated SVs that are 1.3- to 1.4-fold larger in size, show a significant reduction in total SV number, and accumulate ELVs to a greater extent than excitatory synapses
• ELVs often carry partial clathrin coats
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• excitatory terminals (spine synapses in CA1 stratum radiatum) and inhibitory terminals (perisomatic synapses formed on CA1 pyramidal cells) show significantly enlarged SVs relative to those in wild-type controls
• this change is even more pronounced in inhibitory terminals
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• inhibitory synapses show a significant reduction in total SV number
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• 10 of 14 hippocampal slices exhibit marked polyspiking activity (1 mV and higher) relative to only 3 of 14 wild-type slices
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• mice show a moderate activity-dependent reduction of vesicular Vamp2 (Syb2) levels and defects in SV reformation that are particularly pronounced at tonically active inhibitory synapses
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• short-term plasticity (STP) induced by theta burst stimulation is increased relative to wild-type controls
• however, postsynaptic long-term potentiation (LTP) is normal
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• analysis of the input-output relationship of field excitatory postsynaptic potentials (fEPSPs) of hippocampal CA3-CA1 synapses versus fiber volley amplitudes over a range of stimulation intensities indicates that basal synaptic transmission is reduced relative to wild-type controls
• higher stimulation intensities are required to elicit responses with maximal amplitudes, and the ratios of maximal fEPSP amplitudes over the amplitudes of the pre-spike are significantly decreased
• reduced basal neurotransmission and elevated PPF persist in the presence of the GABAA receptor blocker picrotoxin, suggesting impaired excitatory synaptic function
• GABAergic feedback inhibition is reduced and activity-dependent disinhibition induced by 1 Hz stimulation within the hippocampal network shows increased facilitation of population spikes (PSs) and increased polyspiking activity suggesting excitatory/inhibitory imbalance
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• EPSC amplitudes plotted against stimulation intensities indicate that similar stimulation intensities evoke significantly smaller EPSCs relative to those in wild-type controls
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• similar stimulation intensities evoke comparable presynaptic volleys but reduced fEPSP amplitudes relative to wild-type controls
• after an initial facilitation during 20 Hz stimulation the amplitudes of fEPSPs drop faster to a significantly lower level, indicating a faster depletion of the readily releasable vesicle pool relative to wild-type controls
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• similar stimulation intensities evoke significantly smaller IPSCs relative to those in wild-type controls
• inhibitory currents are more severely affected than excitatory currents
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• reduced frequency but normal amplitude of miniature excitatory postsynaptic currents, as measured by patch-clamp recordings
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• acute hippocampal slices show increased paired-pulse facilitation (PPF) of fEPSPs, a parameter for short-term presynaptic plasticity
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