Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2

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1 Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2 Daniela Pietrobon Dept. of Biomedical Sciences, University of Padova CNR Institute of Neuroscience

2 Migraine Common: it affects 17% of women and 8% of men in the European population Disabling: it is ranked by WHO as one of the 20 most disabling diseases Costly: 18.5 billion Euros/year (it mainly affects people in their working and child-bearing years)

3 The development of migraine pain depends on the activation and sensitization of the trigeminovascular sensory afferents innervating the meninges

4 Most migraine attacks start in the brain Migraine is a brain disorder --Hypersensitivity to sensory stimuli and abnormal processing of sensory information in the period between migraine attacks --Migraine triggers (strong sensory stimulation, stress, sleep deprivation, oversleeping, hunger) -- Premonitory symptoms (e.g. difficulty with speech and/or reading, increased emotionality, sensory hypersensitivity) --Migraine aura: transient neurological disturbances most frequently visual precede the headache in 30% of patients

5 Migraine aura is caused by cortical spreading depression (CSD) B Visual aura CSD CSD is a self-sustaining wave of near complete depolarization of a sizable population of brain cells that lasts 1-2 min. CSD slowly propagates across the cortex at a typical rate of 2-5 mm/min. Experimental CSD can be induced in healthy tissue by depolarizing stimuli (e.g. focal electrical stimulation or high KCl application) that increase [K]e above a critical threshold

6 Major open issue Mechanisms of the primary brain dysfunction that lead to the onset of a migraine attack and to episodic activation of the trigeminovascular pain pathway

7 Major open issue Mechanisms of the primary brain dysfunction that lead to the onset of a migraine attack and to episodic activation of the trigeminovascular pain pathway Cortical spreading depression (CSD) can activate the trigeminal nociceptive afferents in the meninges and initiate the headache mechanisms

8 Major open issue Mechanisms of the primary brain dysfunction that lead to the onset of a migraine attack and to episodic activation of the trigeminovascular pain pathway CENTRAL OPEN QUESTION What makes the brain of migraineurs susceptible to ignition of cortical spreading depression (CSD)?

9 Experimental approach Functional consequences of gene mutations causing familial hemiplegic migraine (FHM) in knockin mouse models carrying human mutations in the orthologous gene Wild-type alleles Gene targeting FHM mutant alleles Wild-type mouse FHM knockin (KI) mouse Homozygous R192Q and heterozygous S218L FHM1 KI mice (generated by A. van den Maagdenberg, Univ Leiden) Heterozygous W887R FHM2 KI mice (generated by G. Casari, Univ Vita-Salute San Raffaele)

10 Excitatory synapse pyramidal cell Inhibitory synapse FS interneuron FHM3 SCNA1A FHM1 CACNA1A Na V 1.1 Astrocyte Astrocyte Ca V 2.1 P/Q-type calcium channel Na + Ca V 2.1 Glut-R NMDA-R GABA A -R FHM2 ATP1A2 a 2 Na +,K + ATPase α 2 Na +,K + ATPase is expressed almost exclusively in astrocytes in the adult brain FHM2 mutations cause loss of function of recombinant α 2 Na +,K + ATPases

11 FHM2 mouse model Wild-type alleles Gene targeting FHM2 mutant alleles Wild-type mouse Atp1a2 W887R knockin (KI) mouse In heterozygous W887R/+ FHM2 knockin mice the expression of a 2 Na +,K + ATPase is reduced to half Almost no expression in the homozygous FHM2 KI mouse. HETEROZYGOTE ADULT BRAIN HOMOZYGOTE FETAL BRAIN Leo et al. (2011) Plos Genet

12 FHM2 mutations facilitate the induction and the propagation of cortical spreading depression: Lower threshold for CSD induction and higher velocity of CSD propagation in heterozygous FHM2 KI mice Leo et al. (2011) Plos Genet

13 CENTRAL OPEN QUESTION What makes the brain of migraineurs susceptible to CSD ignition? What are the cortical mechanisms leading to facilitation of experimental CSD in FHM2 knockin mice?

14 In FHM1 knockin mice with gain-of-function of Ca V 2.1 (P/Q-type calcium) channels and enhanced neuronal P/Q-type calcium current : i) facilitation of CSD induction and propagation (van den Maagdenger et al, Neuron 2004; Tottene et al, Neuron 2009) ii) enhanced excitatory synaptic transmission at cortical pyramidal cell synapses due to enhanced glutamate release (Tottene et al, Neuron, 2009; Vecchia et al, Neurobiol Dis 2015 ) iii) cause-effect relationship between enhanced glutamatergic transmission at cortical synapses and facilitation of initiation and propagation of experimental CSD (Tottene et al, Neuron 2009)

15 Astrocyte 3Na + 1K + GLU Hypothesis: reduced expression of α2 Na, K ATPase in W887R/+ FHM2 KI mice results in reduced rate of clearance of synaptically released glutamate at cortical excitatory synapses and hence in excessive cortical glutamatergic transmission ATP 2K + Ca V stimulating electrode

16 patch-clamp electrode voltage-clamp V = -90mV Astrocyte Hypothesis: reduced expression of α2 Na, K ATPase in W887R/+ FHM2 KI mice results in reduced rate of clearance of synaptically released glutamate at cortical excitatory synapses and hence in excessive cortical glutamatergic transmission 3Na + ATP 2K + 1K + GLU GLU Ca V stimulating electrode

17 The time courseof the synaptically-activated glutamate transporter current (STC) elicited in astrocytes upon neuronal stimulation provides a measure of the rate of glutamate clearance by astrocytes patch-clamp electrode voltage-clamp V = -90mV Astrocyte Hypothesis: reduced expression of α2 Na, K ATPase in W887R/+ FHM2 KI mice results in reduced rate of clearance of synaptically released glutamate at cortical excitatory synapses and hence in excessive cortical glutamatergic transmission 3Na + ATP 2K + 1K + GLU GLU Ca V stimulating electrode

18 The synaptically-activated glutamate transporter current (STC) is the rapidly decaying TBOA-sensitive component of the current elicited in astrocytes by neuronal stimulation. The time constant of decay of the STC gives a measure of the rate of glutamate clearance by astrocytes. patch-clamp electrode voltage-clamp V = - 90mV Stimulation TBOA b a STC 10 pa 10 pa 20 ms 20 ms 3Na + ATP 10 pa 20 ms 2K + 1K + GLU 20 ms GLU stimulating electrode a-b t decay = 6.5 ms 10 pa 20 ms Ca V

19 The rate of glutamate clearance by astrocytes in heterozygous +/R887 FHM2 knockin mice is slower than in wild-type mice. The relative slowing is larger after a train of pulses than after a single pulse stimulation and increases with increasing train frequency Single pulse stimulation STC tdecay (ms) *** WT FHM2 KI KI STC t10 (50 Hz) Hz) (ms) Train of 10 pulses 50 Hz 100 Hz *** STC t10 (100 Hz) Hz) (ms) *** WT WT FHM2 KI KI WT WT FHM2 KI KI Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

20 The density of the glutamate transporter GLT-1a in the membrane of cortical perisynaptic astrocytic processes is 50% reduced in heterozygous FHM2 KI mice GLT-1a in cortical perisynaptic astrocytic processes (PAPs) WT FHM2 KI WT FHM2 KI Density of GLT-1a gold particles *** *** t cyt mem t cyt mem Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

21 The density of the glutamate transporter GLT-1a in the membrane of cortical axon terminals is unaltered in heterozygous FHM2 KI mice GLT-1a in cortical axon terminals (AxT) WT FHM2 KI Density of GLT-1a gold particles WT KI t cyt mem t cyt mem Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

22 The FHM2 mutation reduces the density of glutamate transporters FHM2 mutations in the astrocytic reduce the processes rate of surrounding glutamate cortical excitatory clearance synapses at cortical and synapses reduces the rate of glutamate clearance by astrocytes during neuronal activity key role of the α2 Na, K ATPase in the clearance of synaptically released glutamate during neuronal activity tight coupling between the α2 Na, K ATPase and GLT-1a in cortical perisynaptic astrocytic processes

23 Is there a relationship of cause and effect between reduced rate of glutamate clearance at cortical synapses and facilitation of CSD in FHM2 knockin mice?

24 CSD induced by KCl in acute neocortical slices is facilitated in heterozygous FHM2 KI mice KCl puffer CSD threshold CSD velocity mm KCl WT 5% 5% 5 s 5 s KCl FHM2 KI 5% 5% 5 s 5 s 200 mm 300 mm 400 mm 500 mm 600 mm 700 mm CSD threshold (ms) *** WT FHM2 KI CSD velocity (mm/min) *** WT FHM2 KI smoothing smoothing con con Savitzky_Golay Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

25 WT mice Approach 1: Systemic treatment of FHM2 KI mice with ceftriaxone, a drug that increases about 50% the membrane expression of GLT-1 glutamate transporters in cerebral cortex of WT mice: does this treatment rescue CSD facilitation in FHM2 KI mice? % of controls Ctr WT Cef WT * GLT-1a b-actin 2 0 Ctr Cef WT WT Approach 2: Pharmacological inhibition of a fraction of glutamate transporters in WT mice to reduce the rate of glutamate clearance by astrocytes to a value similar to that in FHM2 KI mice: does this treatment facilitate CSD induction and propagation in WT mice to a similar extent as in FHM2 KI mice? STC tdecay (ms) WT mice ** Ctr TBOA WT 1.5

26 Ceftriaxone treatment of heterozygous FHM2 KI mice slightly increases the CSD threshold without affecting CSD velocity FHM2 KI CSD threshold (ms) CSD threshold * Ctr Cef CSD velocity (mm/min) CSD velocity Ctr Cef Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

27 Ceftriaxone treatment of heterozygous FHM2 KI mice does not alter GLT-1a expression in the cerebral cortex and does not alter the density of GLT-1a in the membrane of cortical perisynaptic astrocytic processes FHM2 KI % of controls Ctr Ctr Cef Cef GLT-1a b-actin size GLT-1a+ overlaying VGLUT1+ (mm 2 ) Ctr Ctr Cef Cef Density of GLT-1a gold particles Perisynaptic astrocytic processes (PAP) Ctr Cef t cyt mem t cyt mem Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

28 Ceftriaxone treatment of heterozygous FHM2 KI mice increases the density of GLT-1a in the membrane of cortical axon terminals FHM2 KI Ctr KI Cef KI Density of GLT-1a gold particles Axon terminals (AxT) Ctr KI Cef KI ** ** t cyt mem t cyt mem Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

29 CSD thresh CSD thresh Pharmacological reduction of the rate of glutamate clearance in WT mice 1 1 to a value similar to that in FHM2 KI 50 50mice reduces the threshold for CSD induction and increases the 0velocity 0 of CSD 0 0 propagation Ctr TBOA WT WT CSD velocity CSD velocity Ctr TBOA WT WT STC decay CSD threshold CSD velocity STC tdecay (ms) ** 4 4 Ctr TBOA WT 1.5 CSD threshold (ms) CSD threshold (ms) *** Ctr TBOA WT WT CSD velocity (mm/min) CSD velocity (mm/min) ** Ctr TBOA WT WT Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

30 CSD thre CSD thre The reduced rate of glutamate clearance at cortical excitatory synapses can account for most of the facilitation of CSD initiation and for a large fraction of the facilitation of CSD propagation Ctr TBOA in Ctr FHM2 TBOAKI mice WT WT CSD veloc CSD veloc 2 2 WT WT STC decay CSD threshold CSD velocity STC tdecay (ms) ** 4 4 Ctr TBOA WT 1.5 CSD threshold (ms) CSD threshold (ms) *** Ctr TBOA WT WT CSD velocity (mm/min) CSD velocity (mm/min) ** Ctr TBOA WT WT STC tdecay (ms) *** WT KI FHM2 CSD threshold (ms) *** WT FHM2 KI CSD velocity (mm/min) *** WT FHM2 KI

31 There is a relationship of cause and effect between impaired glutamate clearance at cortical excitatory synapses and facilitation of induction and propagation of experimental CSD in FHM2 KI mice Excessive glutamatergic transmission is a common mechanism underlying susceptibility to CSD in FHM1 and FHM2

32 patch-clamp electrode voltage-clamp V = - 90mV Is the rate of K+ clearance by astrocytes reduced in FHM2 KI mice with reduced expression of the α2 Na, K ATPase? 3Na + 1K + GLU ATP K + K + K + K + 2K + GLU K + Astrocyte stimulating electrode Ca V K +

33 The synaptically-activated slowly-decaying inward current (I K ) elicited in astrocytes by neuronal stimulation is largely a K + current, whose amplitude depends on [K + ]e The time constant of decay of I K gives a measure of the rate of K + clearance. patch-clamp electrode voltage-clamp V = -90mV Stimulation TBOA pa pa ms ms I K 3Na + 1K + GLU ATP K + K + K + K + 2K + GLU K + Astrocyte stimulating electrode I K pa pa t decay = 2.0 s 1 s Ca V Model Model Equation Equation Reduced Chi-Sq Reduced r Chi-Sq r Adj. R-Square Adj. R-Square Smoothed Y2 Smoothed Y2 Smoothed Y2 Smoothed Y2 Smoothed Y2 Smoothed Y2 Smoothed Y2 Smoothed Y2 K +

34 The rate of K+ clearance after a train of action potentials is slower in heterozygous FHM2 KI mice compared to WT mice ** WT 0.1 s FHM2 KI 1s I K tdecay (s) WT 20 KI FHM2 KI Capuani, Melone, Tottene et al. (2016) EMBO Mol Med

35 The FHM2 mutation reduces the rate of K+ clearance during neuronal activity the α2 Na, K ATPase contributes to K+ clearance during neuronal activity The reduced rate of K+ clearance might contribute to the facilitation of experimental CSD in FHM2 KI mice

36 Focal electrical or high K + pulse stimulation V m ; K + ext Ca V 2.1-dependent glutamate release Glial reuptake mechanisms a 2 Na,K ATPase NMDA receptor activation Net inward current Glutamate Pietrobon and Moskowitz, 2014 Nat Rev Neurosci

37 Focal electrical or high K + pulse stimulation V m ; K + ext FHM2 Ca V 2.1-dependent glutamate release Glial reuptake mechanisms a 2 Na,K ATPase NMDA receptor activation Net inward current FHM1 Glutamate FHM2

38 What are the cortical mechanisms leading to facilitation of experimental CSD in FHM1 and FHM2 knockin mice? CENTRAL OPEN QUESTION What makes the brain of migraineurs susceptible to CSD?

39 UNIV. PADOVA CNR INST. NEUROSCIENCE A. Tottene C. Capuani G. Crivellaro UNIV. POLITECNICA DELLE MARCHE F. Conti M. Melone L. Bragina SAN RAFFAELE INST. MILANO G. Casari UNIV. FIRENZE and CNR INST. NEUROSCIENCE T. Pizzorusso

40 Excessive cortical glutamatergic transmission characterizes both FHM1 and FHM2 FHM1 mutations increase the strength of cortical excitatory synaptic transmission but do not alter the strength of inhibitory cortical synaptic transmission Tottene et al. 2009, Neuron; Vecchia et al. (2014) Neurobiol Dis; Vecchia et al. (2015) Front. Cell Neurosci; Pilati et al The α 2 Na, K ATPase is localized in astrocytic processes surrounding cortical excitatory but not inhibitory synapses Cholet et al. 2002, Cereb Cortex Dysregulation of the cortical excitatory-inhibitory balance in both FHM1 and FHM2

41 Working hypothesis FHM mutations enhance cortical excitatory synaptic transmission without altering inhibitory synaptic transmission Functional alterations in the neuronal circuits that dynamically maintain the balance between excitation and inhibition during cortical activity Dysfunctional regulation of cortical E/I balance

42 Working hypothesis FHM mutations enhance cortical excitatory synaptic transmission without altering inhibitory synaptic transmission Functional alterations in the neuronal circuits that dynamically maintain the balance between excitation and inhibition during cortical activity Dysfunctional regulation of cortical E/I balance In certain conditions (cf migraine triggers): Overexcitation Network hyperactivity Abnormal elevation of [K]e, Excessive activation of NMDARs Susceptibility to CSD

43 FS PYR PYR SOM+ FHM mutations may increase the recruitment of interneurons and thus increase inhibition (besides excitation). What is the net effect on E/I balance and network activity?

44 In FHM, the E/I balance may or not be maintained within physiological limits depending on the brain state and the type of stimuli. consistent with the episodic nature of the disease

45 0.2 mv 1 mv During short action potential trains, increased recruitment of FS interneurons subsides; increased recruitment of SOM interneurons may persist or subside, depending on AP frequency. PYR FS PYR SOM+ 25 Hz 100 Hz 50 ms 20 ms Tottene et al, 2009, Neuron Pilati, Forli et al, unpublished

46 Patch-clamp electrode 500 mm 600 mm KCl puffer Block of either the P/Q-type Ca 2+ channels or the NMDA receptors prevents the induction and/or propagation of CSD in WT cortical slices w-agaiva n=9 n=8 D-AP5 KCl pulse (threshold) 10 mv 10 mv 1 min 1 min KCl pulse (10X threshold) KCl pulse (threshold) 10 mv 10 mv 1 min 1 min KCl pulse (10X threshold) Tottene et al., Channels 2011

47 During short trains of APs, increased recruitment of FS interneurons subsides, but increased recruitment of SOM interneurons persists. In FHM1, the excitatory-inhibitory balance may be maintained within physiological limits or may tip towards excitation depending on the cortical network state of activity and the type of stimuli. consistent with the episodic nature of the disease

48 Cortical spreading depression may activate trigeminal nociception and the headache mechanisms --- A single CSD can lead to a long-lasting increase in ongoing activity of meningeal trigeminal nociceptors and central trigeminovascular neurons in the TNC (Zhang et al, 2010 J Neurosci; 2011 Ann Neurol.), possibly by inducing parenchimal inflammatory cascades reaching glia limitans (Karatas et al, 2013 Science). Cf. also previous more indirect evidence (e.g. Bolay et al, 2002 Nat Med). Repeated CSDs cause pain-related facial mimics in freely moving mice (Karatas et al 2013 Science) --- The threshold for CSD induction by electrical stimulation in vivo is: a) increased after treatment with five different migraine preventive drugs (Ayata et al., 2006 Ann Neurol) b) decreased in mouse models of familial hemiplegic migraine (FHM) (van den Maagdenberg et al, 2004 Neuron; 2010 Ann Neurol; Leo et al, 2011 Plos Genet)

49 Excitatory synapse pyramidal cell Inhibitory synapse FS interneuron FHM3 SCNA1A FHM1 CACNA1A Na V 1.1 Astrocyte Ca V 2.1 Na + Ca V 2.1 Astrocyte Glut-R NMDA-R FHM2 ATP1A2 a 2 Na +,K + ATPase GABA A -R Ca V 2.1: voltage-gated P/Q-type calcium channel widely expressed in the brain, plays a dominant role in controlling neurotransmitter release at brain synapses Mutant FHM1 Ca V 2.1 channels open at lower voltages and mediate larger Ca2+ influx than wild-type channels (Hans et al, 1999 J Neurosci; Tottene et al, 2002 PNAS; Tottene et al, 2005 JBC: human recombinant Ca V 2.1 channels ; van den Maagdenberg et al, 2004 Neuron; Tottene et al, 2009 Neuron; Fioretti et al, 2011 J Physiol: neuronal Ca V 2.1 channels in FHM1 knockin mice )

50 10 pa Total sepsc current (pc/min) 30 pa Total sipsc current (pc/min) The FHM1 mutation enhances the total excitatory synaptic current of uncorrelated spontaneous EPSCs onto layer 2/3 pyramidal cells without altering the total inhibitory synaptic current of spontaneous IPSCs. Spontaneous EPSCs (sepscs recorded at the reversal potential of the IPSCs) and spontaneous IPSCs (sipscs at the reversal potential of the EPSCs) in layer 2/3 pyramidal cells in the presence of ongoing network activity : sepscs sepscs WT * WT KI 20 mepsc KI mipsc 50 ms WT KI 50 ms WT KI Fabbro et al

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