~Dr Simson Soren, Dr. Sanjib Borah and Dr Dhirashree Choudhury
Rabies virus infection is characterised by generalised convulsion, aggressiveness, restlessness and overexcitement. It is interesting that no significant changes are seen in histopathological examinations in rabies virus-infected the host. In other words, very little histopathological changes are seen in rabies virus-infected neuron cells. Immuno-histochemical studies revealed a likely indication in the central nervous system (brain and spinal cords). This virus also said to interfere/ affect the neurotransmitter (g-amino-n-butyric acid, acetylcholine, serotonin etc). In-spite of unclear histopathological changes in neurons, this virus infection showed significant clinical signs of aggressiveness and hyperexcitation in the host neurons. It has been demonstrated that rabies virus modifies the membrane ion channels, selectively interrupt some channels resulted in functional impairment of neurons.
The channels through which the ions can move from intracellular to extracellular or vice-versa. The movement of the ions is depended on the concentration gradient of the ions between intra and extracellular fluids. The ions can be pushed forcefully against the concentration gradient using energy (ATP) through the specific channels. There are channels which are voltage sensitive, open at a specific voltage. There are also channels opens after binding with the specific chemicals. So there are many ways the ion channels can be stimulated for its opening. Some of the potassium channels are remained open through which potassium can leak or move across the cell membrane. These channels are known as a leaky/funny channel.
Resting membrane potential (RMP)
Resting membrane potential (RMP) is due to the permeability of ions that is potassium, sodium, calcium and chloride. The movement of ions across the membrane and the opening of selective channels causes the unequal distribution of ions between intracellular and extracellular fluids. Potassium is highly permeable than sodium, about 100 times more than sodium. The availability of potassium leaky channels might be the reason for this. Due to this factors, the cells are polarised as shown in figure 1. The cell membrane maintains negative intracellularly during the resting stage (figure 1). The positively charged ions are always attracted toward intracellularly, but the channels are generally closed for them. Whenever there is an option due to any stimuli these channels will run inside of cells and can convert its negative potential to positive called depolarization. The potassium ion is very rich intracellularly. So, the cell is known as bags of potassium.
Figure 1. Showing the different channels, movement of ions through this channels across the cell membrane (//socratic.org/questions/what-is-the-resting-potential-for-a-neuron)
The cell membrane is negatively charged during its resting i.e. resting membrane potential. The action potential occurs in excitatory cells (neurons, muscle cells). The RMP of nerve cells around -70mv (figure 1, it is showing -60mv). The stimuli on the neurons trigger the opening of sodium channels (figure 2). Positive ion rush inside the cells. If the entry of sodium ions leads the RMP to its threshold potential i.e. -55mv than more sodium channels will open. The later sodium channels are voltage-dependent, they will open at its threshold potential (-55). More entry of sodium ion depolarised the membrane potential (+30mv). These channels open within a fraction of seconds. At the voltage of +30mv, voltage-gated potassium channel opens and then potassium leaves the cells. The leaving of potassium from voltage-gated potassium channel and the leaky channel is very essential to bring back the membrane potential (repolarization). The voltage-gated potassium channel opens only a fraction of seconds, however, potassium continues to moves through the leaky channel and helps the membrane potential to its RMP. This is how the action potential (depolarization and repolarization) moves over the cell membrane.
Figure 2. The depolarization and depolarization (//www.khanacademy.org/science/biology/ human-biology/neuron-nervous-system/a/depolarization-hyperpolarization-and-action-potentials)
Nerve cells communicate with one another through a junction called synapse. They send the information (action potential) from one neuron to another through this junction (figure 3). A neuron has different pats, dendrites and an axon. Information receives by dendrites/dendrite and sends through an axon to another neuron. Most of the synapse are chemical i.e., using chemicals messenger. This chemical messenger (acetylcholine, norepinephrine, dopamine etc.) are released at the end of one neuron (axon terminals) and they propagate the impulse to another neuron by binding with their specific receptor and the opening of sodium channels (figure 3). These chemical messengers are known as neurotransmitter. When these chemicals are bind with their specific receptor and open up the sodium channel then the channels are known as ligand-gated sodium channel. Similarly when the axon end terminal synapse with muscle fibre then it is known as a neuromuscular junction. The chemical signals are released from the terminal end of an axon, the muscle to contract after the opening of the ligand-gated channels.
Figure 3. The release of neurotransmitter from the synaptic vesicle causing an electrical signal in the postsynaptic neuron. (Image: By Thomas Splettstoesser / CC BY-SA 4.0)
Rabies virus affect the host membrane ion channels and neurotransmitters
The experimental studies demonstrated the reduction of voltage depended on sodium channels and inward rectifier potassium channels in rabies virus-infected the host. The movement of these ions is the way of impulse propagation which is required for neuron functioning. Partial and complete inhibiting of these channel leads to neuronal impairment. This rabies virus can interfere with the functioning of some channel (sodium and potassium) through some unknown mechanism. Rabies virus infection can alter the expression of an ion channel in host cells. We know that the opening of voltage-gated channels upstroke the action potential (depolarization) in neuron cells followed by repolarization. The release of neurotransmitters stimulate/fire the other neurons in the brain, spinal cord and peripheral nervous system. The rabies virus can interfere with the neuro-neuronal transmission. It can also cause the reduction in neurotransmitter uptake (g-amino-n-butyric acid). It also interferes with the binding site of neurotransmitters. The inhibition of neurotransmitter release in rabies virus-infected cells also reported. The aggressiveness, hyperexcitability and restless of rabies virus-infected host possibly due to the alteration in the membrane ion channels and neuro-neuronal transmission. It is very amazing that the components/ proteins are released by this virus utilizing host organelles to interfere with the specific ion channels, neurotransmitters without significant histopathological changes. The clinical signs of rabies virus-infected host believed to be due to neuronal dysfunctions.
The excitation of neurons, muscle contraction and relaxation are indispensable for the functioning of our body. The functioning of different channels and the role of rabies virus in interfering these channels are yet to be known. However, experimentation of natural rabies virus is quite difficult. The outcome of rabies virus infection is fatal in natural conditions. The consequences of rabies virus infection are neuronal dysfunction and death.
Authors: Department of Veterinary Physiology & Biochemistry & 1Department of Parasitology, Lakhimpur College of Veterinary Science, Assam Agricultural University, Joyhing, North Lakhimpur – 787051.
Editor’s Note: Re-published from the Compendium on Rabies Awareness Week, 22-28 Sept, 2018, held at LCVSc., AAU, Joyhing, North Lakhimpur, with due permission from the autor.