Misericordia University Neuronal Signaling General Physiology Tony Serino. Ph.D. Biology Dept. Misericordia University

Nervous System Nervous tissue: Generates and conducts electrical Controls and/or modifies all other systems Rapid response time Usually short duration effects Nervous tissue: Generates and conducts electrical Consists of neurons and neuroglia cells

Neuron Anatomy Axonal terminal Nerve ending Synaptic boutons Synaptic knobs

Functional Zones of a Neuron Receptor Zone Initial segment of Axon (trigger zone) Nerve endings Axon

Synapses Areas where neurons communicate with other cells Can be chemical (with neurotransmitters) or electrical (gap junctions) May be in different shapes

Anatomy of Synapse (chemical) Neurotransmission ends when NT diffuses away, re-absorbed by presynaptic neuron, or NT metabolized (degraded) by enzymes in cleft

Neurotransmission Action potential (AP)) descends axon to synaptic terminal Depolarization opens voltage gated Ca++ channels in presynaptic membrane Ca++ enters terminal Triggers a number of synaptic vesicles to fuse with outer membrane which diffuses across cleft NT binds to receptor on postsynaptic membrane This leads to channels opening on postsynaptic membrane changing the membrane’s potential; NT is removed from the cleft A number of vesicles are held in an active zone for secretion by SNARE proteins Synaptotagmin may play role in linking calcium to vesicle secretion

Neurotransmitters Catecholamines

Membrane Potentials Requires: A difference in ion distribution across membrane Selectively permeable membrane Non-diffusible anions Electrogenic pump

Equilibrium Potentials Voltage necessary to stop the movement of a charged particle down its concentration gradient across a semi-permeable membrane Can be calculated using the Nernst Equation Simplifying (filling in constants);

Equilibrium Potential Using the concentration values given; calculate the equilibrium potential for Na+: E ~ +60 mV K+: E ~ -90 mV Cl-: E ~ ?? mV

Distribution of Excess Charges Most of the cytoplasm and extracellular fluid is electrically neutral, only the membrane sees a potential difference This is measurable in mV The total effect of ions on the membrane potential is calculable by Goldman’s Equation; where Vm = membrane potential; Px = permeability of membrane to ion

Goldman’s Constant Field Equation PNa = 0.035 PK = 1 PCl = 0.001 Vm = -70 mV The extremely low chloride permeability and the fact that the membrane is near Cl- equilibrium potential makes its effect on resting membranes negligible. Potassium has by far the greatest influence on the resting membrane potential due to its greater permeability.

Gated Channel Proteins Opening gate allows ions to travel into or out of the cell thereby changing the membrane potential Can be controlled chemically or electrically

Graded Potentials Depolarization Hyperpolarization Transient Decremental Most due to chemically gated channels opening Can be summated Proportional to stimulus strength May be excitatory or inhibitory Depolarization Inside of cell becomes less negative Hyperpolarization Inside of cell becomes more negative

Summation Temporal –a single axon fires repeatedly Spatial –two or more axons fire simultaneously

Typical Receptor Zone Activity

Action Potentials Wave-like, massive depolarization Propagated down entire length of axon or muscle cell membrane All or none No summation possible Due to opening of voltage gated channels and corresponding positive feedback cycle established 1. Foot –graded potentials 2. Uplimb –fast depolarization 3. Downlimb –fast repolarization 4. After Hyperpolarization –overshoot due to ion distribution 2 3 1 4

Events in Membrane during the AP

Refractory Periods Absolute Refractory Period Relative Refractory Period 20 Uplimb Depolarization Na+ enters Downlimb (Repolarization; K+ leaves) Membrane Potential (mV) Threshold -55 -70 1 2 3 4 5 6 Stimulus After-hyperpolarization Resting Potential Time (msec)

-many NT may simply modify neuronal activity rather than leading to an AP directly Neuromodulators

Synaptic Plasticity -long term plastic changes that increase or decrease synaptic function based on synaptic history (or experience) Auto-regulation –modification of firing rate by pre-synaptic neuron sensing degree of activity through monitoring NT in cleft or perceiving some modulator secreted by post-synaptic cell Pre-synaptic Inhibition or Facilitation –adjustment of firing rate by another neurons activity just prior to synapse Habituation –exposure to benign stimulus over time decreases pre-synaptic firing Sensitization –increase responsiveness to a previously habituated stimulus that has been paired with a noxious stimulus LTP (long term potentiation) – a long-lasting increase in synaptic effectiveness due to prolonged use

Glutamate is the most common excitatory NT in CNS Two ligand gated ion channel receptors found in synapse: AMPA (Na+) and NMDA (Ca++) Released Glutamate binds to AMPA and triggers EPSP NMDA receptors require glutamate and a depolarized membrane Repeated firing of pre-synaptic neuron finally raises the membrane potential enough to open NMDA channel Ca++ activates second messenger that increase glutamate sensitivity and maybe release Long Term Potentiation -in glutamate secreting synapses -theory for memory

Drug Intervention Possibilities Increase leakage and breakdown of NT from vesicles Agonize NT release Block NT release Inhibit NT synthesis Block NT uptake Block degradative enzymes in cleft Bind to post-synaptic receptor Stimulate or inhibit second messengers in post-synaptic cell

Axonal Transport Anterograde –towards synapse; flow of synaptic vesicles, mitochondria, etc. Retrograde –towards CB; recycled membrane vesicles, neuromodulators, etc.

AP propagation in unmyelinated axons The depolarization event triggers depolarization in the next area of the axon membrane; followed by repolarization. In this way the AP appears to move in a wave-like fashion over an unmyelinated axon membrane.

AP propagation in myelinated axons The AP appears to jump from node to node (saltatory conduction); the myelin sheath eliminates the need to depolarize the entire membrane.

Regeneration of Nerve Fibers Damage to nerve tissue is serious because mature neurons are post-mitotic cells If the soma of a damaged nerve remains intact, damage may be repaired Regeneration involves coordinated activity among: remove debris form regeneration tube and secrete growth factors regenerate damaged part

Response to Injury Anterograde degeneration with some retrograde; phagocytic cells (from Schwann cells, microglia or monocytes) remove fragments of axon and myelin sheath Cell body swells, nucleus moves peripherally Loss of Nissl substance (chromatolysis) In the PNS, some Schwann cells remain and form a tubular structure distal to injury; if gap or scarring is not great axon regeneration may occur with growth down tube In the CNS, glial scar tissue seems to prevent regeneration If contact with tube is not established then no regeneration and a traumatic neuroma forms

Regeneration in PNS