The History About The Cognitive Function Biology Essay

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Understanding the general mechanisms underlying learning and memory, it is possible to target mental disorders in order to treat them. Long-term potentiation (LTP) in the hippocampus has been the main focus of studies as it was shown that it may trigger long-tem memory function. Changes in synaptic plasticity which is involved in memory formation occurs either in short periods which involves alternation in protein e.g. phosphorylation or long-term these involve synthesis of new proteins, by the activation of cAMP responsive element binding protein (CREB) which plays a significant part in LTP. There are many drug targets for the treatment of neuropsychiatric disorders, in order to aid drug design it is necessary to discover the role and effects of these target in the brain.

As mentions earlier cholinergic target have long been documented for its involvement in learning and memory as a part of the pathophysiology of Alzheimer’s disease. There are two types of receptors in which ACh may bind to, nicotinic receptors which are ligand-gated ion channel receptors and G-protein coupled muscarinic receptors. These both situated centrally and peripherally, and only specific receptor subtypes are able exert a cognitive function in the brain.

Nicotinic acetylcholine receptors (nAChRs) are located thought-out the body whereas two subtype α4β2nAChRs and α7nAChRs are leading receptor in the brain associated with cognition. Therefore drug discovery, design and development have been targeted at these receptors, it has been found that the α4β2nAChR has a role in attention, thus being targeted by drug development programs for the treatment of ADHD and disorders such as schizophrenia. Research and development have produced α4β2nAChR agonists but through clinical trial it was found to have no cognition effect in ADHD, AD and schizophrenia there was no not distinguishing it from placebo. The reason for this is unknown but there a greater focus on developing α7nAChR agonist as it been found they have restricted expression in the peripheral system thus has a low side effect profile. Studies found that α7nAChR activation has not only cognitive effects but neuroprotective properties. Through research and development selective and high affinity the α7nAChR agonist have been made for use as therapeutic drugs, through lead optimisation and structure-activity relationship studies several different pharmacophore have been identified and being used for clinical trials.

The other type of cholinergic receptor are muscarinic receptors (mAChR) theses have five subtypes M1-M5; all types are located peripherally and have a big side effect profile. Only M1 mAChR is predominate in the brain where it regulates effects of ACh, it has been the focus of a potential drug target in improving learning and memory. But due to low efficacy and a bad safety profile it is not possible to develop this has been due to the selectively of the receptor to molecules thus it is now not a potential drug target.

Glutamate is a known neurotransmitter that has a major role in learning and memory processes, it activates both ionotropic and metabotropic receptors. There are two main Ionotropic receptors N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA). Enhanced glutamate release causes the activation of NMDA and AMPA receptors which induce LTP. This is caused by postsynaptic depolarisation, which in turn causes the Mg2+ block of the NMDA receptor to be release and an influx of Ca2+ into cell allowing activation of Ca2+/calmodulin kinase II and protein kinase C and protein kinase A that facilitate LTP, as shown by Fig 2.

It been shown that NMDA receptor is a trigger for LTP, learning and memory in the hippocampus. It was thought that enhancing NMDAR function would increase LTP and cognition, however over activation of NMDAR can lead to epilepsy, neuronal death and hyperalgesia. The NMDA receptor is composed of seven subunits; to activate it requires co-agonist glycine which binds to GluN1 subunit and glutamate which binds to GluN2 subunit. Further studies it was shown that people with Alzheimer’s disease have a marked reduction in both of these subunits and this correlated to the cognitive function of patients. To avoid over activation compounds which moderately block the NMDA receptor, such as partial or full-agonist e.g. memantine, improve cognition. For this to able to be a drug target further studies are required to understand modulation of this receptor in different disorders.OJUIO.jpg

AMPA receptor family is composed of four subunits, GluR1–4; activation due to glutamate leads to induction of LTP and induces change to learning and memory. Positive modulation of AMPA receptor enhances NMDA channel opening and LTP by causing depolarisation. This also enhances cognition by modulating glutamatergic transmission, promoting production of trophic factors such as brain derived neurotrophic factor (BDNF). Pyrrolidones are an example of compounds which enhance cognition by positive modulation. These seem to have high affinity for the receptor and low side effects but they do not produce enough potency however through drug design and structure activity relationship analogue of these compound have one thousand times the potency and stand to be very exciting future development.

Several studies have shown that serotonin (5-HT) has a role in memory, since there is reduction in precursor of 5-HT there is a lower performance of episodic memory retention, this is also supported by memory deficiency in people who suffer from depression since 5-HT is one of the causes. However increase in 5-HT receptor activation or 5-HT may also lower memory performance, this is due to the two action of 5-HT in the hippocampus. There are sixteen different 5-HT receptor types which are split into seven sub-families 5-HT 1-7. There activation causes response through signal transduction pathways, such as inhibiting adenyly cyclase or stimulation of phospholipase C this can influence cognitive impairment in neurodegenerative diseases. Different subtypes of 5-HT receptors are located in different parts of the brain and associated with different cognitive function. It is thought that 5-HT 1,2,3,6 are associated with memory function, blockage of 5-HT6 receptor leads to improvement in learning and memory. Contraindicating it was shown that activation of 5-HT receptor by a selective 5-HT6 receptor agonist may induce LTP. Serotonergic receptors have been targeted for improving cognitive function, but so far they do not show any evidence of efficacy and continuity.

Dopaminergic receptors are involved in many neurological processes such as motivation, cognition and learning. There are five subtypes of dopamine receptors D1-5, these receptors modulate cognitive function via cAMP/PKA signalling and CREB modulation, they also interact with cholinergic and glutamtergic affection anxiety, learning and memory. D1 receptor is the main target in cognition as it is linked to working memory but low and high levels of activation caused impairment in memory. It is therefore necessary to have selective agonists but D1 agonist also have poor tolerability as they cause hypotension and nausea; therefore they are currently no research on the development of these agonists.

GABAA receptors are pentamers constiting of two α, two β and one γ subunits. There are five different subunits of α (α1-5). It is known that α1 is responsible for sedative effects, whilst α2-3 for anxiolytic and α5 for cognitive effects of a receptor agonist. It is therefore necessary for a compound to be a selective α5 GABAA receptor in order to avoid convulsive and anxiolytic side effects. Compounds have been designed to be α5 selective should have pharmacological profile that can improve cognitive function without adverse side effects. But these compounds have come across a number of problems such as potency, efficacy and selectivity. They also cause renal toxicity, not tolerated in the elderly causing them to stop clinical trials in phase I.

There are many drug targets in order to improve cognitive function for many different neuropsychiatric disorders; they all have a similar mechanism which is Long term potentiation through various different pathways as a result improving learning, memory and cognition. Some neurotransmitter and receptors targets have better function at improving cognition than others. I believe that AMPA receptor agonist may be the most important in future development as they not only improve cognition in neuropsychiatric disorders but also in health people as well, they have a low side effect profile and with research I