SSRI and the Memory Mosaic

Introduction

Selective serotonin re-uptake inhibitors SSRI are the first line drug treatment to treat moderate to severe depression. Despite the efficacy of the treatment clinically, there are conflicting evidences, showing the significant effect of SSRI on learning and memory (L&M). L&M stipulate changes of the macromolecules configuration in the brain, resulting in the alteration of brain plasticity via synaptic or non-synaptic changes. This involves range of different neurotransmitters (NT), such as serotonin, triggeringa cascade of excitatory or inhibitory events. Since, SSRI act on these NT, and sufficient studies have shown that L&M involve alterations on lipid composition of the brain. This raises a key question on whether SSRI exerts an effect on lipids composition that result in the modification of L&M. This review will use the Pond Lymnaea snail as a model to analyse the resemblance of neuronal changes in vertebrates and invertebrate models.

I. Vertebrates

1. Memory and learning

1.1 Background on memory and learning

Based on Atkinson and Shiffrin explanation to the three steps of memory formation, different brain regions cooperate to form a new memory. It begins in the cortex, where sensory neurones receive information from organoleptic senses and stores it for less than a second. The transcribed information gets transferred into the hippocampus in the medial temporal lobe. This is where the data is stored for less than 30 seconds, before it gets converted into a short-term memory via a process, called encoding(1).

Protein, lipid and nucleic acids in the hippocampus support the biophysical and biochemical changes in the neurones to create memory traces. These are then converted into a long-term memory (LTM) via a process called memory consolidation. Unlike short term memory, LTM requires greater neural stability(1)(2). Many studies emphasise the importance of proteins and nucleic acids in neuronal development and adaption, yet little is mentioned on the effect of lipids in neuronal modifications. This section would therefore focus on lipidomic alterations in the studies of L&M.

LTM composed of two substrates, a synaptic and non-synaptic plasticity. The synaptic plasticity mainly involves changes in the connection between two neurons. It is grouped to non-declarative (implicit) memory, which presents procedural and emotional conditioning, and declarative (explicit) which is subdivided to semantic that refers to general knowledge or episodic indicating personal experiences. Non-synaptic plasticity, on the other hand, involves applying changes intrinsically on the voltage gated channels. Thus, it reflects on the synaptic plasticity through inhibitory or excitatory action potential (AP) propagation in the post synapse. Alterations in either of these systems has directly been linked to memory and learning. In reality, both of these systems interact to create the memory and learning process. However, the mechanisms in which they interact are still vague(2)(3).

1.2 Synaptic plasticity

According to the father of neuroscience, Santiago Ramon y Cajal, memory forms through the stability of neurons. This provided the foundation of the Hebbian theory, which confirms that, the efficiency of synapse is directly associated with the repetitive activation or high stimulation of the synapse. This builds new connections or strengthens existing ones in a process called long term potentiating (LTP)(4). In the hippocampus the LTP utilises the excitatory neurotransmitter (NT) glutamate. When a certain memory has not been retrieved, long-term depression (LTD) utilises other neurotransmitters such as the inhibitory NT GABA to weaken these synaptic connections, eventually causes the memory to fade(5). The alterations in synaptic connections are known as synaptic plasticity, which contribute to the development of memories and their retrieval. This concept is supported with the synaptic and memory hypothesis, which demonstrates the link of persistent LTP stimulation at a specific synapse and memory formation. This hypothesis was verified through different criteria: (1) detectability, the ability to detect the synaptic activity once recalling a memory with certain experience; (2) mimicry, examines whether weight changes drive the process of information storage. This is expected to induce an apparent memory to a new experience; (3) anterograde alteration, the most supported criterion, any disruptions in the synaptic weight changes during the learning process is expected to obstruct the memory formation of this experience; (4) retrograde alteration, modifications in spatial distribution resulting in impairing memory of that experience(6)(7).

In response to the repetitive stimulus in the pre-synapse, glutamate is released to bind to NMDA and AMPA receptors in the post-synapse. This excites the cell by the influx of Na+ ions through AMPA receptors, triggering an AP in the post synapse. These results in the expulsion of Mg2+ that normally blocks NMDA receptors, allowing more Na+ and Ca2+. Thus, stimulating a forceful AP(8). In the case of high intensity stimulus, these memory traces form LTM in two LTP phases, the early and the late phase(9).

The early phase (first phase) lasts for few hours. It is mediated by Ca2+ activating protein kinases, such as CaMKII and PKC. This phosphorylates AMPA receptors to increase their Na+ influx for stimulating greater AP, and initiating pathways to signal the cell for releasing more AMPA receptors to the surface (figure 1). This phase forms the foundation of short-term memory(5)(10).

The late phase, unlike the early phase, highly depends on gene expression and protein synthesis to sustain changes made in the early phase of LTP. The stimulus effect in the post synapse is maintained via CaMKII stimulating CREB in the nucleus(11), which is regulated by serotonin NT(12)(further discussed in section 3) and BDNF(13). This causes the transcription and translation of genes to AMPA receptors and other macromolecules essential to further empower synaptic connections, forming LTM(figure1)(5)(8).

This was proven in the synaptic tag and capture hypothesis. Where Frey and Morris explained the methods of “tagging” a synapse by proteins made previously in the early phase LTP, which are then captured to express mRNA to reinforce AP when the synapse is stimulated again. This induces long lasting effects, conveying the learning mechanism of a synapse to respond more strongly to the same experience(11)(14). Some evidence supports the effect of epigenetic on late LTP, for example it was shown that histones deacetylation promotes the formation of LTM, whereas this is encountered by methylation(15).

1.3 Non synaptic plasticity

Non-synaptic plasticity involves alterations in ion channels, which impacts the resting membrane potential of the neuron and their likelihood to propagate AP to the post-synapse. The timing and amplitude of the summation of AP in the axon hillock in the pre-synapse defines the membrane potential, which leads to the depolarisation of the presynaptic neurons(16).

Non synaptic plasticity supports L&M in various ways (figure2). Firstly, it modulates the intrinsic excitability of the neuron, releasing more glutamate to the synaptic cleft. This occurs in three ways: (A) increasing the tendency for spike generation by reducing the threshold through the conductance of K+ currents (IA and IK,Ca)(17)(18), which then determines the duration of after hyperpolarisation, thus the AP firing rate; (B) empower synaptic connections, increases the synaptic strengthen some regions in the brain, such as the amygdale, which is responsible for monitoring memory consolidation and emotional-related memories storage. On the contrary to the infralimbic prefrontal cortex (fear and stress expression), where it is down regulated by the currents, helping memory storage(19); (C) even though studies indicate that there is no direct relevance of non-synaptic Axonal adjustmentto L&M. However, it could be beneficial for short term use only(16), as the frequent activity of axon reduces the AP threshold and increasing resting membrane potential, facilitating the propagation of AP, which is indirectly linked to the enhancement of neural plasticity. Other indirect methods could involve shunting, where axonal adjustment controls firing rate through the timing of ion channels responding to undergo hyperpolarisation(20)(21).

If the stimulation of the neuron is persistently low, the neural cells compensate through the decrease of AMPA receptors expression, which encounters synaptic LTP. In other words, the intrinsic excitability in the non-synaptic plasticity regulates the synaptic plasticity, thus alters L&M(21)(22).

Secondly, non-synaptic plasticity helps in maintaining memories via homeostatic plasticity. In which the neurons are regulated through negative feedback mechanisms, as a response to the activity-dependent excitations of the neurons. Based on the Hebbian theory claiming presynaptic stimulation contributes to the post synapse stimulation. This would then reduce the rhythmic AP firing in the post synapse (22).

In summary, non synaptic plasticity affects memory storage through the modification of current conductance. In which it occurs by altering ion channels that are either widespread on the neural bodies or compartmentalised in restricted region on the neuron (22).

2. Lipid composition in the brain contribute to L&M

Many papers studied the importance of nucleic acids and proteins in neurotransmission. Yet few studies have shed the light on lipids. The formation of new memories involves the use of these macromolecules for building new synaptic connections or alters the synapse to enhance its function. Lipids are the most abundant molecule in the brain and a fundamental molecule in the membrane structure. It would highly contribute to neuronal structure and function, thus to L&M. Analysing lipids in certain areas is still under-developed due to the lack of facilities to examine them. However, technologies such the mass spectrometry development facilitated lipidomic studies (23).

The types of lipids in the brain differ based on their structure, and whether they are saturated or unsaturated (double bonds). For example, glycerolipids consist of fatty acids attached to a glycerol group. If a phosphoric acid attaches to a glycerolipid, then it becomes glycerophospholipids, a lipid group that contain the cleavage site for phospholipase A2 and C (PLA2 and PLC, respectively). Sphingolipids is another lipid type, found in the brain that generate sphingomyelin and soluble molecules that act as signalling molecule. Sterol lipids have a ring-based structure and majorly contribute to the texture of membrane(24)(25).

Lipids interfere in L&M through the vesicular release of NT, thus neuroplasticity. It does this either indirectly by modulating the micro-architecture and micro-domain of membranes, or directly by acting as a ligand to ion channels altering the cellular transduction. As stated previously in section (1), L&M is highly defined by the neuroplasticity (synaptic or non-synaptic). Therefore, the literature proves that lipids are capable of altering L&M.

2.1 indirect effect

2.1.1 Geometry of lipids

The environment, such as temperature, can alter the molecular structure of lipid molecules, thus the geometric properties of the membrane. However, at physiological temperature, lipid structure relies highly on whether the proportion of the hydrophobic (tails) is higher than hydrophilic (heads) portion of the lipid creating a cone shaped lipid, or vice versa forming an inverted cone shape (shown in figure 3a). Whereas, at equilibrium, lipids would have a cylindrical shape. PLA2 enzymes help breaks down phospholipids in the membrane into conical fatty acids and inverted cone lysophospholipids. This would affect the vesicular release in the synapse, as the conical lipids when exposed to aqueous environment fuse to the synaptic membrane in a negative curvature manner (shown in figure3b), while a positive curvature is formed in the inverted cone lipid (23)(26).

Initially, the conical shaped lipids, such as DAG, chemically induce exocytosis via the influx of Ca2+ to the pre-synapse. This primes the vesicles to facilitate their fusion to the synaptic membrane. Consequentially, SNARE proteins in vesicles interact with other proteins or lipids in the bilayer(27). This process allows the outer monolayer of the membranes to fuse forming a negative curvature. Afterwards, inverted conical lysophospholipids mechanically widen the fusion pore by causing the membrane bend forming a positivecurvature(26). Hence, manipulating lipid could have an effect on vesicular release(27).

2.1.2 Ion channels regulation

Lipids can also indirectly help regulate mechanosensitive K+ channels (TRAAK; TREK ; NMDA receptors), hence the propagation of signals(28). The intercalation of unsaturated lipids, such as arachidonic acid, in the membrane causes a deformation in the bilayer. Due to the electrostatic interaction of arachidonic acid and positively charged phospholipids in the membrane, such as sphingomyelin. This either stretches the membrane including the receptors or alters the cytoskeleton structure, causing the opening of these channels(24)(26). As mentioned in section (1), regulating ion channels would therefore impact the synapticplasticity through the control of late LTP phase pathways. Also, thenon-synaptic plasticity through current conductance, determining the firing rate. Therefore, this indicate the potential connection between lipids and L&M(26).

2.1.3 lipid rafts

The fluid mosaic model provides a simplified explanation of the structure of the bilayer, where phospholipids provide the fluidity, and proteins are embedded across the membrane. Singer and Nicolson based the model on random scatter of molecules and the freedom of proteins lateral movement(29). However, sufficient evidence proved the presence of clustered areas in the membrane. Subsequently, Klausner developed a better understanding to how molecules are scattered across the membrane and the function they serve. One of the most significant structures were the lipid rafts, also known as membrane domains(30).

Lipid rafts mainly consist of sphingomyelin and cholesterol. These are compartmentalised in certain areas in the membrane. The fact that sphingomyelin has a cylindrical shape and long saturated fatty acids in the tail resultsin a more solid consistency, and stronger van der Waals bonds between the bilayer and the positively charged sphingomyelin. This is, however, balanced by cholesterol, which offers the flexibility to the domain. Also, among these domains there are proteins, such as TRK receptors,that are accurately located within the rafts for cell signalling and transduction(24(26))(31).

Lipid rafts influence the curvature formation for vesicles and signal transduction, in other words lipids influence synaptic plasticity, signalling and maintenance (31). In fact, some studies linked the increase of synaptic density to synaptic lipid rafts. Also, many lipid rafts include proteins that may contribute to BDNF signalling. Since BNDF regulate cholesterol, yet cholesterol play a role in synaptic stability, BDNFregulatory signals could have detrimental effect on the synapse(32)(27).

Therefore, it is important tounderstandthespatial relationship between lipids and proteins and how that intervenes with L&M(31).Yet, there is no solid evidence supporting any effect on the glia and other components in the brain. This concludes that lipid rafts could alter the ion channels configurations, therefore the current conductance. Hence, the non-synaptic plasticity, which plays a major role in the maintenance of memory(22). The effect of lipid rafts on L&M was further investigated by examining loss of neuronal function with aging. Where the cholesterol loss in neurons within age disrupts the function of lipid rafts. Thus, less vesicles fuse to the membrane, leading to neurodegeneration and L&M impairment(33).

2.2 direct effect

Lipids can also act as ligands to receptors and channels. The lipid-signalling molecules are made after a stimulus activates enzymes to modify the precursors of these signalling lipids. The amphipathic nature of lipids signalling molecules allows them to bind to the hydrophobic (inside) or the hydrophilic (outside) layers of the membrane(26).

PIP2, a component in the membrane, gets cleaved by PLC to produce IP3 and DAG as second messengers. IP3 binds to its receptor to control Ca2+ release from endoplasmic reticulum for signalling, whereas DAG remains bound to the membrane, yet it recruits kinases and effector proteins. Subsequently, DAG gets hydrolysed to arachidonic acid (intracellular molecule) and a glycerol. Where arachidonic acid could get modified by oxygen species (RONS) for various purposes(24)(26).

Signalling lipids could be made in several pathways. For instance, Arachidonic acid could also be produced from the cleavage of glycerophospholipids by PLA2. Studies have shown that arachidonic acid impact the pre-synaptic NT release and the propagation of AP by interacting with voltage-sensitive K+ channels mediating LTP. PLA2 also help the transportation of arachidonic acid across the membranes, and it is limited by the phospholipid remodelling(24)(26).

Lipids impact the membrane structure; protein pathways and ions induction. These are essential for vesicular release, strengthening ofthe neuron and the development new dendritic branches. Also, lipids used to protect and repair neuronal cells(27). In which it would enhance brain plasticity, thus modify L&M. Disruptions in lipids is seen in the path physiology of aging, induces oxidative stress(34)(25). This causes excessive peroxidation of the unsaturated membrane lipids, such as arachidonic acid. Therefore, hyperactivation of PLA2 triggers the activation of negative feedback, which limits the electrical excitability, resulting in neuronal loss(34)(35). This reduces plasticity, thus impairs L&M.

Similar results are concluded in neurodegenerative diseases, such as Alzheimer’s disease(35). This is due to the over-activity of sphingomyelinase enzyme, which is vital to breakdown the sphingomyelin in the membrane to signal-inducing molecules. Experimentally, it was observed in mice that higher concentration of ceramide, the product of breaking down sphingomyelin in the membrane,induced Alzheimer’s disease pathology(33)(36)(37). Also, the inhibition of sphingomyelinase has demonstrated promising effects on the Alzheimer’s disease pathology(36).

Disrupting the lipid homeostasis by reducing the sphingomyelin in the membrane results in alterations in the membrane fluidity and curvature-ability, synaptic density and the activity of membrane-bound proteins(31)(36)(38). Moreover, the rate of breaking down sphingomyelin determines the signalling molecules, which is vital for the post-synaptic excitability. However, over-expression of these signalling molecules could activate a negative feedback activity. All these pathways induced by lipids alterations affect the signal transduction, consequently the vesicular release. Therefore, impact neuroplasticity and L&M pathways(31).

The significance of serotonin in L&M

5-hydroxytryptophan (5-HT), so-called serotonin, is a monoamine neurotransmitter, derived from the amino acid tryptophan. It is associated to emotional learning, which explains why serotonin deficiency forms the pivot point of depression pathophysiology. Treatment for depression act by manipulating the levels of serotonin in the brain. As serotonin help regulate mood and memory, disrupting serotonin levels could leave an enormous impact on L&M neural pathways. Therefore, it is essential to observe the role of serotonin in L&(39)(40)(41).

The synthesis of serotonin in the Raphae nuclei requires the presence of tryptophan, which needs a transporter to cross the blood-brain barrier. In order to observe the influence of serotonin depletion on L&M, patients were deprived from dietary tryptophan and were supplied with other amino acids to competitively inhibit the tryptophan transporter(42). This results to the drastic drop of serotonin levels in the brain, this experiment is known as the tryptophan depletion experiment(42)(43). It concluded that there is a correlation between Hypo-serotonergia and declarative memory impairment and depressive symptoms(44). These were also reversed once the levels of serotonin in the brain have recovered. This guarantees a non-intrusive simple experiment. However, it is unclear whether there are other compensatory mechanisms in the brain for tryptophan depletion(45).

Both synaptic and non-synaptic systems work synergistically to form LTM. However, the mechanisms in which both of these systems interact is still vague. Yet, growing evidence has shown that serotonin links both of these systems(21)(46). Serotonin enhances the non-synaptic plasticity, by acting intrinsically through the conduction of K+-mediated currents (IA; IK,Ca), leading to the reduction of hyperpolarisation amplitude. Therefore, enhance glutamate release for synaptic LTP. This frequent excitability helps strengthen the synapse, therefore forming LTM(21)(47).

Serotonin, also, affect L&M in multifarious ways depending on the serotonergic receptors (5-HT receptors) it binds to. Serotonergic receptors are classified into 14 different receptors according to their distribution in the brain, the ligands and the effects they intervene(40). As shown in figure1,these receptors exert their action either via the inhibition or activation of adenyl cyclase that catalyses ATP to the second messenger cAMP, which helps in generating inhibitory or excitatory response, respectively(41).

One of these serotonergic receptors that has shown solid evidence to be linked to L&M is 5-HT1A. Which is an auto-receptor neuromodulator found on the somatodendrites. 5-HT1A functions as a negative feedback by suppressing the release of serotonin in the neuron, limiting the release of glutamate. Hence, reduced excitation(48). 5-HT1A are also found on the post-synapse in certain regions of the brain, such as the hippocampus and amygdale, which are vital areas for memory formation. Nonetheless, experiments demonstrated the insignificant effect of 5-HT1A on memory, yet it illustrated an effect on the learning process. This argument could be refuted with the fact that NT have different outcomes in different regions in the brain, these results only indicated the effect of serotonin availability in the hippocampus, but little light was given to other areas in the brain that could offer alternative pathways to contribute to memory formation(48)(49).

The role of serotonin in the brain surpasses the direct effect on neuronal function. It plays a major role in the modulation of other NT, such as glutamate, in the brain, which could result in the modulation of receptors function, ion channels and signalling pathways (PLC; adenylate cyclase; G-proteins) These NT, also, participate in the formation of new memories. Where glutamate interfere in the encoding step(50).

Glutamate and serotonin function as co-transmitters to mediate excitatory post-synaptic potential(51). For instance, both glutamatergic receptor NMDA and 5-HT2 intervene in the breakdown of glycerophospholipids in the membrane which generates the arachidonic acid that function as a signal transduction molecule (section 2.2)(49). Furthermore, Serotonin prevents NMDA activation and enhance the current generated by AMPA receptors which suppresses synaptic LTP. Another route emphasises the serotonin impact on glutamate is through the exertion of 5-HT1A inhibitory effect on serotonin. Which reduces cAMP, this equates to a reduction in CREB and other pathways that contribute to glutamatergic effect (figure1). Hence, diminished neural excitability(50). Nonetheless, experiments demonstrated the insignificance effect of 5-HT1A on glutamate. The reciprocity of serotonin and glutamate is seen in different areas in the brain and with different receptors subtypes inducing multifarious outcomes in the pre-synapse and the post-synapse. These interactions between serotonin and glutamate carry a direct control over synaptic plasticity and the formation of new memories(50).

The relevance of serotonin to L&M is further exhibited through examining memory impairment in depression(49). Hence, unravelling the link between serotonin and L&M could be a subject of a new pharmacological treatments to memory impairments associated with chronic mental health disorders.

4. Antidepressants

4.1 Background

Despite the fact that depression is a leading cause of morbidity and mortality(52), minor progress is seen in establishing its aetiology. Up to our date the path physiology of depression is explained through the monoamine hypothesis, which postulate that the depletion of monoamines NE and serotonin in the brain form the underlying cause of depression(53)(54)(55). This concept was emphasised when monoamine antagonist, such as reserpine, induced depression. However, the limitation of this theory is seen through the two to four weeks discrepancy between the clinical and the physiological effect, where raising the monoamines availability didn’t treat depression immediately(56). Nevertheless, other extensive studies have shown the exclusive effect of serotonin depletion in the path physiology of depression. This is supported with two main theories: (a) the tryptophan depletion theory, which as explained above, links depression to the reduced synthesis of serotonin in the brain; (b) the association of polymorphism in serotonergic receptors, such as SERT and 5-HT1A and depression(45)(56)(57).

Anti-depressants (AD) were discovered in the early 1950s to treat moderate to severe Major depression disorders. The NICE guidelines recommend the use of Serotonin re-uptake inhibitors (SSRI) as a first-line treatment for depression. This is because SSRI, including sertraline, fluoxetine, and citalopram, act more selectively on serotonergic receptors. SSRI were favoured to other AD as they were proven to be as effective yet has less side effects and tends to have a safer profile in overdose in comparison to other AD, which allowed the usage of AD over a larger range of age groups within population, including the elderly and children(58). However, SSRI influence on L&M is still controversial.

4.2 Mechanism of action of SSRI

The serotonin activity in the synaptic cleft is limited by the re-uptake of the NT by serotonin transporter (SERT) to the pre-synapse, where they get broken down by MAO enzymes to be recycled. SSRI blocks the re-uptake of serotonin from the synaptic cleft by inhibiting SERT. This increases serotonin availability to readily bind to the serotonergic receptors and trigger a cascade of events(59).

The increase in serotonin concentration due to SSRI activates 5-HT1A receptors, resulting in the suppression of neural activity due to the decrease of NT release in the synaptic cleft. However, the chronic increase of serotonin. accompanied with administering SSRI, results in the desensitisation of 5-HT1A receptors(56). This causes the down regulation of 5-HT1A in different regions in the neurones, subsequently, the NT release in the synapse is increased. This could take up to four weeks, as it involves genetic modifications to the expression of these receptors as a compensatory mechanism. Which could explain the delayed onset of action of SSRI(57). Few studies shown the consequential effect of 5-HT1A antagonist, pindolol, has enhanced the efficacy of SSRI in L&M, yet impaired emotional memory(60).

As the location of 5-HT1A receptor define the outcomes. Some argue that an agonist to the post-synaptic 5-HT1A receptor in the dentate gyrus mediate behavioural response similar to antidepressants. This occurs through the secretion of BDNF and VEGF, triggering the proliferation and the development of neurons, enhancing the neuroplasticity(13)(61). Whereas, the decrease of BDNF levels in depression reduces CREB function. Which results in neuronal loss in the hippocampus, known as hippocampal atrophy(62). A study on mice with knocked out 5-HT1A receptor genes has demonstrated poorer neurogenesis and behavioural response to chronic fluoxetine use. This illustrates the significance of 5-HT1A receptors in the Dentate gyrus in the hippocampus support neuronal growth, thus strengthened plasticity(57)(63).

4.3 SSRI effect on L&M

Memory impairment is one of the main symptoms associated with depression. The controversy on the effect of SSRI on L&M makes it important to understand the effect of anti-depressive therapies. This prevents any future exacerbations; besides it minimises the non-adherence to medications.

Theoretically, SSRI treatments are thought to enhance L&M, this was also proven on studies carried out on rats, where fluoxetine and sertraline assisted in the up-regulation of BDNF, thus exhibited improvement in neuroplasticity and neurogenesis(64)(65). Some papers demonstrate that chronic use of fluoxetine correlate to hippocampal neurogenesis, thus enhanced L&M. All these results could be explained through the role of 5-HT receptors in cognitive behaviour (explained in section 3)(47).

However, clinically patients tend to complain about memory loss. This was highlighted on the MMSE score results by Popovic, which indicated that, SSRI actually cause memory impairment(66). Nonetheless, these results are concluded using a questionnaire that measures cognition, which means it does not distinguish whether memory loss is a symptom of depression or a side effect of SSRI use. Some studies deny the link of SSRI, particularly sertraline, to cognitive dysfunction(66)(67). These results were further elaborated comparing the effect of sertraline and bupropion on memory retrieval, unexpectedly, neither of these drugs has induced any negative or positive changes(68). In fact, some authors assured that these are symptoms associated with depression due to the weakening of neurones and lack of neurogenesis. This is confirmed by many other studies that indicate the interference of neurobiology of depression in the study of pharmacotherapy(69).

A study carried out on rats has shown the detrimental effect of fluoxetine on the release of glutamate by altering the SNARE proteins, found in lipid rafts that help in vesicular release. The decrease in glutamate release then would reduce the excitation of the synapse, thus impaired L&M(70). Nevertheless, Hajzsan stated that fluoxetine was capable of restoring the deleterious effect on L&M associated with depression, this was experimentally proven by Vetencourt(71).

Yet, it is worth mentioning that different drugs in SSRI could have different outcomes. For instance, a study made by Furlan and Kallan examined both sertraline and paroxetine in depressed patients. Paroxetine expressed detrimental effects on L&M, on the contrary to sertraline that illustrated more positive effects on cognition(72). This means that alterations on L&M do not solely rely on the neurobiology of depression, but SSRI also seem to contribute to the functioning of L&M. This is, also, supported in a study that measured the effect of fluoxetine on improving memory, this study eliminated the interference of depression neurobiology by comparing the improvement of similar clinical cases of depression using different classes of antidepressant(65)(73).In conclusion, SSRI were shown to improve cognitive behaviour and mood, yet reduce the verbal L&M(74).

4.4 SSRI effect affects the lipid composition of the brain

The fact that lipids in neurones contribute to L&M (section 2), also omega-3 show antidepressant effect raises a key question of whether SSRI could impact lipidomic.

Research has tested the lipid profile after chronic administration of paroxetine and fluoxetine using mass spectrometry. Paroxetine has shown an increase of ceramideconcentration (a by-product of sphingomyelin cleavage)(36), indicating for a reduction in the neural phospholipids. This could be due to the activation of PLA2, which as mentioned in section 2, cleaves these phospholipids to fatty acids that help in signal transduction, and Lysophospholipids which are vital for vesicular release in the synapse(75).

Another way to observe the lipid alteration with depression is to view the brain under MRI. As a result of neuronal loss, many regions of the brain would diminish. The use of sertraline and fluoxetine has illustrated an opposing effect through the enlargement of the hippocampus and increased thickness of the prefrontal cortex(76)(77). This occurs due to the neuroprotective properties of serotonin and increased neurogenesis due to BDNF secretion(64).However, this does not illustrate the effect of SSRI specifically on lipidomic as the study includes other classes of antidepressants. Besides, such results could only be seen in patients with established damage of lipids due to depression, some other studies argue that using sertraline on healthy vertebrates could carry detrimental effect on the volume of hippocampus(76)(78).

SSRI tends to accumulate in lipid rafts in the initial two to four weeks, which could serve as another explanation to their delayed onset of action. The accumulation indirectly affects L&M through altering vesicular release and signalling transduction bymanipulating the positioning of the proteins located in the lipid rafts, or their exposure to their ligands. Tubulin, a protein in lipid rafts essential for microtubules formation for membrane structure, is altered in depression.Escitalopram was shown to relocate the protein tubulin and fluoxetine increased tubulin acetylation. Hence, promote the stability of the membrane structure of neurons. This stability would then affect neuroplasticity, thus the formation of L&M. This was investigated by tracing the cAMP pathway shown in figure 1 in rodents through the expression of BDNF and CREB, which signposts the anti-depressive effect(58)(79)(80).

II. Invertebrates

1. Why use snails as a model

Despite the fact that, animal models involve systems that could directly correspond to humans, previous research describing the effect of SSRI on L&M using rats models faced a common limitation, which is the interference of pathway sgeneratedless conclusive results(3). On the other hand, a clear understanding of the neural circuitry in the Lymnaea was recently developed, what made it a commonly used model to study the mechanisms and behavioural changes in L&M. Moreover, the fact that the neural system in the Lymnaea is simplistic, it enables us to isolate a single neuron and quantify the gene expression of certain proteins, such as BDNF and CREB, that contribute majorly to L&M(81). Therefore, the Pond Lymnaea snails were selected as a model in this paper.

2. L&M in the pond Lymnaea

Analysing the feeding behaviour of the Lymnaea is highly used to examine the L&M trajectory. It involves the interaction of interneurons, sensory and motor neurones to generate rhythmic feeding habits, known as rasping. The cerebral giant cells (CGC) and the Cerebrobuccal interneurons (CBI) actively control CPG interneurons, which controls each step of the feeding motions. This creates a feeding rhythm that is defined by the excitatory inputs that spike an AP. CGC in turn would facilitate the response to food stimulus, and CBI command-like cells provide the reward behaviour, experimentally amyl acetate is used for this purpose(82).

The modulation of networks between the sensory, motor and inter-neurons in the Lymnaea either due to synaptic or non-synaptic plasticity motivate the memory formation and behavioural changes(82).

This is briefly seen when firing rates and connectivity modify the motor neurons according to the sensory neurons pathways. The inter-connection between these neurones in the feeding system are regulated by interneurons. The response changes are closely observed through synaptic plasticity alterations in the habituation, sensitization and classical conditioning between motor and sensory neuron, and the non-synaptic plasticity between the sensory neurons and interneurons(83).

2.1 Synaptic mechanisms

The reward conditioning system regulated by CBI form the foundation of feeding system. It is mainly based on supplying neutral stimulus with a strong stimulus, this correlates to stimulus generalisation in vertebrates between different sites of the body. The tactile reward conditioning is observed through motor neurons activity as a representative of the feeding system. Cerebral ganglia include the CBI act as an initiating neuron to activate CPG. The persistent firing of CBI strengthens the excitatory neurons connections(84). whereas similar to vertebrates where LTD is generated in inhibitory neurons, the Lymnaea reduce the inhibitory neurons activation, which results in the reduction of spike generation threshold. This makes it easier to respond to sensory neurons, favouring the stimulation of feeding network. Hence, it alters synaptic plasticity through regulating long term facilitation (LTF, corresponds to LTP invertebrates) by CGC interneurons and tonic synaptic inhibition(82).

These consistent changes form LTM by the intrinsic expression of cAMP, through the voltage-clamp experiments measuring the the K+ conductance (IK and IK.Ca) in the CGC(85). These lead to long-term alterations in ion channels on synaptic membrane and the depolarisation that causes NT release due to a learning stimulus(82)(85). Similar to what was previously explained in the vertebrate’s synaptic plasticity, the western blot of the buccal and cerebral ganglia in the Lymnaea has shown that the activation of CamKII and NMDA intervenes in LTM formation in both early and late phases. It was also observed that the reward conditioning increased the expression of CREB, this is involved in genetic modification to induce long term changes(83). These pathways in the Lymnaea, as well as in the vertebrates, emphasises the important link of cAMP pathway and CREB-dependent gene expression changes in L&M.

2.2 Non synaptic mechanisms

Growing evidences show the significance of non-synaptic plasticity in L&M of Lymnaea. Upon consistent stimulation, the neurons trigger changes in neurons, for instance: (a) input resistance, mechanoreceptors are an example of resistance that increase spike generation(86), similar to vertebrates, serotonin regulate IK and IKCa, this allows the increase in AP firing rates ; (b) membrane potential, it was shown experimentally that the chronic LTF due to new memory traces causes persistent depolarisation of CBI through the alteration the membrane potentials, this indirectly increases the calcium-induced response in the port synapse; (c) bursting properties, the rhythm in feeding is regulated initially by the protraction burst then the regularity of oscillation of feeding behaviour is generated through changes in endogenous properties(82). The establishment non-synaptic plasticity form compartmentalised calcium-induced presynaptic changes for a specific memory trace, which would have no influence on other circuits. This, therefore, increase synaptic efficacy towards a certain behaviour(87). This indicates that as for vertebrates the non-synaptic mechanisms in the Lymnaea majorly regulate synaptic plasticity. This was confirmed experimentally by Brons and Woody, where it was shown that the response to a certain stimulus that caused an excitation by conditioning is faster. As indicated by Benjamin, these results are linked to modifying membrane potential of the Lymnaea(88). However, this effect varies in different regions of the brain. Moreover, persistent excitation results in alterations in the NMDA receptors, where they become more susceptible to induce LTF(83)(89).

Invertebrates have both synaptic and non-synaptic systems work concomitantly to form LTM. As for vertebrates, the invertebrate model also lacks clear explanation on how both systems interact(87). The excitation results from a short-term sensitisation of sensory neurons, increases the motor neurons stimulation, which is beneficial to induce neuromuscular contraction. Hence, this have demonstrated the effect of learning-induced changes on the formation of memory traces, neuronal changes and the storage mechanisms of these traces to form LTM(83).

3. Serotonin and SSRI in the Lymnaea

The transmission of serotonin from CGC to motor neurons controls feeding motion. Also, serotonin empowers CBI, which regulates the feeding network. The strength of serotonergic transmission defines neuroplasticity in the Lymnaea(90). Moreover, serotonin links synaptic and non-synaptic plasticity through the connection between sensory and motor neurons (83).

Serotonin induces neuroplasticity alterations through calcium-dependent K+ conductance (IA; IKCa), through the increase of intracellular cAMP and PKA enzyme. This enhances firing rates of sensory neurons, amplifying the rasping muscular contraction(82).

Not only this, but serotonin in Lymnaeaalso, similar to vertebrates, function as a regulatory NT to glutamate release. As shown in figure 4, serotonin activates adenylyl cyclase and PKA increasing the glutamatergic release acting as an anterograde signal. glutamate then activate NMDA and AMPA inducing LTF(91). These cascades as mentioned earlier highly correspond to the mechanisms seen in vertebrates. In which this activates intrinsic modifications in the non-synaptic mechanisms and enhance the synaptic plasticity, provoking the formation of LTM(82)This was proven experimentally, applying serotonin increased the activity of sensory neurons for more than 24hours, which modulates gene expressions to induce long-term changes, thus forming LTM(83)(92).

There is strong evidence on the relevance of serotonin in L&M in the Lymnaea. However, the effect of SSRI in the Lymnaea SSRI is still unclear. An Experiment carried out by Aaonuma has shown that lower monoamines content correlate with improved L&M(93), which puts in theory that SSRI would impair L&M. However, this is only applicable if there is an excess of the monoamines, which would activate the 5-HT1A negative feedback mechanisms to compensate the neural activity(91). This study was also countered by wildering and colleagues, where their experiment utilised ageing Lymnaea, as ageing was proved to have deleterious effects on L&M in the Lymnaea. Subsequently, it was demonstrated that when applying fluoxetine these deleterious effects on L&M associated with ageing were restored(47). Nevertheless, fluoxetine has shown to suppress the synaptophysin expression, a vital protein in vesicular release, thus, reducing the synaptic transmission and the synaptic strength which would hinder the formation of LTM. This indicates that by theory fluoxetine impairs L&M. Nonetheless, these findings were not applicable to citalopram(94).

This raises the argument that SSRI in invertebrates could work differently than in vertebrates, where it is suggested that SSRI could bind to serotonergic receptors directly rather than inhibit SERT. Moreover, it was shown that mechanism of action of SSRI in invertebrates is not exclusive to serotonergic neurones only. This was proven when fluoxetine blocked synaptic transmission between cholinergic neurons, which has detrimental effects on neurogenesis and synaptic transmission. Therefore, this emphasises the importance to further investigate the SSRI effects on the different pathways of L&M.

4. Lipids in the Lymnaea

Main studies on L&M in the Lymnaea involve the study of RNA molecules and proteins, yet few were done on the lipidomic and how it affects L&M, current studies(47).

Similar to vertebrates, the lipoxidation of neurons result in changes of the neural physiology, which impacts the signal transduction between neurons, implicating the deterioration of L&M observed with age. Lipoxidation occurs when inflammatory modulators are formed as a by-product to PLA2 cleaving the membrane phospholipids to generate arachidonic acid. Oxidative stress in this case act as a positive feedback that disrupts the homeostasis of lipids(95)(96). It was proved when an antioxidant (alpha-tocopherol) has reversed the age-induced physiological effect on L&M. Therefore, disrupting the metabolism of lipids in the membrane affects the formation of signalling molecules that help strengthen neuroplasticity to form LTM. Similar effects were shown when fluoxetine was applied L&M impairment was restored(47). This raises a question of whether SSRIs affect L&M through alterations in the lipid composition of neurons.

Both vertebrates and invertebrates have synaptic and non-synaptic mechanisms, in which both systems are linked by the transmission of serotonin. These mechanisms either increase the vesicular release of the excitatory NT glutamate, ordisrupting the ion channels that stabilise membrane potential, therefore, impacting the formation of L&M. Both models also utilise 5-HT1A as negative feedback compensation to the increase of serotonin in the synaptic cleft, playing a major role in neuroplasticity. Not only this, but both models also showed resemblance in the significance of lipids in neural functioning. Particularly, the importance of lipid rafts in both vesicular release and ion channels distribution. The use of SSRI antidepressants on both models altered L&M in different ways. Therefore, it is important to further investigate how these medications affect L&M.

Conclusion

Sufficient studies have linked L&M impairment to depression. Yet few studies clearly illustrated the effect of SSRI antidepressants on L&M, whilst it is accepted that, dysregulation of serotonin significantly impact L&M, and lipids in the membrane affect neuroplasticity, thus impacting the formation and storage of memory traces. No studies clearly linked both serotonin and lipids pathways and their impact on L&M. Therefore, the mechanisms, in which SSRI impact L&M remain unanswered, from the research analysed in this review, it is suggested that SSRI theoretically enhances L&M. However, the impact on L&M experimentally is still controversial. Vertebrates have shown positive results on the L&M neurophysiology, yet negative results on cognition, whereas, the use of SSRI on invertebrates demonstrated negative results on the neurophysiology. Moreover, main studies on the effect of SSRI focused on the use of fluoxetine, but the research in this review illustrated that different SSRI had different effects on L&M. Besides, the fact that sertraline is one of the most prescribed medications clinically emphasises the importance of viewing how sertraline could impact L&M. Due to the simple nervous system of the pond snail Lymnaea and the similarities of L&M pathways to vertebrates. This review adopted the Lymnaea as a model to determine the impact of sertraline on L&M pathways. Therefore, we hypothesize that sertraline, through the lipidomic analysis of the Lymnaea, could enhance L&M

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