“Speech impaired” Mice T N T N FOX FOX polyQ polyQ FOX FOX polyQ polyQ T N T N FOX FOX polyQ polyQ FOX FOX polyQ polyQ Speech impaired Speech normal
Speaking mice? Mice homozygous for humanized Mice homozygous for wildtype Foxp2 ( Foxp2 hum/hum ) Foxp2 ( Foxp2 wt/wt )
Analysis of humanized Foxp2 mice • German Mouse Clinic Screen • Gene expression • Neuroanatomical analysis • Neuronal stem cells • Elektrophysiology • Vocalisation kHz 15 10 5 2 4 6 s
Molecular function of FOXP2 • FOXP2 is an ~ubiquitously expressed transcription factor Lai et al. 2001 • FOXP2 is usually expressed in a subset of cell types in a given tissue Shu et al. 2001
Molecular function of FOXP2 • FOXP2 is expressed in postmitotic neurons in the brain Mouse; Ferland et al, 2003
Questions • Which of the organic systems/cell types in which FOXP2 is expressed might be affected by the human-specific amino acid changes? • Could such changes be related to the evolution of speech and language and if yes, how?
Mouse Clinic Screen German Mouse Clinic Consortium; Helmholtz Center; Munich y m g y s o y l g i a l r l o o g o c t t s r h b n i l n o a i p a u m e i r t r l L u H e o C e e M h M N C n o y i y t g r p g o o e o l i c o v l e o i a h y c n h E t o a u e N P m B m I Foxp2 hum/hum mice are healthy, explore their enviroment more carefully, but show no difference in over 250 cardiovascular, immunological, pathological, morphological or respiratory measurements.
Mouse Clinic Screen German Mouse Clinic Consortium; Helmholtz Center; Munich y m g y s o y l g i a l r l o o g o c t t s r h b n i l n o a i p a u m e i r t r l L u H e o C e e M h M N C n o y i y t g r p g o o e o l i c o v l e o i a h y c n h E t o a u e N P m B m I Foxp2 wt/ko mice are healthy, show a variety of subtle differences in lung function, metabolism, blood pressure, hearing and immune function and explore their enviroment slightly more.
Neurotransmitter levels Christine Winter and Reinhard Sohr, Charite, Berlin Frontal cortex Cerebellum Caudate-Putamen Nucleus accumbens Globus pallidus Glutamate Serotonin GABA Dopamine
Neurotransmitter levels Christine Winter and Reinhard Sohr, Charite, Berlin ** 250% ** * * Foxp2hum/hum 200% rel. to wildtype 150% Foxp2 wt/ko * 100% ** * 50% 0% Striatum Cerebellum Globus pallidus Cortex Nucleus accumbens Foxp2 hum/hum mice show reduced dopamine levels (p<0.001) Foxp2 wt/ko mice show increased dopamine levels (p<0.05)
Cortico-striatal circuits Foxp2 •Striatum is the major target of dopaminergic neurons •Foxp2 is expressed in a large fraction of striatal neurons
Cortico-basal ganglia circuits and Foxp2 The caudate nucleus has less grey matter and is overactivated in humans having only one functional copy of FOXP2 Vargha-Khadem et al., PNAS, 1998
Cortico-basal ganglia circuits and Foxp2 Reduced FoxP2 expression in striatal neurons impairs vocal imitation in birds Haesler et al., PlOS Biology, 2007
Striatal gene expression patterns •Analysed gene expression patterns in 70 striatal biopsies of embryos (E16.5), adolescent (P15- P21) and adult (3 month) mice •Find significant but very subtle effects that are not enriched in particular functional categories •Find tendencies for opposite effects in Foxp2 hum/hum mice and Foxp2 wt/ko mice
Striatal neurons in vitro Sabine Gehre, Eun und Johannes Schwarz; Neurology; Leipzig •In vitro differentiated neurons from Foxp2 hum/hum show longer, more branched neurits 500 Foxp2 wt/wt * 400 neurite length ( � m) Foxp2 hum/hum Foxp2 wt/wt 300 200 100 * 0 * all primary secondary tertiary quartery Foxp2 hum/hum
Striatal neurons in vivo Sabine Gehre und Johannes Schwarz; Neurology; Leipzig •Striatal neurons of adult mice have longer dendritic trees Foxp2 wt/wt Foxp2 hum/hum 1500 * * dendrite length [ � m] 1250 Foxp2 wt/wt 1000 Foxp2 hum/hum 750 500 Foxp2 wt/ko 250 0
Striatal synaptic plasticity Johannes Schwarz; Neurology; Leipzig From cortex Striatal neuron •Changes in the strength of cortico-striatal synapses, i.e. synaptic plasticity, is thought to be important for learning action patterns
Striatal synaptic plasticity Johannes Schwarz; Neurology; Leipzig From cortex Striatal neuron striatum Long-term depression is a frequently studied form of synaptic plasticity at cortico- striatal synapses From Gerdeman, et al., 2003
Striatal synaptic plasticity Johannes Schwarz; Neurology; Leipzig •Long term depression in medium spiny neurons 110 100 normalised amplitude (%) 90 80 70 60 Foxp2 wt/wt 50 40 -5 5 15 25 time (min)
Striatal synaptic plasticity Johannes Schwarz; Neurology; Leipzig •Striatal Foxp2 hum/hum neurons show stronger long term depression (LTD) 110 * ** ** 100 * * normalised amplitude (%) * * * 90 * * * * 80 70 60 Foxp2 wt/wt 50 Foxp2 hum/hum 40 -5 5 15 25 time (min)
Striatal synaptic plasticity Groszer et al., 2008 •Striatal neurons of mice carrying one non-functional FOXP2 allele show weaker long term depression
Recommend
More recommend
