Postsynaptic mechanisms

Postsynaptic mechanisms
Neurotransmitters can either excite or inhibit the activity of a cell with which they are in contact. When an excitatory transmitter such as acetylcholine, or an inhibitory transmitter such as GABA, is released from a nerve terminal it diffuses across the synaptic cleft to the postsynaptic membrane, where it activates the receptor site. Some receptors, such as the nicotinic receptor, are directly linked to sodium ion channels, so that when acetylcholine stimulates the nicotinic receptor, the ion channel opens to allow an exchange of sodium and potassium ions across the nerve membrane. Such receptors are called ionotropic receptors. The generation of action potentials by nerve axons and muscle fibres was first described by the German physiologist Emil DuBois-Reymond in 1849.However, it was not until over a century later that the underlying mechanism was explained in terms of the properties of the specific membrane proteins forming the voltage-gated ion channels of sodium and potassium ions. Second messenger system When receptors are directly linked to ion channels, fast excitatory postsynaptic potentials (EPSPs) or inhibitory postsynaptic potentials (IPSPs) occur. However, it is well established that slow potential changes also occur and that such changes are due to the receptor being linked to the ion channel indirectly via a second messenger system.For example, the stimulation of b- adrenoceptors by noradrenaline results in the activation of adenylate cyclase on the inner side of the nerve membrane. This enzyme catalyses the breakdown of ATP to the very labile, high-energy compound cyclic 3,5-adenosine monophosphate (cyclic AMP). Cyclic AMP then activates a protein kinase which, by phosphorylating specific membrane proteins, opens an ion channel to cause an efflux of potassium and an influx of sodium ions. Such receptors are termed metabotropic receptors.
Many monoamine neurotransmitters are now thought to work by this receptor-linked second messenger system. In some cases, however, stimulation of the postsynaptic receptors can cause the inhibition of adenylate cyclase activity. For example, D2 dopamine receptors inhibit, while D1 receptors stimulate, the activity of the cyclase. Such differences have been ascribed to the fact that the cyclase is linked to two distinct guanosine triphosphate (GTP) binding proteins in the cell membrane, termed GI and GS. The former protein inhibits the cyclase, possibly by reducing the effects of the GS protein which stimulates the cyclase.The possible role of the family of protein kinases which translate information from the second messenger to the membrane proteins. Many of these kinases are controlled by free calcium ions within the cell. It is now established that some serotonin (5-HT) receptors, for example, are linked via G proteins to the phosphatidyl inositol pathway which, by mobilizing membrane-bound diacylglycerol and free calcium ions, can activate a specific protein kinase C. This enzyme affects the concentration of calmodulin, a calcium sequestering protein that plays a key role in many intracellular processes. Structurally G-proteins are composed of three sub-units termed alpha, beta and gamma. Of these, the alpha sub-units are structurally diverse so that each member of the G-protein super-family has a unique alpha sub-unit. Thus the multiplicity of the alpha, and to a lesser extent the beta and gamma, sub-units provides for the coupling of a variety of receptors to different second messenger systems. In this way, different receptor types are able to interact and regulate each other, thereby allowing for greater signal divergence, convergence or filtering than could be achieved solely on the basis of the receptor diversity. The functional response of a nerve cell to a transmitter can change as a result of the receptor becoming sensitized or desensitized following a decrease or increase, respectively, in the concentration of the transmitter at the receptor site. Among those receptors that are directly coupled to ion channels, receptor desensitization is often rapid and pronounced.Most of the experime ntal evidence came initially from studies of the frog motor end-plate, where it was shown that the desensitization of the nicotinic receptor caused by continuous short pulses of acetylcholine was associated with a slow-conformational change in that the ion channel remained closed despite the fact that the transmitter was bound to the receptor surface.A similar mechanism has also been shown to occur in brain cells. For example, continuous exposure of b-adrenoceptors on rat glioma cells in vitro results in a rapid reduction in the responsiveness of the receptors. This is followed by a secondary stage of desensitization, whereby the number of b-receptors decreases. It seems likely that the receptors are not lost but move into the cell and are therefore no longer accessible to the transmitter.It must be emphasized that there is considerable integration and modulation between the various second messenger systems and these interactions lead to cross-talk between neurotransmitter systems. Such cross-talk between the second messenger systems may account for changes in the sensitivity of neurotransmitter receptors following prolonged
stimulation by an agonist whereby a reduction in the receptor density is associated with a reduced physiological response (also termed receptor down-regulation).

Presynaptic mechanisms

Presynaptic mechanisms
Another important mechanism whereby the release of a neurotransmitter may be altered is by presynaptic inhibition. Initially this mechanism was thought to be restricted to noradrenergic synapses, but it is now known to occur at GABA-ergic, dopaminergic and serotonergic terminals also. In brief, it has been shown that at noradrenergic synapses the release of noradrenaline may be reduced by high concentrations of the transmitter in the synaptic cleft. Conversely, some adrenoceptor antagonists, such as phenoxybenzamine, have been found to enhance the release of the amine. It is now known that the subclass of adrenoceptors responsible for this process of autoinhibition are distinct from the a1 adrenoceptors which are located on blood vessels, on secretory cells, and in the brain. These autoinhibitory receptors, or a2 adrenoceptors, can be identified by the use of specific agonists and antagonists, for example clonidine and yohimbine respectively. Drugs acting as specific agonists or antagonists on a1 receptors, for example the agonist methoxamine and the antagonist prazosin, do not affect noradrenaline release by this mechanism. The inhibitory effect of a2 agonists on noradrenaline release involves a hyperpolarization of the presynaptic membranes by opening potassium ion channels. The reduction in the release of noradrenaline following the administration of an a2 agonist is ultimately due to a reduction in the concentration of free cytosolic calcium, which is an essential component of the mechanism whereby the synaptic vesicles containing noradrenaline fuse to the synaptic membrane before their release.There is evidence that a number of closely related phosphoproteins associated with the synaptic vesicles, called synapsins, are involved in the short-term regulation of neurotransmitter release. These proteins also appear to be involved in the regulation of synapse formation, which allows the nerve network to adapt to long-term passage of nerve impulses. Experimental studies have shown that the release of a transmitter from a nerve terminal can be decreased or increased by a variety of other neurotransmitters. For example, stimulation of 5-HT receptors on noradrenergic terminals can lead to an enhanced release of noradrenaline. While the physiological importance of such a mechanism is unclear, this could be a means whereby drugs could produce some of their effects. Such receptors have been termed heteroceptors. In addition to the physiological process of autoinhibition, another mechanism of presynaptic inhibition has been identified in the peripheral nervous system, although its precise relevance to the brain is unclear. In the dorsal horn of the spinal cord, for example, the axon terminal of a local neuron makes axo-axonal contact with a primary afferent excitatory input, which leads to a reduction in the neurotransmitter released. This is due to the local neuron partly depolarizing the nerve terminal, so that when the axon potential arrives, the change induced is diminished, thereby leading to a smaller quantity of transmitter being released. In the brain, it is possible that GABA can cause presynaptic inhibition in this way.

Stages of neurotransmission in the brain

Stages of neurotransmission in the brain
1. Action potential depolarizes the axonal terminal.
2. Depolarization produces opening of voltage-dependent calcium channels.
3. Calcium ions diffuse into the nerve terminal and bind with specific proteins on the vesicular and neuronal membranes.
4. Vesicles move towards the presynaptic membrane and fuse with it.
5. Neurotransmitter is released into the synaptic cleft by a process of exocytosis and activates receptors on adjacent neurons.
6. The postsynaptic receptors respond either rapidly (ionotropic type) or slowly
(metabotropic type) depending on the nature of the neurotransmitter.

Synaptic transmission

Synaptic transmission
The sequence of events that result in neurotransmission of information from one nerve cell to another across the synapses begins with a wave of depolarization which passes down the axon and results in the opening of the voltage-sensitive calcium channels in the axonal terminal. These channels are frequently concentrated in areas which correspond to the active sites of neurotransmitter release. A large (up to 100 mM) but brief rise in the calcium concentration within the nerve terminal triggers the movement of the synaptic vesicles, which contain the neurotransmitter, towards the synaptic membrane. By means of specific membrane-bound proteins (such as synaptobrevin from the neuronal membrane and synaptotagrin from the vesicular membrane) the vesicles fuse with the neuronal membrane and release their contents into the synaptic gap by a process of exocytosis. Once released of their contents, the vesicle membrane is reformed and recycled within the neuronal terminal. This process is completed once the vesicles have accumulated more neurotransmitter by means of an energy-dependent transporter on the vesicle membrane.
The neurotransmitters diffuse across the synaptic cleft in a fraction of a millisecond where, on reaching the postsynaptic membrane on an adjacent neuron, they bind to specific receptor sites and trigger appropriate physiological responses.There are two major types of receptor which are activated by neurotransmitters. These are the ionotropic and metabotropic receptors. The former receptor type is illustrated by the amino acid neurotransmitter receptors for glutamate, gamma-aminobutyric acid (GABA) and glycine, and the acetylcholine receptors of the nicotinic type. These are examples of fast transmitters in that they rapidly open and close the ionic channels inthe neuronal membrane. Peptides are often co-localized with these fast transmitters but act more slowly and modulate the excitatory or inhibitory actions of the fast transmitters. By contrast to the amino acid neurotransmitters, the biogenic amine transmitters such as noradrenaline, dopamine and serotonin, and the non-amine transmitter acetylcholine acting on the muscarinic type of receptor, activate metabotropic receptors. These receptors are linked to intracellular second messenger systems by means of G (guanosine triphosphate-dependent) proteins. These comprise the slow transmitters because of the relatively long time period required for their physiological response to occur. It must be emphasized however that a number of metabotropic receptors have recently been identified that are activated by fast transmitters so that the rigid separation of these receptor types is somewhat blurred. Over 50 different types of neurotransmitter have so far been identified in the mammalian brain and these may be categorized according to their chemical structure.

Neurotransmitter receptor mechanisms

Role of ion channels in nerve conduction
Ion channels are large proteins which form pores through the neuronal membrane. The precise structure and function of the ion channels depend on their physiological function and distribution along the dendrites and cell body. These include specialized neurotransmitter-sensitive receptor channels. In addition, some ion channels are activated by specific metal ions such as sodium or calcium. The structure of the voltage-dependent sodium channel has been shown to consist of a complex protein with both a hydrophilic and a hydrophobic domain, the former domain occurring within the neuronal membrane while the latter domain occurs both inside and outside the neuronal membrane. Four regions containing the hydrophilic units are arranged in the membrane in the form of a pore, with two units forming the remaining sides of the pore. This allows the sodium ions to pass in a regulated manner as the diameter of the pore, and the electrical charges on the amino acids which comprise the proteins lining the pore, determine the selectivity of the ion channel for sodium. Advances in molecular biology have shown that the DNA sequences which code for the proteins that make up the ion channels can enable the protein structure to be modified by point mutations. By changing the structure of the protein by even a single amino acid it is now apparent that the properties of the ion channel also change resulting, for example, in the opening and closing of the channel for longer or shorter periods of time or in carrying larger or smaller currents. As a consequence of molecular biological studies, it is now recognized that most ion channels of importance in neurotransmission are composed of three to five protein subunits. Their identification and characterization have now made it possible to map their location on specific neurons and to correlate their location with their specific function .

Neuronal plasticity

Neuronal plasticity
Neuronal plasticity is an essential component of neuronal adaptability and there is increasing evidence that this is primarily a biochemical rather than a morphological process. The neuron is not a fixed entity in terms of the quantity of transmitter it releases, and transmitters which are co-localized in a nerve terminal may be differentially secreted under different conditions. This, together with the repeated firing of some neurons that appear to have ‘‘leaky’’ membranes, may underlie the rhythmicity of neuronal activity within the brain. Plasticity is also evident at the level of the neurotransmitter receptors. These are fluid structures that can be internalized into the membrane so that their density, and affinity for a transmitter, on the outer surface of the nervemembrane may change according to functional need. Perhaps it is not surprising to find that our knowledge of how the brain works and where defects that lead to abnormal behaviour can arise is so deficient. The approach to understanding the biochemical basis of psychiatric disease is largely based on the assumption that the brain is chemically homogeneous, which is improbable! Nevertheless, there has been some success in recent years in probing the changes that may becausally related to schizophrenia, depression and anxiety. It should be apparent to anyone interested in the neurosciences that the brain is more than a sophisticated computer that follows a complicated programme, and any dogmatic approach to unravelling the complexities of this dynamic, plastic collection of organs which we call ‘‘brain’’ is doomed to failure.

Structure and function of nerve cells

Structure and function of nerve cells

Nerve cells have two distinct properties that distinguish them from all other types of cells in the body. First, they conduct bioelectrical signals for relatively long distances without any loss of signal strength. Second, theypossess specific intracellular connections with other cells and with tissues that they innervate such as muscles and glands. These connections determine the type of information a neuron can receive and also the nature of the responses it can .Essentially all nerve cells have one or more projections termed dendrites whose primary function is to receive information from other cells in their vicinity and pass this information on to the cell body. Following the analysis of this information by the nerve cell, bioelectrical changes occur in the nerve membrane that result in the information being passed to the nerve terminal situated at the end of the axon. The change in membrane permeability at the nerve terminal then triggers the release of the neurotransmitter. There is now evidence that the mammalian central nervous system contains several dozen neurotransmitters such as acetylcholine, noradrenaline, dopamine and 5-hydroxytryptamine (5-HT), together with many more co-transmitters, which are mainly small peptides such as met-enkephalin and neuromodulators such as the prostaglandins. It is well established that any one nerve cell may be influenced by more than one of these transmitters at any time. If, for example, the inhibitory amino acids (GABA or glycine) activate a cell membrane then the activity of the membrane will be depressed, whereas if the excitatory amino acid glutamate activates the nerve membrane, activity will be increased. The final response of the nerve cell that receives all this information will thus depend on the balance between the various stimuli that impinge upon it. Although different neurotransmitters can be produced at different synapses within the brain, the individual neuron seems capable of releasing only one major neurotransmitter from its axonal terminal, for example noradrenaline or acetylcholine. This view was originally postulated by Sir Henry Dale in 1935 and was subsequently called Dale’s Law, not incidentally by Dale himself! It is now known that, in addition to such ‘‘classical transmitters’’, peptides and/or prostaglandins may also be co-released, and Dale’s Law has been modified in the light of such evidence. The nature of the physiological response to any transmitter will depend on the function of the target receptor upon which it acts. For example, acetylcholine released from a motor neuron will stimulate the nicotinic receptor on a muscle end-plate and cause muscle contraction. When the same neurotransmitter is releasedfrom the vagus nerve innervating the heart, however, it acts on muscarinic receptors and slows the heart. Recently it has become apparent that neurotransmitters can also be released from dendrites as well as axons. For example, in dendrites found on the cells of the substantia nigra dopamine may be released which then diffuses over considerable distances to act on receptors situated on the axons and dendrites of GABAergic and dopaminergic neurons in other regions of the basal ganglia. Another means of communication between nerve cells involves dendrodendritic contacts, where the dendrites from one cell communicate directly with those of an adjacent cell. In the olfactory bulb, for example, such synapses appear to utilize GABA as the main transmitter. Thus any neuron responding to inputs that may converge from several sources may inhibit, activate or otherwise modulate the cells to which it projects and, because many axons are branched, the target cells may be widely separated and varied in function. In this way, one neuron may project to an inhibitory or excitatory cell which may then excite, inhibit or otherwise modulate the activity of the original cell. As most neurons are interlinked in an intricate network the complexity of such transmitter interactions becomes phenomenal! In brief, neurons can be conceived as complex gates which integrate the data they receive and, via their specif c collection of transmitters and modulators, have a large repertoire of effects which they impose upon their target cells.