Signal processing in neurons Metabotropic neurotransmission Electrical signals in dendrites Active properties of dendrites Signal processing at the Synapse (post) Dendrite Soma Synapse (pre)

Neuronal Anatomy Dendrites Cell Body/Soma Axon Input-spine Output-bouton

Neural circuits, cartoon version Spindle afferents excite the homonymous motor neuron and inhibit antagonists MNa Agonist Ia Antagonist MNb IN Inhibitory synapse Excitatory synapse

Synaptic structure Garner 2002

Modulation of Input E/I PSPs Synaptic strength (fast) Efficiency of neurotransmitter release Area/receptor number Channel conductance/sensitivity Dendrite morphology (slow) Input resistance Membrane capacitance Electrical propagation

NMDA receptor mediated plasticity Glutamineric synapses have both AMPA and NMDA receptors Long term potentiation: Tetanus increases subsequent EPSPs Tetanic depolarization relieves Mg2+ block (NMDA) Calcium induced channel phosphorylation increases conductance Long term potentiation Ca2+ influx via NMDA receptors DepolNMDACa2+CaMKIIAMPA Ca2+(PKA)-|I1->PP1-|AMPA High frequency stimulation High Calcium I1 is inhibited Reduces PP1 Increases AMPA

Metabotropic neurotransmission GPCRs Gs Adenyl Cyclase AC->PKA->channel phos (NaV) Gq phospholipase C PLC->DAG->PKC->channel phos (AMPA) Gbg GirK G-coupled inward rectifying potassium channel Gbg CaV N, P, Q type voltage gated calcium channel Slow – seconds to minutes

Girk Hippocampal neurons GABAA channel GABAB GPCR 1300 pA Cl- current GABAB GPCR 50 pA K+ current Slow kinetics Different GABA sensitivity Cooperative currents different time Picrotoxin blocks GABAA Ba2+ blocks K+ GABAA GABAB Distinct I-V curves Different reversal potentials Sodickson & Bean 1996

Metabotropic Neuromodulation DSI stimulation triggers fast and slow depolarization Slow depolarization is GTP dependent Blocked by non-exchangeable GDP-b-S Fast Ionotropic depolarization Stimulation Recording Slow metabotropic depolarization Blocks metabotropic process

mGluR1 suppression of m-current M-Current: potassium current, near threshold, helps set excitability After-hyperpolarization EPSPs recorded in CA3 neurons of guinnea pig DHPG is an mGluR agonist Brief exposure Long exposure Prolonged exposure to DHPG results in sustained inactivation of m-current Sustained, but not immediate suppression requires p38 MAP kinase Young S R et al. J Neurophysiol 2008;99:1105-1118

Dendrite Morphology Multiple synapses (10k+) Multiple morphologies Post-synaptic density VI Popov et al., 2004 Neuroscience

Electrical interaction in dendrites Local depolarization propagates Internal resistance Membrane capacitance Time constants RC Signal attenuation Leak current Extracellular Rm Cm Rm Cm Ri Intracellular

Active properties of dendrites NaV Low density prevents AP PSP regeneration, amplification CaV T-type, low threshold “Window current” bistatility Additional calcium-mediated magic Ih Slow depolarization Pacemaker

Multiple inputs Consider Unitary PSP 5 mV Simultaneous PSP Input current ~ 750pA = GV = G(0.060-(-0.060) G=6250 pS (multiple channels at one synapse) Simultaneous PSP G=12,100pS Input current 1500 pA Second PSP during coincident wave: G=6250; V=(0.06-(-0.055))= 115 mV Input current = 720 pA Dendritic branches isolate circuits

Coincidence reinforcement “Hebbian” plasticity Neurons that fire together, wire together Reinforcement of synapse consequent to AP Back-propagation of AP, faster than PSP Stuart & Hauser, 2001

Current interactions Kleak KNa Ih (Nah) NMDA LVA (CaT) NaV HVA (CaL) Kir KCa Cl Multiple ions, multiple gatings Local to synapse or distributed Experimental models are incomplete: Intact, decerebrate, isolated spine, slice, culture Unique populations of neurons See Grillner (2003); construct potential in a CPG or motor neuron w/nifedipine, stychnine, etc

Axon hillock Integrates signals across dendritic tree Dense NaV, highest probability of AP Rheobase Chronaxie . 2 4 6 8 1.0 1 3 5 Stim Duration (ms) Stim Ampl (nA) Action Potential No Action Rheobase 2x Rheobase Chronaxie

Output Action Potential Presynaptic inhibition Ionotropic Sub threshold depolarization of bouton Reduce Ca2+ influx Metabotropic mGluR group II & IIII Local NT release feeds back on presynaptic neruon

Sea slug (tritonia) locomotion Characteristic escape response Alternate, vigorous body flexion Simple neural circuit Lawrence & Watson 2002

Intracellular potential Tritonia CPG Escape is a programmed response Katz, et al., 2004 Dorsal Swim Interneuron Ventral Swim Interneuron Ventral Flexion Neuron Dorsal Flexion Neuron Flex Extend Intracellular potential of neurons Stimulate sensory neurons to elicit escape

Tritonia Metabotropic Neuromodulation DSI stimulation triggers fast and slow depolarization Slow depolarization is GTP dependent Blocked by non-exchangeable GDP-b-S Fast Ionotropic depolarization Stimulation Recording Slow metabotropic depolarization Blocks metabotropic process