Phenotypes associated with this allele

• Allele Symbol: Clptm1^{tm1a(KOMP)Wtsi}
• Allele Name: targeted mutation 1a, Wellcome Trust Sanger Institute
• Allele ID: MGI:4419487
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Clptm1^tm1a(KOMP)Wtsi/Clptm1^tm1a(KOMP)Wtsi	B6J.B6N-Clptm1^tm1a(KOMP)Wtsi	MGI:7780034
ht2	Clptm1^tm1a(KOMP)Wtsi/Clptm1^+	B6J.B6N-Clptm1^tm1a(KOMP)Wtsi	MGI:7780033

Genotype
MGI:7780034

hm1

• Allelic Composition: Clptm1^{tm1a(KOMP)Wtsi}/Clptm1^{tm1a(KOMP)Wtsi}
• Genetic Background: B6J.B6N-Clptm1^{tm1a(KOMP)Wtsi}
• Cell Lines: EPD0395_5_D10

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

postnatal lethality, complete penetrance ( J:357551 )

• although heterozygous intercrosses yield homozygous embryos at expected Mendelian frequencies at E18, no homozygotes are recovered at P9-P11, suggesting lethality at early postnatal stages

craniofacial

craniofacial phenotype ( J:357551 )

N • homozygous embryos show no evidence of cleft lip or palate at E18

Genotype
MGI:7780033

ht2

• Allelic Composition: Clptm1^{tm1a(KOMP)Wtsi}/Clptm1⁺
• Genetic Background: B6J.B6N-Clptm1^{tm1a(KOMP)Wtsi}
• Cell Lines: EPD0395_5_D10

nervous system

nervous system phenotype ( J:357551 )

N • adult heterozygotes show no apparent defects in gross brain morphology

abnormal hippocampus neuron morphology ( J:357551 )

• cultured hippocampal neurons show significantly increased surface levels of the GABA_AR alpha5 subunit, suggesting that Clptm1 regulates tonic inhibition by limiting alpha5 surface expression

impaired synaptic plasticity ( J:357551 )

• high-frequency stimulation (100 Hz, 1 s) of Schaffer collateral fibers fails to induce long-term potentiation (LTP) in hippocampal CA3CA1 synapses at P16-P19, suggesting a block in excitatory synaptic plasticity

• however, no changes are noted in the input/output curve of evoked excitatory postsynaptic currents (eEPSCs) or paired-pulse ratio of eEPSCs from CA1 pyramidal cells with multiple interpulse intervals at P15-P18 and the input/output relationship of the slope of the CA1 fEPSP in response to increasing stimulation of Schaffer collateral fibers is normal at P15-P16, suggesting that basal excitatory synaptic transmission is normal

abnormal CNS synaptic transmission ( J:357551 )

• juvenile and adult heterozygotes show increased GABAergic phasic and tonic inhibitory transmission with no differences between male and female mice

abnormal GABA-mediated receptor currents ( J:357551 )

• recordings from hippocampal CA1 pyramidal neurons in brain slices show a significant increase in the amplitude of tonic GABAergic currents in both sexes at P15-P18, as calculated by the difference between the holding current before and after the application of bicuculline (a GABA_AR-competitive antagonist)

• moreover, GABA_AR-mediated tonic currents are significantly increased in adult mice at P43-P50

increased inhibitory postsynaptic current amplitude ( J:357551 )

• recordings of evoked inhibitory postsynaptic currents (eIPSCs) from CA1 pyramidal neurons while stimulating the stratum radiatum with increasing multiples of threshold intensity at P16-P18 show a significant increase in eIPSC amplitude at stimulation with >4x threshold intensity

• however, no changes are detected in the paired-pulse ratio of eIPSCs from CA1 pyramidal cells with multiple interpulse intervals at P16-P18

reduced long-term potentiation ( J:357551 )

• high-frequency stimulation (100 Hz, 1 s) of Schaffer collateral fibers fails to induce LTP in Schaffer collateral to CA1 synapses in hippocampal slices at P16-P19; potentiation of fEPSPs is significantly reduced both at 0-2 min and at 55-60 min poststimulation, suggesting a deficit in LTP induction

• a significant reduction in HFS-induced LTP magnitude is also noted in hippocampal slices at P43-P49

• application of L-655,708 (a negative allosteric modulator of the extrasynaptic GABA_AR) alpha5 subunit) restores the magnitude of LTP to wild-type levels

increased miniature inhibitory postsynaptic current amplitude ( J:357551 )

• whole-cell recordings from hippocampal CA1 pyramidal neurons in brain slices show a significant increase in mIPSC amplitude in both sexes at P15-P18 and at P42-P49

• however, no changes in mIPSC frequency or decay time are noted in juvenile (P15-P18) or adult mice (P42-P49)

• moreover, no changes in miniature excitatory postsynaptic current (mEPSC) frequency or amplitude are noted in CA1 pyramidal neurons at P16-P17

behavior/neurological

impaired contextual conditioning behavior ( J:357551 )

• in a contextual fear conditioning task, mice show normal freezing behavior during the baseline habituation and immediate aftershock periods but exhibit significant deficits in contextual fear memory 24 h later, with no detectable differences between sexes

• application of L-655,708 (a negative allosteric modulator of the extrasynaptic GABA_AR) alpha5 subunit) restores the deficit in contextual fear memory to wild-type levels