Sophisticated Synapses: Modeling Synaptic Modulation by Astrocytes Suhita Nadkarni

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1 Sophisticated Synapses: Modeling Synaptic Modulation by Astrocytes Suhita Nadkarni Indian Institute of Science Education and Research

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3 Simple vs Complex Synapses are immensely complex - a large number of ion channels and a plethora of neurotransmitters and receptors operating over multiple of timescales. Yet most computational studies take simplistic view of the synapse General approach is 1. devise biophysical models which incorporate a more sophisticated view of these neural components. 2. calibrate and test these models with experimental data that can then be used to make testable predictions 3. work towards understanding the implications of component sophistication for network dynamics.

4 Model Constraints Realistic synaptic morphology from serial section EM reconstruction of hippocampal neuropil (collaboration with Kristen Harris, UT Austin)

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6 Synaptic transmission VDCC Ca Glu Astrocyte Ca Calcium signal necessary and sufficient for neurotransmitter release Action potential arrives Voltage Dependent Calcium Channels (VDCC) open Increase in intracellular [Ca Stochastic release of neurotransmitter vesicle Astrocytic involvement opens another source of Ca Modulation of release probability of neurotransmitter

7 Realistic Model of Synapses in Hippocampal Neuropil Illustrative List 100nM resting Ca 2+ level PMCA pumps and Na + /Ca 2+ exchangers Postsynaptic L & R type VDCCs NR2A and NR2B type NMDA receptors at the PSD AMPA receptors at the PSD Diffusible Calbindin-D28k in the cytosol Calmodulin CAMKII Calcineurin SERCA pumps IP3 and RyR receptors Mitochondrial Ca 2+ pumps presynaptic P/Q type VDCCs presynaptic vesicular release pathway with SNARE complex Astrocyte feedback SERCA IP3 receptors Cytosolic Ca2+ ER Ca2+ Gliotransmitters

8 Glia, more than just brain-glue? Astrocyte The prejudice that the relation between neuroglial fibers and neuronal cells is similar to the relation between connective tissue and muscle or gland cells, that is, a passive weft for merely filling and support (and in the best case, a gangue for taking nutritive juices), constitutes the main obstacle that the researcher needs to remove to get a rational concept about the activity of the neuroglia. S Ramon y Cajal Nobel Prize 1906

9 Phylogenic advantage Topographic advantage 1:25 1:3 1.3:1 Up-to 300, 000 synapses can be contacted by a single astrocyte and 90 % of the cortical volume accessed by astrocytes Astrocytes as transistors of neural circuitry Ideal position to provide long distance modulation and control

10 An Astrocyte basis of epilepsy Guo-Feng Tian et. al

11 Gliotransmission Controversy

12 Signaling in Astrocytes Intracellular Calcium Response 1. activation of mglurs on the astrocyte 2. production of IP 3 3. release of Ca 2+ from internal store Intercellular Calcium Waves 1. IP 3 diffusion thru gap junctions 2. Consequent release of Ca IP 3 regeneration Ca 2+ Endoplasmic Reticulum Ca 2+ Ca2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ Ca 2+ IP 3 ATP, Glutamate Ca 2+ uptake leak

13 335 µm 150 µm 240 µm Eric Newman Lab, University of Minnesota

14 Neurons stimulate Ca 2+ response in astrocytes Astrocyte Ca 2+ ASTRO PRE Postsynaptic Presynaptic The Tripartite Synapse POST Presynaptic action potential Release of glutamate (Glu) GLU binds to mglurs on the astro Ca2+ release from stores (ER) Ca2+ oscillations (waves)

15 How much glutamate is there? Peak concentration in cleft ~ 1 mm Only few Glu molecules bind to receptors Glu removed rapidly through Glu transporters

16 Glutamate Dose response + Experimental Data Theoretical Fit 100µM Glu Cornell-Bell et al. Science 247, 373 (1990) d[ IP 3 ] dt = 1 IP 3 τ IP3 ([ ] * [ IP 3 ]) + ν[glu]n κ n + [glu] n Θ(t t r ) Θ(t t r 2ms) ν = ρ mglur S V astro + N A n=0.3 Nadkarni and Jung, 2003

17 Synaptic activation of astrocytes d[ IP 3 ] dt d[ Ca 2 + ] dt Calcium dynamics in astrocytes = J channel ([IP 3 ],[Ca 2 + ],q) J pump J leak + ξ(t) dq dt = α 1 q ( ) βq = 1 IP 3 τ IP3 ([ ] * [ IP 3 ]) + ν[glu]n κ n + [glu] n Θ(t t r ) Θ(t t r 2ms) ν = ρ S mglur V astro + N A n=0 (Nadkarni & Jung 2005, Li &Rinzel, 1994)

18 Astrocytes talk to neurons Neuron Astrocytes Neuron on astrocyte micro-island I astro = 2.11 µa Θ(ln y)ln y 2 cm y = [Ca 2+ ]/nm Parpura and Haydon, PNAS 2000

19 Neural Glial Circuit (f=1.0) d[ IP 3 ] dt = 1 IP 3 τ IP3 ([ ] * [ IP 3 ]) + ν[glu]n f κ n + [glu] n Θ(t t r ) Θ(t t r 2ms) ν = ρ S mglur V astro + N A I astro = 2.11 µa Θ(ln y)ln y 2 cm y = [Ca 2+ ]/nm

20 Larger abundance of mglurs (f~30) bursting spiking

21 Larger abundance of mglurs Astrocytes from epileptic foci: mglurs are over-expressed by a factor of about (rat models and human tissue). Ulas et al., Glia 30, 352 (2000), Tang and Lee, J. Neurocytology, 30, 137 (2001), Aronica et al. Europ.J. Neurosci., 12, 2333 (2000)

22 Feedforward Multimodal control of synaptic transmission Astrocytic glutamate activates another synapse downstream causing excitatory inward currents Parpura and Haydon, PNAS 1999 Nadkarni & Jung, PRL, 91,2003, Nadkarni & Jung, Phys.Bio. 2004, Liu et al, PNAS 101, 2004

23 SYNCHRONIZATION Exciting and synchronizing not connected neuronal circuits Remote synapses influenced by independent astrocytic circuitry allowing for cross talk between distant synapses - mechanism of associative learning?

24 Feedback Neuronal firing activates synaptic astrocyte. Resulting astrocytic glutamate acts to potentiate the vesicle release of the presynaptic neuron itself Volterra & Medolse, Nat Revs NeuroSci. 2005

25 Ca 2+ induced Ca 2+ release (CICR) Activation of mglurs Production of IP3 - an important secondary messenger Activation of IP3Rs on the ER and a consequent release of Ca 2+ from the ER Oscillatory response of Ca 2+

26 Astrocytes Potentiate Synaptic Transmission Experimental Evidence: Astrocyte activity enhances transmission success probability and spontaneous activity from ~ 0.30 to ~0.6 ( ΔP 0.3) Increase asynchronous release and decrease in amplitudes of the postsynaptic currents Kang et.al Nat NeuSci 1998 Fiacco and McCarthy, J of NeuSci Perea and Araque, Science, 2007.

27 Intracellular stores mediated enhanced released probability

28 The Story Induced vesicle release and Asynchronous release presynaptic Ca 2 Astrocyte Ca 2+ Ca 2+ α Activity dependent increase in presynaptic Ca 2+ and synaptic transmission probability Glu Ca 2+ Neurotransmitter resource limited --> depletion --> postsynaptic depression Optimal synaptic potentiation by astrocyte

29 Postsynaptic response to astrocyte coupling α=0.0 α=0.04 α=

30 Modeling the Transmitter Release Activity dependent depletion of neurotransmitter dr dt = I τ rec U SE R δ(t t rel ) U SE R δ(t t async ) Release site has 4 independent gates. Usually one vesicle is released at hippocampal synapses de dt = E τ rec + U SE R δ(t t rel ) +U SE R δ(t t async ) d[ca store ] dt 2 = γ [Ca + store ] + 2 α[ca astro ]Θ([Ca astro 196.4nM) I =1 R E I post = A post E 2 d[ca + AP ] dt = γ 1 2 [Ca + AP ] + α 1 Θ(v 35mV ) [Ca ] = [Ca + 2 store ] + [Ca + AP ] Tsodyks and Markram, PNAS,1997 Nadkarni, Jung and Levine, PLoS Comp Bio Bertram, Sherman & Stanley J of N.Phys 96 Nadkarni and Jung, Physical Biology 2007

31 Modeling ATP signaling Astrocytes release glutamate, D-Serine, ATP, GABA Adenosine derived from this ATP (~500 ms) causes heterosynaptic suppression via presynaptic inhibition of vesicular release - a mechanism for distant synapses to crosstalk. ATP modulated vi P2X (cation)and P2Y(metabotropic leading to IP3 production) Pascual et al. Science 2005 Zhang et al. Neuron 2003 Kazuhide et. al 2010 Khakh et. al 2012

32 Outlook Neuron and astrocytes share receptors and signaling pathways. This makes use of pharmacological tools to discern the role of glia from neurons extremely difficult and can make computational modeling a very valuable tool. Functional implication of the dichotomy facilitation-depression and increase in noise seen in correlation with astrocyte activity. Tripartite synapse can operate at a transmission probability that is in the optimal regime due feedback from astrocytes The goal is to arrive at general principles as well as unique features of synaptic transmission across systems, understanding of structure-function reln: Postdiction and Prediction Models of real synapses astrocytes, dendritic trees etc. can be built based on increasing biophysical knowledge. Challenge will be to figure out which of these degrees of freedom are essential for which types of information processing

33 Acknowledgements Postdoc Anup Gopalkrishna Pillai, IISER Pune Collaborators Tom Bartol, Salk Institute Peter Jung, Ohio University Terry Sejnowski, Salk Institute Herbert Levine, Center for Theoretical Biological Physics, Rice University