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Neurotransmission (Latin:transmissio "passage, crossing" fromtransmittere "send, let through") is the process by which signaling molecules calledneurotransmitters are released by theaxon terminal of aneuron (the presynaptic neuron), and bind to and react with thereceptors on thedendrites of another neuron (the postsynaptic neuron) a short distance away. A similar process occurs inretrograde neurotransmission, where the dendrites of the postsynaptic neuron release retrograde neurotransmitters (e.g.,endocannabinoids; synthesized in response to a rise inintracellularcalcium levels) that signal through receptors that are located on the axon terminal of the presynaptic neuron, mainly atGABAergic andglutamatergicsynapses.[1][2][3][4]
Neurotransmission is regulated by several different factors: the availability and rate-of-synthesis of the neurotransmitter, the release of that neurotransmitter, the baseline activity of the postsynaptic cell, the number of available postsynaptic receptors for the neurotransmitter to bind to, and the subsequent removal or deactivation of the neurotransmitter by enzymes or presynaptic reuptake.[5][6]
In response to a thresholdaction potential orgraded electrical potential, a neurotransmitter is released at thepresynapticterminal. The released neurotransmitter may then move across the synapse to be detected by and bind with receptors in the postsynaptic neuron. Binding of neurotransmitters may influence the postsynaptic neuron in either aninhibitory orexcitatory way. The binding of neurotransmitters to receptors in the postsynaptic neuron can trigger either short term changes, such as changes in themembrane potential calledpostsynaptic potentials, or longer term changes by the activation ofsignaling cascades.
Neurons form complex biological neural networks through which nerve impulses (action potentials) travel. Neurons do not touch each other (except in the case of anelectrical synapse through agap junction); instead, neurons interact at close contact points called synapses. A neuron transports its information by way of an action potential. When the nerve impulse arrives at the synapse, it may cause the release of neurotransmitters, which influence another (postsynaptic) neuron. The postsynaptic neuron may receive inputs from many additional neurons, both excitatory and inhibitory. The excitatory and inhibitory influences are summed, and if the net effect is inhibitory, the neuron will be less likely to "fire" (i.e., generate an action potential), and if the net effect is excitatory, the neuron will be more likely to fire. How likely a neuron is to fire depends on how far itsmembrane potential is from thethreshold potential, the voltage at which an action potential is triggered because enough voltage-dependentsodium channels are activated so that the net inward sodium current exceeds all outward currents.[7] Excitatory inputs bring a neuron closer to threshold, while inhibitory inputs bring the neuron farther from threshold. An action potential is an "all-or-none" event; neurons whose membranes have not reached threshold will not fire, while those that do must fire. Once the action potential is initiated (traditionally at theaxon hillock), it will propagate along the axon, leading to release of neurotransmitters at thesynaptic bouton to pass along information to yet another adjacent neuron.
and activates a receptor in the postsynaptic membrane.
Neurotransmitters are spontaneously packed in vesicles and released in individual quanta-packets independently of presynaptic action potentials. This slow release is detectable and produces micro-inhibitory or micro-excitatory effects on the postsynaptic neuron. An action potential briefly amplifies this process. Neurotransmitters containing vesicles cluster around active sites, and after they have been released may be recycled by one of three proposed mechanisms. The first proposed mechanism involves partial opening and then re-closing of the vesicle. The second two involve the full fusion of the vesicle with the membrane, followed by recycling, or recycling into the endosome. Vesicular fusion is driven largely by the concentration of calcium in micro domains located near calcium channels, allowing for only microseconds of neurotransmitter release, while returning to normal calcium concentration takes a couple of hundred of microseconds. The vesicle exocytosis is thought to be driven by a protein complex calledSNARE, that is the target forbotulinum toxins. Once released, a neurotransmitter enters the synapse and encounters receptors. Neurotransmitter receptors can either be ionotropic or g protein coupled. Ionotropic receptors allow for ions to pass through when agonized by a ligand. The main model involves a receptor composed of multiple subunits that allow for coordination of ion preference. G protein coupled receptors, also called metabotropic receptors, when bound to by a ligand undergo conformational changes yielding in intracellular response. Termination of neurotransmitter activity is usually done by a transporter, however enzymatic deactivation is also plausible.[9]
Each neuron connects with numerous other neurons, receiving numerous impulses from them.Summation is the adding together of these impulses at the axon hillock. If the neuron only gets excitatory impulses, it will generate an action potential. If instead the neuron gets as many inhibitory as excitatory impulses, the inhibition cancels out the excitation and the nerve impulse will stop there.[10] Action potential generation is proportionate to the probability and pattern of neurotransmitter release, and to postsynaptic receptor sensitization.[11][12][13]
Spatial summation means that the effects of impulses received at different places on the neuron add up, so that the neuron may fire when such impulses are received simultaneously, even if each impulse on its own would not be sufficient to cause firing.
Temporal summation means that the effects of impulses received at the same place can add up if the impulses are received in close temporal succession. Thus the neuron may fire when multiple impulses are received, even if each impulse on its own would not be sufficient to cause firing.[14]
Neurotransmission implies both a convergence and a divergence of information. First one neuron is influenced by many others, resulting in a convergence of input. When the neuron fires, the signal is sent to many other neurons, resulting in a divergence of output. Many other neurons are influenced by this neuron.[citation needed]
Cotransmission is the release of several types of neurotransmitters from a singlenerve terminal.
At the nerve terminal, neurotransmitters are present within 35–50 nm membrane-encased vesicles calledsynaptic vesicles. To release neurotransmitters, the synaptic vesicles transiently dock and fuse at the base of specialized 10–15 nm cup-shapedlipoprotein structures at the presynaptic membrane calledporosomes.[15] The neuronal porosomeproteome has been solved, providing the molecular architecture and the complete composition of the machinery.[16]
Recent studies in a myriad of systems have shown that most, if not all, neurons release several different chemical messengers.[17] Cotransmission allows for more complex effects atpostsynaptic receptors, and thus allows for more complex communication to occur between neurons.
In modern neuroscience, neurons are often classified by their cotransmitter. For example, striatal "GABAergic neurons" utilizeopioid peptides orsubstance P as their primary cotransmitter.
Some neurons can release at least two neurotransmitters at the same time, the other being a cotransmitter, in order to provide the stabilizing negative feedback required for meaningful encoding, in the absence of inhibitoryinterneurons.[18] Examples include:
Noradrenaline andATP aresympathetic co-transmitters. It is found that the endocannabinoidanadamide and thecannabinoidWIN 55,212-2 can modify the overall response to sympathetic nerve stimulation, and indicate that prejunctionalCB1 receptors mediate thesympatho-inhibitory action. Thus cannabinoids can inhibit both the noradrenergic andpurinergic components of sympathetic neurotransmission.[19]
One unusual pair of co-transmitters is GABA and glutamate which are released from the same axon terminals of neurons originating from theventral tegmental area (VTA),internal globus pallidus, andsupramammillary nucleus.[20] The former two project to thehabenula whereas the projections from the supramammillary nucleus are known to target thedentate gyrus of the hippocampus.[20]
Neurotransmission is genetically associated with other characteristics or features. For example,enrichment analyses of different signaling pathways led to the discovery of a genetic association with intracranial volume.[21]
Thus, it is conceivable that low levels of CB1 receptors are located on glutamatergic and GABAergic terminals impinging on DA neurons [127, 214], where they can fine-tune the release of inhibitory and excitatory neurotransmitter and regulate DA neuron firing.
Consistently, in vitro electrophysiological experiments from independent laboratories have provided evidence of CB1 receptor localization on glutamatergic and GABAergic axon terminals in the VTA and SNc.
Direct CB1-HcrtR1 interaction was first proposed in 2003 (Hilairet et al., 2003). Indeed, a 100-fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed ... In this study, a higher potency of hypocretin-1 to regulate CB1-HcrtR1 heteromer compared with the HcrtR1-HcrtR1 homomer was reported (Ward et al., 2011b). These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact. ... The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction. ... Acting as a retrograde messenger, endocannabinoids modulate the glutamatergic excitatory and GABAergic inhibitory synaptic inputs into the dopaminergic neurons of the VTA and the glutamate transmission in the NAc. Thus, the activation of CB1 receptors present on axon terminals of GABAergic neurons in the VTA inhibits GABA transmission, removing this inhibitory input on dopaminergic neurons (Riegel and Lupica, 2004). Glutamate synaptic transmission in the VTA and NAc, mainly from neurons of the PFC, is similarly modulated by the activation of CB1 receptors (Melis et al., 2004).
