Correlated network activity in the developing hippocampus: role in synaptogenesis

Transcription

1 Enrico Cherubini Correlated network activity in the developing hippocampus: role in synaptogenesis SPACE PHYSICS and BIOLOGY Dubna, December 19-23, 2010

2 The construction of the brain relies on genetic and environmental determinants nature and nurture While nature provides a set of genes that control the general organization of the brain, nurture ensures that genetically built neuronal circuits adapt to the environment Learning constitutes an adaptive process involving experience-or activity-dependent mechanisms regulating several developmental steps, including synapses formation and elimination

3 Correlated neuronal activity constitutes a hallmark of developmental networks

4 Giant depolarizing potentials (GDPs)

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6 Immature EEG (30 weeks post-conception) «tracé discontinu» Dreyfus-Brisac et al. 1976

7 GDPs are generated by the synergistic action of glutamate and GABA

8 GABAergic Hub Neurons Orchestrate Synchrony in Developing Hippocampal Networks Published by AAAS Bonifazi et al. Science 2009;326:

9 GABA depolarizes and excites tagged neurons by an outwardly directed flux of chloride

10 GABA A -mediated postsynaptic responses at P2 (perforated patch) Tyzio et al. Epilepsia 48 Suppl 5:96-105, 2007

11 GABA A -mediated postsynaptic responses at P15 Tyzio et al. Epilepsia 48 Suppl 5:96-105, 2007

12 Changes in chloride homeostasis modify synaptic signaling by GABA Cl - Cl - Cl - Cl - Cl - Depolarization Hyperpolarization E Cl V m V m E Cl

13 Developmental regulation of Cl - homeostasis in neurons immature neurons mature neurons NKCC KCC2

14 Developmental regulation of the K + /Cl - co-transporter KCC2 Rivera et al. Nature 397, , 1999

15 Changes in E GABA are independent of the resting membrane potential A B Ito & Cherubini, J. Physiol., 440, 67-83, 1991

16 Early GABA excitation is critical for morphological maturation of neonatal cortical neurons Cancedda et al. J. Neurosci. 27: , 2007

17 GDPs emerge when synaptic trafficking and cell firing exceed a certain frequency threshold

18 GDPs are typically preceded by an increased number of spontaneous synaptic events Safiulina et al. Mol. Neurobiol. In press

19 Burst firing is controlled by axo-somatic INaP and IM Beck and Yaari, 2008

20 Intrinsic bursting activity in neonatal and juvenile neurons

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22 Low expression of Kv7/M channels in immature neurons

23 Low expression of IM in immature hippocampal neurons

24 Single point mutations in Kv7/Mchannels are responsible for Benign Familial Neonatal Convulsions (BFNC)

25 Dye-coupled hilar interneurons Strata et al. J. Neurosci. 17, , 1997

26 GDPs act as coincident detectors to enhance synaptic efficacy at GABAergic and glutamatergic synapses

27 Pairing GDPs with Schaffer collateral stimulation A B Mohajerani et al. PNAS 104: , 2007

28 Pairing GDPs with Schaffer collateral stimulation induces a persistent increase in synaptic efficacy Mohajerani et al. PNAS 104: , 2007

29 * pairing no pairing Amplitude (%) GPSCs amplitude

30 Pairing-induced potentiation is prevented when calcium in the postsynaptic cell is chelated with BAPTA Kasyanov et al. PNAS 101, , 2004

31 BDNF mimics the effects of pairing on synaptic potentiation

32 BDNF-induced increase in synaptic strength is dependent on the activation of Trk B receptors localized on presynaptic neurons. K252a in the pipette K252a in the bath Mohajerani et al. PNAS 104:

33 Pairing-induced increase in frequency of sepscs requires the activation of TrkB receptors by BDNF

34 Pairing-induced increase in synaptic efficacy requires the activation of the ERK pathway Mohajerani et al. PNAS 104:

35 Pairing-induced increase in synaptic efficacy requires the activation of the ERK pathway pairing no pairing U0126 Mohajerani et al. PNAS 104:

36 Overview of the signal transduction pathway involving BDNF TrkB TrkB VSCCs Ca 2+ BDNF Ca 2+ VSCCs Ca 2+

37 TrkB TrkB VSCCs Ca 2+ BDNF Ca 2+ VSCCs Ca 2+

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39 GDPs are network driven events generated by the interplay between glutamate and GABA, which early in development, depolarizes and excites targeted cells GDPs are generated when synaptic trafficking and cell firing reach a certain threshold Pairing GDPs with stimulation of afferent inputs persistently enhances synaptic efficacy at both GABAergic and glutamatergic synapses GDPs render the immature hippocampus more prone to seizures

40 International School for Advanced Studies (SISSA), Trieste, Ita Elena Avignone Sonia Bolea Alexander Kasyanov Majid Mohajerani Victoria Safiulina Sudhir Sivakumaran Fabrizio Strata Institute of Higher Nervous Activity, Russian Academy of Sciences, Moscow, Russia Leon Voronin

41 Synchronous activity in the subiculum of epileptic patients Cohen et al. Science 298, , 2002

42 Interictal events recorded on the EEG are very similar to those recorded in vitro

43 GABA depolarizes targeted cells Cohen et al. Science 298, , 2002

44 GABA released from MF terminals depolarizes principal cells EGPSCs Control: -47 mv Bume: -71 mv Sivakumaran et al. J. Neurosci. 29: , 2009

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46 Pairing GDPs with mossy fibers Kasyanov et al. PNAS 101, , 2004

47 The pairing procedure persistently enhances synaptic efficacy at low probability MF-CA3 synapses Kasyanov et al. PNAS 101, , 2004

48 The pairing procedure switches on presynaptically silent synapses Kasyanov et al. PNAS 101, , 2004

49 Developmental changes in the effect of synaptic activation of GABA-A receptors with MUA Tyzio et al. Epilepsia 48 Suppl 5:96-105, 2007

50 Mesial temporal lobe epilepsy subiculum pyramidal neurons

51 A general sequence for the maturation of coherent electrical activity patterns Allene & Cossart, J. Physiol. 588:83-91, 2010

52 Expression of KCC2 mrna in the developing rat hippocampus revealed by in situ hybridization Rivera et al. Nature 397, , 1999

53 GABA released from GABAergic interneurons drives principal cells Mohajerani & Cherubini, Eur. J. Neurosci. 22: , 2005