How do neurons communicate?

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Answer three out of the following four questions. Some of the questions are fairly broad in nature. You should provide as much detail as possible and reference articles from the literature when appropriate.

1) There are topographic maps of stimulus features in the cortex.

1A) In the cerebral cortex neurons with similar receptive fields are often co-located. Why is that? Please give a computational argument.

1B) The visual cortex of cats but not rodents has orientation maps in layer 2/3. Why might there be species differences?

Topographic maps of stimulus features are present in somatosensory, visual, auditory, and motor systems in the cortex, in which adjacent areas in the central nervous system represent adjacent locations in the periphery (skin, muscle) or external environment (visual space, frequency distribution). A theory for the origin of topographic maps is the chemoaffinity hypothesis, which suggests that growing axons are primed to reach their appropriate target regions. In development, growth cones of extending axons are likely guided by molecular gradient cues via an interaction between Eph receptors and a dispersed gradient of ephrin (as well as other guiding molecules) in order to lead to the proper formation of neuronal connections. These gradients lead to differential affinities for axonal growth and guide basic topographical mapping. In addition, radial glial cells provide a cellular framework for newly generated neurons to reach their appropriate targets. With this theory, it seems only reasonable that peripheral bordering areas would navigate through the brain alongside neighboring axons to similar central regions, guided by the need for a similar molecular gradient. Grouping neurons from similar locations that are destined to be interconnected is advantageous in cortical organization, since it is metabolically costly for neurons to make long-distance connections, and it would take longer to process signals and have the appropriate output. Organization in topographic maps allows for shorter, more locally-controlled interconnections and more efficient synaptic transmission to take place.

Recent work by Ko et al has elucidated the mechanisms by which neurons form local sub-networks that process related sensory information.1 This work found that at eye opening, neurons were highly efficient at responding to precise visual features, but that neurons responding to similar visual stimuli were not yet preferentially connected. It was not until after eye opening the visual cortex experienced a rapid reshuffling of local synaptic connections, in favor of connections between neurons with similar responses and an elimination of connectivity between dissimilar neurons. While the initial formation of feature preference (in the form of feedforward input selection) is mediated by early gap junction coupling prior to visual experience, the precise connectivity of neurons with similar receptive fields occurs following patterned input. The authors generated a computational algorithm consisting of 23 recurrently connected excitatory and inhibitory integrate-and-fire neurons receiving 500 feedforward inputs modulated by a voltage-based spike timing dependent plasticity (vSTDP) learning rule that updated weights of feedforward and recurrent synapses. Specifically, the authors found that local cell pairs were more likely to develop the same receptive field if they had been connected by gap junctions that influenced recurrent connectivity, which is precisely what occurs in development.

Although the stereotypic six-laminae organization of neocortex is somewhat conserved across mammalian species, distinct differences in organization are often found. One noticeable variation between the visual cortex of cats and rodents is the presence of ocular dominance columns and orientation maps in feline visual cortex. In cats, thalamic afferents segregate into ocular dominance columns in layer 4 and orientation pinwheels in layer 2/3 and are precisely organized into hypercolumns responding to similar visual stimuli. In rodent primary visual cortex, however, there are no ocular dominance columns and no discernable structure and systematic distribution of orientation preference. This can be do to several reasons, one of which consists of biological evolutionary mechanisms – in which higher order mammals such as cats and primates exhibit more functional organization than rodents – or can be due to the smaller brain size of rodents compared to felines or primates – there might just not be room for the spatial distribution required to separate orientation-specificity into distributed maps in rodents. Regardless, although ocular dominance columns and orientation maps are not present in the rodent visual system, neighboring neurons can still have highly distinct orientation selectivity. Another evolutionary explanation for this difference comes down to the relative significance of different senses to different species. While cats are highly visual animals, rodents have been suggested to rely more heavily on their sense of smell and somatosensation via vibrissae to assess their external environments, and the precise maps of these senses are evident in the rodent brain.

1.Ko, H., Cossell, L., Baragli, C., Antolik, J., Clopath, C., Hofer, S. B., Mrsic-Flogel, T. D. The emergence of functional microcircuits in visual cortex. Nature 496, 96-100 (2013).

2.Ohki, K., Chung, S., Ch'ng, Y. H., Kara, P., Reid, R. C. Functional imaging with cellular resolution reveals precise micro-architecture in visual cortex. Nature 433, 597-603 (2005).

2) Communication between neurons can occur via electrical or chemical synapses.

2A) What are the advantages/disadvantages of these two signaling systems?

2B) Electrical synapses are common in development? Why might this be?

2C) Give examples of the role of electrical synapses in adult cortex. Where are they? What could be a role for communication by electrical synapses?

Communication between neurons can occur via two different types of synapses. The more ‘conventionally’ thought of synapses are chemical synapses, in which transmission is done via release of synaptic vesicles containing neurotransmitters at synaptic clefts, resulting in the activation of receptor molecules such as AMPA and NMDA receptors and postsynaptic membranes. However there also exist electrical synapses, in which current flows directly between multiple neurons via a specialized form of membrane channel called gap junctions. Gap junctions are formed by the connection of hexameric complexes on the membranes of two neighboring neurons and allow cytoplasmic continuity between connected cells. The pore formed by gap junctions is much larger (and inherently less specific) than pores formed by voltage-gated ion channels, permitting the passive and unobstructed flow of current (in all ion forms) and larger substances, such as ATP and other secondary messengers. One advantage of this communication mechanism is that the transmission of information can be bidirectional – current can flow in either direction and can change postsynaptic membrane potentials in this way. This leads to a second equally advantageous benefit, that it allows much faster transmission and essentially, instantaneous current flow. On the other hand, chemical synapses have no intercellular continuity and thus no direct current flow. Presynaptic and postsynaptic neurons are separated by a synaptic cleft, and current flows only in response to transmitter secretion. A disadvantage of this mechanism is the delay in transmission caused by the elaborate sequence of events required to trigger exocytosis. However, the main advantage is that this system permits smaller and more selective signals to occur, thus generating complex behaviors. Unique intracellular events can occur without automatic transmission to all neurons in the vicinity. Furthermore, by creating a discontinuity between neurons, excitotoxic damage is limited because disturbance in one cell does not automatically result in damage to other cells (for example, by deficient extrusion and thus accumulation of certain ions).

Electrical synapses have a unique role in development and thus are found commonly at early stages in life. Due to their ability to conduct passive flow of current and thus electrical continuity, they are especially advantageous in propagating correlated spontaneous activity in the form of oscillations and activity waves necessary for proper cortical organization and guiding circuit formation.1 In the cortex, groups of neurons undergo spontaneous intracellular calcium changes that propagate via gap junctions as highly correlated patterns of activity that do not require synaptic transmission, but are instrumental in proper circuit formation.2 It has also been shown that intracolumnar synchronization of cortical activity via cholinergic oscillations in rodent barrel cortex (driven by subplate) is mediated by gap junctions. Furthermore, the extent of cytoplasmic continuity within subplate in early development has been revealed by filling a single subplate neuron with a dye that passes through gap junctions,3 which can help mediate the spread of early organization-determinant cortical activity. Recent work has added to the function of gap junctions in development by illustrating their role in influencing the functional specificity of recurrent connections.4 Using a computational algorithm supported by experimental evidence, the authors show that when clonally related neurons are electrically coupled early in development, they are more likely to develop the shared feature selectivity (same receptive fields) before also becoming synaptically connected. This suggests that transient gap junctions have a role in instructing adult connectivity.

A degree of electrical continuity also persists in the adult, where it plays a role in the control of rhythmic and coordinated activity, and events that require synchrony and precise, rapid timing. Electrical synapses in the crayfish and other adult fish, for example, allow for their rapid evasion from predators by minimizing reaction time between stimulus occurrence and motor response. In fish, synapses from vestibular nerve afferents onto Mauther cells are via electrical synapses, which results in the instantaneous transmission of current to generate the rapid tail-flip escape behavior stereotypic to their predator-evasion. In the brainstem, gap junctions between neurons generate the rhythmic electrical activity that underlies breathing. Furthermore, it has been shown that electrical synapses exist between GABA-releasing interneurons in the cortex, thalamus, and cerebellum, which likely play a role in the prevention of widespread excitatory activity. In addition, rapid labeling of glia by Ca2+-sensitive fluorescent dyes (among other indications) suggests that the dyes are rapidly spread by gap junctions between astrocytes.5 Cytoplasmic continuity might be critical for glial cells, which form large intracellular networks via gap junctions and aid in homeostatic mechanisms. By permitting the diffusion of large molecules, gap junctions in glial cells such as astrocytes may serve to sequester high concentrations of neurotransmitters from synaptic clefts and prevent damage to neurons by dispersing neurotransmitters.

1.Banerjee, A., Ellender, T. J. Oscillations in the developing cortex: A mechanism for establishing and synchronizing an early network? J Neurosci 29, 15029-15030 (2009).

2.Katz, L. C., Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133-1138 (1996).

3.Kanold, P. O., Luhmann, H. J. The subplate and early cortical circuits. Annu Rev Neurosci 33, 23-48 (2010).

4.Ko, H., Cossell, L., Baragli, C., Antolik, J., Clopath, C., Hofer, S. B., Mrsic-Flogel, T. D. The emergence of functional microcircuits in visual cortex. Nature 496, 96-100 (2013).

5.Bandyopadhyay, S., Shamma, S. A., Kanold, P. O. Dichotomy of functional organization in the mouse auditory cortex. Nat Neurosci 13, 361-368 (2010).

3) Calcium is an important second messenger.

3A) What important functions does Calcium serve inside neurons?

3B) How does Calcium get into neurons?

3C) How is Calcium regulated? Where does it go?

3D) Describe differences in Calcium regulation between inhibitory and excitatory neurons. Why might there be differences?

An action potential reaching the axon terminal of a presynaptic neuron results in a change in membrane potential that leads to the opening of voltage-gated calcium channels (N-type, P-type, T-type, and more). Due to the steep concentration gradient of calcium ([Ca2+]i = 0.0001 mM, [Ca2+]o = 10 mM), this causes a rapid influx of calcium ions into the terminal. Calcium can also enter neurons via receptor-mediated Ca2+-channels such as the NMDA receptor, if the magnesium block is relieved via depolarization. Once inside a cell, calcium can act on a multitude of intracellular proteins and enzymes and has many specialized functions, including regulating neuronal excitability, muscle contraction, exocytosis, as well as controlling cellular activities such as gene expression. The value of this crucial ion is emphasized by the precise steps that neurons take to regulate its passage. First and foremost, calcium binds to synaptotagmin, a protein on the membrane of synaptic vesicles, and results in the release of the complexin brake holding the energetically favorable SNARE proteins, syntaxin and SNAP-25, in place. Once this brake is released, primed vesicles spontaneously fuse with the membrane of the active zone and release neurotransmitter into the synaptic cleft to propagate neuronal signals. Previous studies have revealed that a rise in intracellular calcium is both necessary and sufficient for neurotransmitter release, by showing that injection of Ca2+ into presynaptic terminals triggers transmitter secretion without any membrane depolarization, as well as by revealing that when calcium chelators are applied into the presynaptic terminal, no amount of depolarization is enough to trigger transmitter release. Calcium entry into presynaptic terminals has also been revealed by fluorescence imaging studies, in which Ca2+-sensitive fluorescent dyes demonstrate an increase in cytosol fluorescence following an action potential. In seminal experiments conducted by Fatt and Katz,4 lowering extracellular calcium resulted in the reduction of the size of the end-plate potential (EPP), and this quantal reduction was attributed to the fact that a diminished number of vesicles fused with the presynaptic terminal membrane when there was less calcium present. In addition to acting on neuronal signaling via calcium-dependent vesicle release, calcium also acts on other enzymes such as Ca2+/calmodulin-dependent protein kinases (CaMKII), protein kinase C, cyclic AMP, adenylyl cyclase, nitric oxide synthase, and a variety of other enzymes that have widespread functions, and also has a large effect in mediating CREB-dependent transcription and therefore in learning and memory.

Following an action potential and release of synaptic vesicles, the neuron must return intracellular calcium levels back to the very low resting value as its survival is dependent on calcium homeostasis. This is done by extrusion of calcium across the plasma membrane via various pumps and exchangers, as well as by sequestering calcium in internal calcium stores such as within the mitochondria and endoplasmic reticulum. The Na+/ Ca2+ exchanger and the Ca2+-ATPase act to extrude free intracellular calcium ions back into the extracellular matrix, and a Ca2+ uniporter and H+/Ca2+ exchanger helps to sequester calcium in intracellular stores. Additionally, as soon as calcium flows into the neuron it interacts with calcium buffers and binding proteins that serve enhance the spatial and temporal precision of calcium effects. Some of these include calbindin, calretin, and parvalbumin. Buffers and binding proteins are important in limiting calcium-dependent effects in that only free calcium ions are biologically active.

One of the ways calcium is differentially regulated in inhibitory and excitatory neurons is through the distinct use of various calcium buffers. Inhibitory neurons express parvalbumin, which has slower binding kinetics and a higher affinity for calcium. Inhibitory neurons can therefore help to prevent excitotoxicity by helping to buffer extracellular calcium. A distinct kinetic profile of calcium buffering in inhibitory cells can also have a temporal effect in modulating neuronal activity and maintaining appropriate levels of activity. Furthermore, a spatial modulatory effect of calcium dynamics is inherent to inhibitory neurons resulting from the presence of gap junctions electrically connecting inhibitory neurons into adulthood. This connectivity allows the instantaneous widespread flow of calcium and resultant postsynaptic membrane changes to effect a larger area of neurons.

1.Grienberger, C., Konnerth, A. Imaging calcium in neurons. Neuron 73, 862-885 (2012).

2.Tsien, R. W., Tsien, R. Y. Calcium channels, stores, and oscillations. Annu Rev Cell Biol 6, 715-760 (1990).

3.Berridge, M. J., Bootman, M. D., Roderick, H. L. Calcium signalling: Dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol 4, 517-529 (2003).

4. Fatt, P., Katz, B. Spontaneous subthreshold activity at motor nerve endings. J Physiol 117, 109-128 (1952).

4) Ion channels critically define the spiking pattern of neurons.

4A) Give at least 2 examples of different spiking patterns that are due to the expression of specific Na-channels and explain in detail how channel properties (gating behavior and kinetics) give rise to the spiking pattern.

4B) Give at least 2 examples of different spiking patterns that are due to the expression of specific potassium channels and explain in detail how channel properties (gating behavior and kinetics) give rise to the spiking pattern.

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