Interneurones spike timing perception synchronous clapping R

Interneurones, spike timing, perception & synchronous clapping R Miles, INSERM EMI 0224, Paris.

The message for perception, action potentials must be generated with precise timing. for precise timing, a precise stimulus isn’t enough. for precise timing, the stimulus must be biphasic. positive depolarising - negative. hyperpolarising

Important article on synchronous clapping Self organising processes: the sound of many hands clapping. Neda et al Nature (2000) Global sound intensity Local sound intensity Index of synchrony 0 10 Time sec 20 30 After a performance, audiences clap at first randomly and then synchronously. Can we compare synchronous clapping to neuronal synchronisation…

Gamma frequency oscillations synchronous oscillations at 30 – 70 Hz cortex, hippocampus perception, attention, and sensorimotor coordination the binding problem – how to link the activity of different neurones engaged in the same cognitive task. Gamma oscillation evoked by visual stimulation in area 17 of the visual cortex Of the awake cat (Gray, 1994)

Clapping and interneurons: common mechanisms for synchrony Synchronous clapping I cells in gamma oscillations 1 Must be excited Interaction between members of audience Synaptic interactions between interneurones Must not clap at different rhythms Interneurones must have similar properties 2 3

Excitatory drive to interneurones in gamma oscillations In vivo – glutamatergic excitation and liberation of ACh. Slow, excitation of layer 5 cortical P cell Initiated by stim of cholinergic pedunculopontine tegmental nucleus cat - ketamine / xylazine (Steriade & Amzica, PNAS, 1996) 20 m. V Control m. ACh. R blocked 0. 2 s Stim In vitro « models » of gamma oscillations tetanic stimulation – glutamate plus? agonists at muscarinic ACh. R agonists at kainate receptors agonists at m. Glu. R Mouse somatosensory cortex. 0. 3 µM kainate + 20 µM carbachol Buhl, Tamas & Fisahn J Physiol, 1998 Intra Spikes Power Field 1 Freq 10 Hz 100 -20 0 Time 20 ms

Interneurone connectivity a) Interneurons that inhibit any target cell b) Interneurons that inhibit exclusively interneurons c) Interneurons that excite interneurons What molecular and developmental mechanisms underly the formation of distinct connectivities?

Interneurons that inhibit any target cell I-cell intra 20 m. V extra 20 µV 20 ms Popln Activity Sp / s 0 50 Time 100 ms (Cohen & Miles, 2000) In a network, these interneurons generate an inverse synchrony in principal cells – they tell them when not to clap…

Interneurons that inhibit interneurons Interneurons containing Calretinin contact selectively other I-cells 200 µm 20 m. V I cell IPSP 2 m. V Random firing 20 m. V Synchrony 10 µm Reconstruction: Red – axons Black – soma dendrites Black – CR+ I-cell axon Brown –CB+ I cell soma Gulyas, Hajos & Freund, 1996 20 ms Synchrony occurs when IPSPs cohere with intrinsic cellular AHP These cells generate a rhythm by synchronising IPSPs within the population of I-cells. They synchronise and spread an anti-clapping message. Lytton & Sejnowski, 1991 Wang & Rinzel, 1993

Interneurons that excite interneurons. Gap junctions occur between subsets of cortical and hippocampal interneurons. Gibson Bierlein & Connors, 1999 Galaretta & Hestrin, 1999 Mediate electrotrotonic coupling Formed by the connexin family of proteins Transmit electrical signals rapidly between coupled cells 0. 1 µm 200µm 20 µm Tamas, Buhl, Lorincz & Somogyi, Nat Neurosci, 2000

Gap junctional coupling between cortical interneurons Gap junctions transmit signals rapidly 1 n. A Current 30 m. V Cell 1 0. 5 m. V Cell 2 They act as low pass electrical filters. Slow events (AHP) are better transmitted than fast events such as action potentials. A presynaptic action potential induces a postsynaptic « spikelet » of 0. 5 – 2 m. V. 10 m. V CR 0. 5 m. V 25 ms Freq Hz Gap junctions and GABAergic synapses may exist between two interneurones 0. 5 m. V Galaretta & Hestrin, Nature 1999 Gibson, Beierlein & Connors, Nature 1999 5 ms

Interneurons should have similar properties… Interneurones form ~10% of cortical nerve cells. Diversity in co-transmitter peptides – VIP, CCK, SS Ca-binding proteins – PV, CB, CR. Morphological diversity Dendritic arborisation – which fibres can excite? Axonal arborisation – site of inhibition: somatic, dendritic, axonal. Parra, Gulyas & Miles, Neuron, 1998

Interneurons should have similar properties … Diversity in firing patterns – fast firing cells – Kv 3 channel (Lien & Jonas 2003) Diversity in expression of AMPA, NMDA and m. Glu. Rs. Receptors for modulating transmitters. Cluster analysis - Cortical I cells 20 m. V Musc m. Glu. R SLM NA SR 5 HT Linkage Glu. R 2 m Markers SO Physiol Tout Musc ACPD NA 5 HT Parra et al 1998 Cell number Cauli et al 2000

Differences in expression of proteins associated with gamma Group 1 m. Glu. Rs Type I Connexins t. ACPD 20 m. V Type II 4 m. V Type III Type IV 100 p. A 10 s Electrical coupling Cx 36 100 ms Cx 32 % Of Cells m. Glu. R 1 5 1+5 Single cell RT-PCR for m. Glu. R 1 & m. Glu. R 5 Van Hooft et al, J Neurosci 2000 Expression of two distinct connexins in 6 interneurons from RT- PCR Venance et al PNAS, 2001

So, as for synchronous clapping, inhibitory cells…. Recieve a slow excitation Interact between themselves Have quite similar properties But to understand how the rhythm emerges, must think about interactions involving I cells … Interactions between inhibitory cells Synaptic excitation of inhibitory cells Excitation of pyramidal cells

Three types of interaction between inhibitory cells GABA-mediated inhibition Excitation mediated by gap junction Chemical inhibition + gap junction 0. 5 m. V 50 ms 200 ms Biphasic signals generated by gap and GABAergic interactions give the best spike 1 m. V transmission at gamma frequencies Tamas et al, Nat Neurosci, 2002

Synaptic excitation of inhibitory cells I cells have active dendrites Active post-synaptic properties modify EPSP shape -55 m. V 0. 25 m. V -75 m. V 5 ms hot spots Voltage-dependent activation of both 50 µm Ca transients evoked by somatic firing Kaiser et al J. Physiol, 2001 Inward – peak of EPSP enhanced and Outward – decay of EPSP accelerated Galarretta & Hestrin, Science, 2001

Temporal precision of EPSP – spike coupling in hippocampal neurones (Fricker & Miles Neuron 2000) Inhibitory cell Pyramidal cell EPSP 2 m. V 20 ms Firing 20 m. V Temporal precision 20 0 0 50 100 ms

Mechanism of precise EPSP – spike coupling in I-cells V-clamp response to EPSP waveform EPSP voltage dependance Command -47 -55 200 p. A 5 m. V -70 m. V Inward plus outward 20 ms 40 p. A 10 ms Integral Peak -80 -60 Vm m. V -40 Outward (TTX) Inward (4 AP+TEA) So precise spike timing depends on a biphasic signal EPSP initiates inward - outward current

But is pyramidal cell spike generation precise or imprecise? Fricker & Miles say isolated events initiate spikes with variable timing but Mainen and Sejnowski say noisy stimuli initiate firing with millisecond precision Or maybe the precision of the timing depends on the variance / amplitude of the noisy stimulus? High variance Low variance 200 p. A 20 m. V noisy stimulus 30 m. V 200 p. A square pulse 200 ms Mainen & Sejnowski, Science, 1995 200 ms Axmacher & Miles, soumis

Noise amplitude – cellular currents – precision in P-cells Low variance High variance Noise 20 m. V -80 -96 -64 -74 -50 -88 -55 -70 Cellular current -56 -46 -83 -51 -HP PP m. V -HP 20 p. A PP m. V Firing 20 ms Low variance noise elicits purely inward currents and give low temporal precision High variance noise elicit inward – outward currents and give precise firing (maybe voltage dependent inactivation of K current and enhanced persistant Na current) Axmacher & Miles

Precision in timing of Pcell firing: EPSP – IPSP sequence Voltage clamp Current clamp EPSP Di-synaptic IPSC sum 2 ms Afferent EPSC Inhibition functional Di-synaptic EPSP 2. 5 ms …blocked 10 ms Two puise – Inhibition functional - Inhibition blocked Precise spike timing depends on a biphasic EPSP – IPSP sequence Pouille & Scanziani, Science, 2001

Somatic vs Dendritic summation - precision Soma Dual somatic –dendritic records Dendrite afferent EPSP sum Dendrite sum Soma di-synaptic IPSP Double pulse summation Summation 200 0 -100 -20 0 Interval 20 ms Feedforward inhibition terminates on the soma Restricted somatic window for summation. Pouille & Scanziani, Science, 2001

Biphasic signals generate precisely timed spikes Gap junctional excitation – chemical IPSP 1 ms EPSP initiates inward - outward current 10 ms Monosynaptic EPSP - di-synaptic IPSP 2. 5 ms

But why do we need precise spike timing? Oscillations - binding problem LTP LTD depend crucially on pre- and post spike timing Binaural sound discrimination depend on resolving timing differences in 100µs. Olfactory discrimination depend on resolving signals from oscillations And is imprecise, or delayed, firing ever useful? Late firing can maintain persistent activity in a network (XJ Wang) Reverberating circuits.