Synaptic Integration

Transcription

1 Synaptic Integration 3 rd January, 2017 Touqeer Ahmed PhD Atta-ur-Rahman School of Applied Biosciences National University of Sciences and Technology

2 Excitatory Synaptic Actions

3 Excitatory Synaptic Action is Mediated by Glutamate-Gated Channels The excitatory transmitter released from the stretchreceptor (under study here) neurons is L. glutamate. The EPSP in these neurons results from the opening of glutamate gated channels permeable to both Na + and K +. This ionic mechanism in glutamate gated channels is similar to that produced by ACh at the neuromuscular junction where the ACh-gated channels conduct both Na + and K +, with nearly equal permeability. The glutamate-gated channels conduct both Na + and K +, with nearly equal permeability. As a result, the reversal potential for current flow through these channels lies at 0 mv Most important point in case of excitation: When you disturb membrane potential, it will try to move towards the reversal potential

4 Glutamate Receptor The glutamate receptors can be divided into two broad categories: Ionotropic receptors (three sub-types: AMPA, kainate, and NMDA) that directly gate channels Metabotropic receptors that indirectly gate channels through second messengers The action of glutamate on the ionotropic receptors is always excitatory, while activation of the metabotropic receptors can produce either excitation or inhibition.

5 Non-NMDA Receptors The motor neuron has both non-nmda and NMDA receptors. At the normal resting potential the non-nmda ionotropic receptors generate the large early component of the EPSP in motor neurons (as well as in most other central neurons) in response to stimulation of the primary afferent sensory fibers. These receptors gate cation channels with relatively low conductances (<<20 ps (picosiemens)) that are permeable to both Na + and K + but are usually less permeable to Ca 2+, whereas, NMDA receptors are more permeable to Ca 2+ ions than Na + ions.

6 NMDA Receptors The NMDA receptor-channel, which contributes to the late component of the EPSP, has three exceptional properties. First, the receptor controls a cation channel of high conductance (50 ps) that is permeable to Ca 2+ as well as to Na + and K +. Second, opening of the channel requires extracellular glycine as a cofactor; the channel will only function in the presence of glycine. Under normal conditions the concentration of glycine in the extracellular fluid is sufficient to allow the NMDA receptor-channel to function efficiently. Third, the channel is unique among transmitter-gated channels thus far characterized because its opening depends on membrane voltage as well as a chemical transmitter.

7 Non-NMDA and NMDA Receptors Functioning Non-NMDA early Current Non-NMDA early + APV NMDA (late) Current NMDA receptors contributes only a small late component in the normal EPSC as shown in cells in the hippocampus. NMDA receptor-channels are present in motor neurons and throughout the brain. A. These traces show excitatory postsynaptic current at three different membrane potentials. The difference between the traces (blue region) represents (NMDA contribution). At -80 mv there is no current through the NMDA receptor-channels because of pronounced Mg 2+ block. At -40 mv a small late inward current is evident. At +20 mv the late component is more prominent and has reversed to become an outward current. The vertical dotted line indicates a time 25 ms after the peak of the synaptic current and is used for the calculations of late current in B. B. The current through the non-nmda receptors was measured at the peak of the synaptic current and is plotted as a function of membrane potential (filled triangles). The current through the NMDA receptors was measured 25 ms after the peak of the synaptic current (dotted line in A; a time at which the non-nmda component has decayed to zero) and is shown as filled circles. Note that the non-nmda receptor-channels behave as simple resistors; current and voltage have a linear relationship. In contrast, current through the NMDA receptors is non-linear and increases as the membrane is depolarized from -80 to -40 mv, owing to progressive relief of Mg 2+ block. The reversal potential of both receptor-channel types is at 0 mv. Note how APV blocks the late (NMDA) component but not the early (non-nmda) component of the EPSP.

8 NMDA Receptors and Disease Imbalance in excitatory transmitters such as glutamate may, under certain circumstances, contribute to disease. Excessive amounts of glutamate are highly toxic to neurons. Most cells in the brain have receptors that respond to L-glutamate. In tissue culture even a brief exposure to high concentrations of glutamate will kill many neurons, an action called glutamate excitotoxicity. In many cell types glutamate excitotoxicity is thought to result predominantly from excessive inflow of Ca 2+ through NMDA-type channels. High concentrations of intracellular Ca 2+ may activate calcium-dependent proteases and phospholipases and may produce free radicals that are toxic to the cell. Glutamate toxicity may contribute to cell damage after stroke, to the cell death that occurs with episodes of rapidly repeated seizures experienced by people who have status epilepticus, and to degenerative diseases such as Huntington disease. Agents that selectively block the NMDA receptor may protect against the toxic effects of glutamate and are currently being tested clinically.

9 Inhibitory Synaptic Actions

10 Role of Spontaneous Inhibition in Firing Pattern Many cells in the brain are spontaneously active and synaptic inhibition can exert powerful control over spontaneously active nerve cells By suppressing the spontaneous generation of action potentials in these cells, synaptic inhibition can shape the pattern of firing in a cell

11 Inhibitory Synaptic Action Inhibitory synaptic action is usually mediated by GABA- and glycine-gated channels that conduct chloride The IPSP and inhibitory synaptic current reverse at the equilibrium potential for Cl- ions

12 GABA- and Glycine- Gated Channel Currents The unitary currents through single GABA and glycine gated channels (patch-clamp). Both transmitters activate Cl - channels that show all-or-none step-like openings, similar to the ACh- and glutamate-activated current. The conductance of a glycine-gated channel (46 ps) is larger than that of a GABAgated channel (30 ps) so that the unitary current steps activated by glycine are somewhat larger than the current steps activated by GABA. This difference in single-channel conductance is due to the larger pore diameter of the glycine-gated channel compared with that of the GABA-gated channel. (Fig C and D ): Comparison of excitatory and inhibitory currents and their reversal potentials are shown.

13 Synapses on Cell Bodies Are Often Inhibitory The impact of an inhibitory current in the postsynaptic neuron depends on the distance the current travels from the synapse to the cell's trigger zone. In this hypothetical experiment the inputs from inhibitory axosomatic and axodendritic synapses are compared by means of recordings from both the cell body (V 1 ) and the dendrite (V 2 ) of the postsynaptic cell. Stimulating cell B at the axosomatic synapse produces a large IPSP in the cell body. Because the synaptic potential is initiated in the cell body it will not decay before arriving at the trigger zone in the initial segment of the axon. Stimulating cell A at the axodendritic synapse produces only a small IPSP in the cell body because the potential is initiated so far from the axon hillock; it decays as it spreads to the cell body. That s why it is more efficient to have axosomatic synapses to be inhibitory