PNN’s and Neuropsychiatric Illnesses 1 Spiering Implication of PNN’s in Neuropsychiatric Illnesses Thatcher Spiering University of Wyoming PNN’s and Neuropsychiatric Illnesses 2 Spiering Abstract Perineuronal Nets (PNN’s) were first discovered at the end of the 19th century. A PNN is a specialized extracellular matrix (ECM) structure that surrounds specific cell types within the central nervous system. PNN’s serve a wide variety of functions, including protection, assisting normal function, providing anchor points for neurons and glial cells, aiding in neurotransmission, neurodevelopment, and neuroplasticity. Recently ECM has been incorporated as a functioning unit into the model of the standard synapse. The standard model of the synapse is now viewed as a “tetrapartite” synapse made of four parts: presynaptic neurons, postsynaptic neurons, glial cells, and the ECM. Each of these plays a key role in successful and correct neurotransmission. This paper will present a review of the research regarding the roll of PNN’s in three different neuropsychiatric diseases: Alzheimer’s, Schizophrenia, and Major Depressive Disorder (MDD). The dominating view of neuropsychiatric illnesses and treatments for the last several decades has been one of a two part synapse. With treatment focusing primarily on correcting the neurotransmitter imbalances seen in these diseases. Current research is challenging the understanding of how the basic synapse works, and the involvement of glial cells and the ECM in a variety of neurological diseases. Alterations in ECM function has been shown to be at least partially responsible for the pathology seen in the three diseases analyzed. This provides a novel approach to new treatments that do not rely on neurotransmitter replacement therapies and could possibly enable patients to receive better treatment in the future. Key Words: Plasticity, PNN, Alzheimer’s, Schizophrenia, Major Depressive Disorder, ECM, Tetrapartite synapse, Neurotransmission. PNN’s and Neuropsychiatric Illnesses 3 Spiering Methods Research methods were very basic. Background research was done on the neurological symptoms of Alzheimer’s, schizophrenia, and MDD. Background research was conducted on PNN’s, their basic structure, and their functions in the CNS. Current theories on the three previous neuropsychiatric illnesses were also research for background and discussed. Then research was conducted looking for possible links between the symptomology and pathology displayed in these neuropsychiatric diseases and PNN’s. No exclusion or inclusion criteria were used due to the largely new field of research that this is. Introduction Approximately 10-20% of the volume of the human brain is occupied by the ECM (Bosiaki 2019). The ECM is a dense matrix of a variety of different molecules that condense to form PNN’s. PNN’s are made of chondroitin sulphate proteoglycans (CSPG’s), tenascin, link proteins (HAPLN-1, -3, -4), and a hyaluronan backbone. PNN’s surround primarily the cell bodies and dendrites of parvalbumin positive (PV+) interneurons, and mediate synaptic transmission and neuroplasticity within this subpopulation of neurons. PNN’s will be discussed in more detail in the “PNN” section of this paper. Alzheimer’s disease, Schizophrenia, and Major Depressive Disorder (MDD) have all traditionally been thought of as neurotransmitter imbalanced diseases (less so with AD). All of the major treatments for these three diseases revolve around correcting a neurotransmitter imbalance(5,8,14,15). Whether it is a serotonin deficiency in MDD, a dopamine problem in schizophrenia, or an acetylcholine issue in AD the treatment aims are to correct this imbalance. Pharmaceutical drugs such as SSRI’s and anti-psychotics like clozapine have shown efficacy in PNN’s and Neuropsychiatric Illnesses 4 Spiering improving the life of individuals with these diseases (19,14,15). However, current research suggest there are primarily underlying pathologies that cause these neurotransmitter imbalances as a secondary outcome. The purpose of this paper is to investigate the role of PNN’s as a primary cause of neurological dysfunction. Perineuronal Nets As discussed in the introduction, PNN’s are a specialized ECM structure composed of CSPG’s, hyaluronan, link proteins and integrins. PNN’s form at different rates throughout the central nervous system (20). The development of PNN’s is completed in early adulthood in animal studies, with different cortical regions developing at different rates as well. The development of PNN’s has been shown to be activity dependent, relying on action potentials, NT release, calcium permeable AMPA receptors, and L-type voltage gated calcium channels (21). A primary idea regarding PNN’s is that they limit neuroplasticity in adult hood, and degradation or loss of PNN’s reverts the brain to a childhood-like state of neuroplasticity (figure 1). This return to plasticity enables neurons to produce new axons, synapses, and enables healing of injuries. Among the many functions of PNN’s, some of their most key roles are those of development, neuroprotection, synaptic plasticity, and synaptogenesis (22,23,24,25,26). PNN’s and Neuropsychiatric Illnesses 5 Spiering Figure 1: showing a cartoon schematic of a PNN blocking synaptogenesis and prescence of MMP’s enabling synaptic formation This paper will now briefly examine the structure of PNN’s so their role in neuropsychiatric diseases can be better understood. As discussed, PNN’s are made up of four classes of ECM molecules. Within these four classes of molecules, there are a variety of isoforms that will not be discussed as they are not relevant to the diseases discussed. However, it is worthy to note that due to the variety of isoforms, PNN’s come in a variety of different forms with varying biochemical functions(19). PNN’s are primarily found in the adult brain surrounding parvalbumin positive (PV+) GABAergic interneurons with some PNN’s also surrounding glutamatergic neurons (28,29). The role of PNN’s in these neuron populations (especially the PV+ GABAergic populations) is thought to be protection from oxidative stress. PV+ GABAergic interneurons are characterized as fast spiking neurons, and are essential for coordinating synchronous activity during cognitive tasks. The term “fast spiking” refers to the rate at which these cells depolarize and release neurotransmitters, which means they have an exceedingly high metabolic rate (30). These cells are protected from oxidative stress due to PNN’s and Neuropsychiatric Illnesses 6 Spiering their high metabolic rate by PNN’s (30). Dysfunction of these GABAergic interneurons are a hallmark of the pathophysiology of schizophrenia which will be discussed in detail later. The role of PNN’s in neuroplasticity is hypothesized to be threefold: altering formation of new connections, acting as scaffolding for molecules that alter synaptic formation, and limiting the movement of receptors at a synapse (31,32,33,34,35). These three aspects of neuroplasticity will be key in the following discussions regarding PNN’s and their implications in the following diseases. Alzheimer’s Disease Alzheimer’s disease (AD) is characterized by massive brain atrophy. The cause of this atrophy has three hypothesis. Beta-amyloid plaque (senile plaques, SP) deposition, neurofibrillary tangles (NFT’s) of phosphorylated Tau proteins, and a cholinergic deficit. Beta- amyloid build up is caused by improper processing of the amyloid precursor protein (APP) which leads to the production of amyloid-beta aggregates and eventually cell death (36). NFT’s are caused when the Tau protein becomes hyperphosphorylated which causes it to aggregate into NFT’s. This aggregation is secondary to SP formation, and in turn enhances SP production (37,38). The brains of AD patients also exhibit a cholinergic deficit which is a late feature of the disease, yet is the target of pharmacological AD therapy (3). Due to the severe memory deficits shown in Alzheimer’s, attention has been turned to the role of PNN’s in the disease. Since PNN’s are so heavily involved in memory and learning as has been shown in my PI’s research, it is a natural assumption to assess the implications of PNN’s in AD. PNN abnormalities have been shown in the brains of AD patients post mortem (13). Specifically, post mortem brains of AD patients show reduced levels of PNN’s in the hippocampus which is responsible for learning and PNN’s and Neuropsychiatric Illnesses 7 Spiering memory (40,41). It has been shown in rodents, that neurons sheathed in PNN’s are more resilient to exogenous beta-amyloid plaques than their PNN lacking counterparts (42). It has been further shown that degradation of these PNN’s results in faster cell death when incubated with beta-amyloid plaques as well (42). In humans, studies done post mortem have reflected this same result. Areas with high concentrations of PNN’s are spared from the lesioning to a much greater extent than those without PNN’s. In fact in a study from Bruckner et al, in six out of seven cases, cortical neurons associated with PNN’s were spared almost entirely from NFT damage (23)(figure 2). Unfortunately, the loss of neurons that are surrounded by PNN’s has been observed to be up to 2/3 of the total PNN+ neurons (41). Figure 2: a cartoon showing the effects PNN’s have on protecting neurons from tau tangles and cell death The mechanism by which these PNN’s are lost is not fully known. Hypothesis for the loss of these PNN’s center on the dysfunction of enzymes that are responsible for their degradation called matrix metalloproteinases (MMP’s). In several models of neurodegeneration, various MMP’s and their inhibitors tissue inhibitor of metalloproteinase (TIMP’s) show altered balance that in turn results in altered levels of PNN’s (44,45,46,47). Perhaps further directions will look PNN’s and Neuropsychiatric Illnesses 8 Spiering into the possible therapeutic benefits of trying to rescue these PNN’s from degradation to in turn attempt to salvage the remaining synapses in AD patients. This paper will now go on to discuss PNN’s and their implications in Schizophrenia. Schizophrenia 3 4 Schizophrenia is a progressive neurological disorder that displays reduction is gray matter and white matter, reductions in temporal lobe volume, issues with connectivity between brain regions (16,17). Figure 3: Shows a brain scan from a longitudinal study done by DeLisi et al which shows the enlargement of ventricles indicating loss of brain volume. Figure 3: showing scans at 0, 5, and 10 years apart in a patient with chronic schizophrenia Cellularly, schizophrenia is characterized by dysfunction of cortical interneurons, leading to a loss of excitatory and inhibitory balance within neurological systems (figure 4). These GABAergic interneurons appear to be PV+ and are surrounded by PNN’s as shown in post mortem studies of schizophrenic patients (21,22,23). There has also been observed abnormal synchrony specifically in gamma oscillations during a variety of cognitive tasks, which these PV+ GABAergic interneurons are responsible for (24, 38). PNN’s and Neuropsychiatric Illnesses 9 Spiering Figure 4: shows the results of PNN degradation by MMP- 9 and the resulting hyper excitability of neuronal networks. Further evidence of PV+ involvement is the oxidative stress that has been found in PFC of patients with schizophrenia (10,57). Naturally with so much dysfunction in cell types that are primarily the location of PNN’s, a look into PNN’s is warranted (28,29). Lower numbers of PNN’s have been observed in a variety of locations within schizophrenic brains. Lower PNN levels have been found in the amygdala, entorhinal cortex, and prefrontal cortex specifically within the regions expected to contain GABAergic interneurons (45). Further studies have also shown that PNN’s are not only decreased in PV+ GABAergic neuron populations, but globally there were reductions in at least two other major isoforms of PNN’s (59). Interestingly, while there have been large losses of PNN’s observed in schizophrenic patients, there is not a concurrent death of those cells following de-netting (60- 61). This loss of PNN’s suggest that neurological dysfunction within schizophrenia is less of a neuronal death issue, and more a functional issue. It is not clear what is driving this loss of PNN’s and subsequent cortical dysfunction but there are some hypothesis. One hypothesis is PNN’s and Neuropsychiatric Illnesses 10 Spiering that the sugar side chains within PNN’s help to regulate the chemical microenvironment around PN+ interneurons. While not proven, using chABC (enzyme that degrades PNN’s) to remove these sugar side chains has been shown to reduce the spiking of PN+ neurons and reduced variability (62). Another study has shown that alterations in different lectican levels composing PNN’s can also alter input and firing frequency of PV+ neurons (63). Schizophrenia has also been associated to elevated MMP-9/TIMP1 ratios, which may help account for the loss of PNN’s in cortical regions (14). A polymorphism has been found in schizophrenia patients for the MMP- 9 gene, and clinical trials are being conducted using MMP-9 inhibitors in conjunction with other medications (64, 65). Along with the implications of MMP-9 in PNN’s dysfunction, other hypothesis suggest stress and immune involvement play key roles in the remodeling of PNN’s. As stress and the immune system have both been shown to have powerful modulating effects (66, 67). Overall, the mechanism by which PNN’s are lost or modulated in schizophrenia are not yet clear. Although the interplay between altered PNN’s and the clinical manifestation caused by GABAergic interneuron dysfunction are slowly being elucidated, for treatment purposes much more research needs to be done on the mechanism of PNN alterations. This paper will now go on to discuss the implications of PNN’s in Major Depressive Disorder. Major Depressive Disorder Major Depressive Disorder (MDD) is a disease with clinical manifestations of persistent feelings of sadness, loss of interest in daily life, and fatigue. In the brain, MDD has been observed to cause grey matter abnormalities and a decreased volume in the prefrontal cortex and hippocampus. Cellularly, MDD is thought to have several hypothesis that could potentially PNN’s and Neuropsychiatric Illnesses 11 Spiering be at play. The monoamine hypothesis is perhaps the most widely known. The monoamine hypothesis states that the primary dysfunction within depression is a deficiency in norepinephrine (NE), serotonin (5-HT), and/or dopamine (DA). Unfortunately data is inconclusive as to if the monoamine hypothesis is true in all cases. Several studies have shown that deficiencies in NE, 5-HT, or DA are to blame in some instances, but do not provide sufficient depressive symptoms in other cases (68, 69). Treatments for MDD in the present focus on the monoamine hypothesis by attempting to correct the NT imbalance patients present with. Tri cyclic antidepressants (TCA’s), Selective serotonin reuptake inhibitor (SSRI’s), and Selective norepinephrine reuptake inhibitors (SNERI’s) are among the most commonly used medications for depression today. Due to their efficacy in treating the symptomology of depression, it can be concluded that there are indeed monoamine issues at play, yet it cannot be concluded that they are the primary issue. Ketamine has been recently discovered to have strong anti-depressive effects. Ketamine is a noncompetitive NMDAR antagonist that has been shown to produce rapid and long lasting anti-depressive effects (70). Reduced PFC function is a hallmark of depression, shown by a variety of neuroimaging studies (71). This PFC hypofunction has been shown to be reduced by ketamine (72). One hypothesis for the anti-depressive effects are due to the creation of an LTP- PNN’s and Neuropsychiatric Illnesses 12 Spiering like plasticity. Ketamine primarily binding to/and antagonizing cortical GABAergic interneurons, would decrease their inhibition on cortical pyramidal neurons (73) (figure 5). Figure 5: a cartoon of the disinhibition of pyramidal cells and neuroplasticity following ketamine intervention. Due to the involvement of PNN’s with synaptic plasticity, and the involvement of NMDAR’s in synaptic plasticity (Brown, et al.) it is reasonable to examine if there are any links between the two and MDD. The data is very inconclusive as to the involvement of PNN’s in MDD. There has not been substantial research into the topic. One study showed that there was no difference in the density of PNN’s nor the density of PV+ interneurons between MDD patients and a control (74). Other studies have suggested that the process of PNN dysfunction may begin at an earlier stage of development due to effect chronic stress can have on early brain development (21,75). The most informative study reviewed an MDD state was induced in rats using a model of depression different from the forced swim test. The use of the forced swim test is a good model to model the effects of NT depletion, but not structural changes caused by MDD. The model used in this study was the social defeat induced persistent stress model (SDPS). A model that PNN’s and Neuropsychiatric Illnesses 13 Spiering more closely resembles the complex symptomology of MDD seen in human (76). What was found was in increase in the number of PNN coated PV+ interneurons in the hippocampus. Interestingly, this was a time dependent relationship. 72 hours following the SDPS model there was a reduction in the number of PNN+/PV+ neurons when compared to control. Thus, this stress model induces rapid remodeling of the ECM, and return to a more plastic state. At weeks 2 and 4 post SDPS no difference was found in the number of PNN+/PV+ neurons between control and SDPS models. Only at 8 weeks following SDPS was there an increase in the number of PNN+/PV+ neurons when compared to control. In addition to the upregulation of PNN’s in the long term following prolonged stress, it was also found that there were decreases in levels of MMP-2 at the 8-week time mark. This is perhaps the most intriguing study found on the links between MDD and PNN’s. As stated earlier, there is not a substantial amount of research done on the implications of PNN’s and MDD. Drawing from the above discussed data, it seems reasonable to hypothesize that a depressive state could be caused by an upregulation of PNN’s on cortical inhibitory neurons thereby enhancing their inhibitory effect on pyramidal output. As seen with ketamine, an inhibition of these GABAergic interneurons seems to release the cortical pyramidal neurons from their inhibition thereby alleviating depressive symptoms. Much more research must be done to discover the full implications of PNN’s in MDD. Discussion Clearly PNN’s have implications in all three of the diseases focused on in this paper. New evidence is clearly showing the widespread importance of correct ECM structure to proper neuronal function. PNN’s have a wide array of functions that are crucial to the health of the PNN’s and Neuropsychiatric Illnesses 14 Spiering brain. PNN’s serve as the modulators of neuroplasticity, protecting cell populations from death, assisting in neurotransmission, and aiding in development. These four major PNN’s ideas have been investigated with their role in the pathophysiology of Alzheimer’s, schizophrenia, and MDD. Traditional views of these common neuropsychiatric diseases are being challenged, and these new sources of data provide valuable insight into the true psycho-neuropathology underlying these diseases. It may be a bold hypothesis, but evidence not included in this paper link PNN’s to many other neurodegenerative and mental problems as well, so it could reasonably be hypothesized that PNN’s/ECM are involved in most if not all brain related disorders. It is of utmost importance to rigorously explore these avenues of research in attempts to create better treatment options for patients. Doctors are trained to treat underlying pathologies, not just symptomologies, if at all possible. This paper highlights the need for reevaluation of common clinical practices towards these diseases, and innovation of new drugs targeting the underlying pathology, not just the symptomology. PNN’s and Neuropsychiatric Illnesses 15 Spiering Personal Statement Firstly, I would like to thank Dr. Travis Brown for being my mentor for this project. This project forced me to take something that I had been familiar with (PNN’s) from research in Dr. Brown’s lab and apply it to something I was very unfamiliar with (neuropsychiatric illnesses). I would have to say that my biggest take away from this project is the importance of staying humble. The scientific community is full of amazing researchers, providing world changing studies all the time. The “cutting edge” of science never stays the cutting edge for long. Clearly, something as widespread as MDD, with hundreds of medications, millions of sufferers, is still poorly understood. The new data being presented regarding neuropsychiatric illnesses shows the need for intuitive and innovative new lines of thinking to push us forward. We as a scientific community must think outside the box, be creative, artistic, and imaginative. My mentor, Dr. Brown, made an incredible discovery in his doctoral work when he took his chances on an intuitive hypothesis. Progress isn’t made by simply replicating the past and looking for nuances. What scientific discovery that propelled the world forward was ever planned? Very few I am willing to bet. A theoretical physicist once said, “sometimes science is more art than science, a lot of people don’t get that.” I think these are good words to take into science with me. Science is an art, a journey of discovery into the unknown, an adventure to help others and learn along the way. This project has above all made me excited for the future, excited to see what the next world changing thing will be, maybe it will even be me! 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