the negative symptoms and the deficient state that is seen in schizophrenia and other forms of psychosis implies that there's under activity or a lack of proper functioning mesocortical dopamine projections a leading theory for why this might be is that this is the consequence of neurodevelopmental abnormalities in the in methyl deasportate or nmda glutamate system so this lecture will talk about the glutamate system and how that hypothetically contributes to the signs and symptoms of psychosis and schizophrenia the glutamate theory of psychosis proposes that nmda which is in methyl d aspartate this subtype of glutamate receptor is hypofunctional at critical synapses in the prefrontal cortex and disruption of the nmda glutamate functioning could hypothetically be due to neurodevelopmental abnormalities like you would see with schizophrenia to neurodegenerative abnormalities like you might see in alzheimer's disease and other dementias and to the nmda receptor blocking actions of drugs and dissociative and anesthetics like ketamine or then cyclidine which is pcp and you can see that sort of summarized with this table here but in order to understand then how glutamate dysfunction could lead to positive negative and cognitive symptoms of psychosis with these various disorders and also how glutamate dysfunction might cause the downstream hypo hyper dopamine inertia like we discussed in the other lecture we have to first review glutamate and its receptors and the glutamate pathways like we did with dopamine so first let's establish what glutamate actually is so it's an amino acid that acts like a neurotransmitter and it's the major workhorse of the brain and glutamate neurons make up more than half of the excitatory neurons without glutamate the brain does not get started or keep running glutamate and another excitatory transmitter called aspartate are non-essential amino acids and they don't cross the blood-brain barrier otherwise our diet could alter our neural activity so consequently glutamate must be synthesized in the brain from glucose and other precursors glial cells assist in the reuptake degradation and the replenishment of glutamate for neurons which we'll explore in depth so remember that glutamate which is also called glutamic acid it's a neurotransmitter that is an amino acid so it's predominantly used in the body not as a neurotransmitter but as an amino acid building block for protein synthesis but when it's used as a neurotransmitter it is synthesized from glutamine which is in glial cells and these glial cells also assist in the recycling and regeneration of more glutamate following the release of glutamate that happens during neurotransmission so when glutamate is released from synaptic vesicles of the glutamate neurons it interacts with receptors in the synapse and then it's transported into neighboring glia by this reuptake pump that's called the excitatory amino acid transporter or eaat which you can see in this picture here the presynaptic glutamate neuron and the postsynaptic site of glutamate neurotransmission may also have eats but those eats don't seem to play a important role so much and the glutamate recycling and regeneration as the ones that are located on the glial cells so after the glutamine is taken back into the glia glutamate is converted into glutamine inside the glial by this enzyme that's called glutamine synthetase and it's possible that glutamate is not simply reused but it's rather converted into glutamine to keep in a pool for neurotransmitter use rather than being lost into the pool from protein synthesis so they hang on to it and don't necessarily use it for other things but glutamine is released from glial cells by a reverse transport via a pumper transporter and that's known as the specific neutral amino acid transporter or snat glutamine may also be transported out of glia by a second transporter and it's called the glial alanine serine cysteine transporter or the asct so there are these two transporters basically that can transport the glutamine into or out of the glial cells so reinforcing what i mentioned on the other slide just to recap i after the glutamate is taken up into the glia it's converted into glutamine inside that glia by this enzyme called glutamine synthetase and remember it's possible that the neuron holds on to that glutamate for use to become a neurotransmitter rather than letting it become something that forms proteins but that glutamine then is released from the glial cell by basically two transporter pumps one of them is the specific neutral amino acid transporter or snat and it's transported out of the glia from reverse transport and the other way that it's transported out of the glia is through asct when glial snaps and ascts operate in the inward direction so the opposite basically uh they would then transport the glutamine and other amino acids into the glia so they're reversed so that glutamine can get out of the glia and hopper right onto the neuron via different type of neuronal snats and operating inwardly in a reuptake manner so basically the the transporters can either be going outward to release it or inward to take it back in so once that glutamine is taken back up into the neuron it's converted back into glutamate to be used as a neurotransmitter by a different enzyme that's in the mitochondria called glutaminase glutamate then is transported into synaptic vesicles with a transporter called the vesicular glutamate transporter or v-glut and it's then stored for subsequent release during neurotransmission and once released glutamate's actions are stopped not by the breakdown with enzymes like you see with other neurotransmitter systems but they're removed by those eats on neurons or glia and then the whole cycle starts back over again there are three prominent glutamate receptors and those are the nmda receptor the ampa receptor and the kinetic receptor and each of these have several subtypes but generally they got their name after artificial agonists that selectively activate them so nmda activates the nmda receptor but not the ampa or kyanite receptors nmda and ampa receptors constitute the bulk of fast excitatory synaptic transmission in the brain and the role of kyanate is not clearly understood nmda and ampa receptors often coexist on the same postsynaptic receptor and they both allow the rapid entry of sodium into the cell which would also lead to the simultaneous exit of potassium and by doing so they generate the depolarization of the postsynaptic cell now nmda receptors are unique and that they also allow the entry of calcium and calcium can act as a second messenger inside the cell and that can have profound impact on the cell resulting in lasting changes which we'll talk about as we explore the nmda receptor in more detail glutamate systems themselves are very curious in that one of the key receptors for glutamate requires a co-transmitter to be present in addition to glutamate in order for it to function and that receptor is the nmda receptor and the co-transmitter is either the amino acid glycine or another amino acid that's closely related to it known as d-serine so this slide will talk a bit about glycine it's not known to be synthesized by glutamate neurons so they have to get this glycine from somewhere else in order for those nmda receptors to function and so glycine is either coming from glycine neurons or it seems to be coming from the glia now the glycine neurons don't seem to be the big players here because they seem to keep their glycine and reuse it for themselves and they have their own special transporter that takes it back up so it's thought then that the neighboring glia are the main source of most of the glycine that's made available for glutamate synapses so glycine itself can be taken up into the glia as well as into the glue to make neurons from the synapse by this type 1 glycine transporter and it can also be taken up by a different transporter on the glia called a snap the specific neutral amino acid transporter now it doesn't appear to be that glycine is stored in synaptic vesicles of the glia but its companion that other co-transmitter that can be used dieserine possibly can be stored but somehow by ways we're not so sure yet glycine in the cytoplasm of the glia is available for the release into the synapses and it leaves those glia cells by writing outside them into the glutamate synapse on this reversed glutamate or excuse me glycine transporter or it can go into the glia on a glycine transporter just depends on which direction it's going whether it's reversed or if it's going inward and it's that reuptake of it that's the main mechanism that terminates the action of synaptic glycine now these glycine type 1 transporters are probably located on the glutamate neuron but any release or storage from the glutamate neuron is not really understood at this point in time it can be synthesized from the amino acid l serine which is taken up from extracellular space the bloodstream and our diet and transported into the glia by another transporter called the l-serine transporter or the l-cert and it's converted from l-serine into glycine by an enzyme in the glia called hydroxy methyl transfer or shmt this enzyme works in both directions so it either converts l-serine into glycine or glycine into l-serine so then let's talk a bit about this other co-transmitter that can be used for the nmda receptor to function in addition to glutamate and that's d-serine so how is d-serine produced well it's unusual and that it's a d amino acid the 20 known essential amino acids are all l amino acids including d serine's mirror image amino acid l-serine which remember l-serine is something that can be turned into glycine with that serine hydroxymethyltransferase enzyme but d-serine happens to have a high affinity for the glycine site on the nmda receptors and glia are also equipped with an enzyme that can convert regular l-serine into the neurotransmitting amino acid d-serine by an enzyme that can go back and forth between the d and l-serine known as the d-serine resimase so that means d-serine can be derived either from glycine or from l-serine both of which can be transported into the glia by their own transporters and once they're inside there glycine is converted into l-serine by that enzyme shmt and l-serine is then converted into d-serine by that enzyme d-serine resimase so interestingly this d-serine may be produced and stored in some type of vesicle in the glia which is different from glycine and it can be released from this reversed glial d-serine transporter or the d-cert for neurotransmitting purposes that glutamate synapses that contain that nmda receptor so d-serine's actions are not only terminated by the synaptic reuptake from inward acting glial cell d surge transporters but also by an enzyme that's called d amino acid oxidase or dao and it converts destiny into inactive hydroxy pyruvate so just to summarize there's several types of glutamate receptors and those include neuronal presynaptic reuptake pumps like the eat the vesicular transporter for glutamate into the synaptic vesicles that v-glut and both of those are types of receptors so transporters can act as receptors and that's talked about in chapter two of stahls text also on presynaptic neurons as well as the postsynaptic neurons are the metabotropic glutamate receptors and the metabotropic glutamate receptors are those receptors that are linked to g proteins that's also talked about in a chapter two of stahl now there's at least eight subtypes of metabotropic glutamate receptors and they're organized into three separate groups and it looks like group two and group three metabotropic receptors can occur presynaptically where they function as autoreceptors and remember autoreceptors act like brakes so they block glutamate release so drugs that stimulate those presynaptic autoreceptors or act as agonists on those receptors can reduce glutamate release it's like they really press the brakes hard the group one metabotropic glutamate receptors on the other hand seem to be located more so postsynaptically and they seemingly interact with other postsynaptic receptors to facilitate and strengthen responses that are mediated by ligand-gated ion channel receptors for glutamate during excitatory glutamate neurotransmission additionally like we talked about before we have the nmda receptor the ampa receptor and the kyanate receptors for glutamate and recall that all of those are named that way because of the artificial agonists that selectively bind to them and all of those are members of the ligand-gated ion channel family of receptors so that's talked about in earlier chapters of stall you can revisit that if you don't remember what that's about but these receptors tend to be post-synaptic and they work together to modulate excitatory postsynaptic neurotransmission that's triggered by glutamate so ampa and kyanate may mediate fast excitatory neurotransmission by allowing that sodium to enter the neuron to depolarize it but the nmda receptors in their resting state are normally blocked by magnesium which plugs its calcium channel so we'll talk about this nmda receptor a little bit more so in its resting state the nmda receptor is blocked by magnesium it's like you got this magnesium plug that's blocking the calcium channel and that nmda receptor requires both glutamate and a change in the voltage to happen before it's going to allow sodium and calcium to enter through it so three things have to happen basically at the same time in order for that nmda receptor to let the calcium into the neuron to then trigger postsynaptic actions from that glutamate activity and so the three things are the glutamate has to occupy its binding site on that mda receptor one of its co-transmitters has to also occupy its site on the nmda receptor and remember its co-transmitters can either be glycine or d-serine and then depolarization has to occur which allows the magnesium plug to be removed and then the entry of sodium and calcium can go into that channel and term potentiation can happen in addition to synaptic plasticity and that's really important because it has significant impact on the capacity for neurons to change as a result the nmda receptor is really a key receptor that's being looked at for psychiatric medications so glutamate this excitatory neurotransmitter seems to excite pretty much any neuron that it makes contact with in the brain and that's why it's often called this master switch and there's about half a dozen specific glutamate pathways that are relevant to psychopharmacology in particular with the pathophysiology of schizophrenia and so you can see here in this picture they are the cortico brainstem pathway the corticostriatal pathway the hippocampal striatal the thalamocortical the corticothalomic and then the direct cortical cortical and the indirect corticocortical now you don't need to stress out too much by trying to memorize all of these just sort of take this in that there's various pathways and various projections and some of their roles can differ so with the cortical brainstem glutamate pathway that's very important it's a descending glutamate pathway that comes from cortical pyramidal neurons in the brainstem neurotransmitter centers and that includes really our um monoamines so it kind of takes projections from the roth a for serotonin the ventral tegmental area and the substantia for dopamine and the locus ceruleus for norepinephrine and that pathway then is a key regulator of neurotransmitter release so if you were to directly innervate those monoamine neurons in the brainstem by this excitatory pathway it would stimulate neurotransmitter release or if you were to indirectly innervate those neurons by excitatory pathway through the gaba interneurons it would block neurotransmitter release so you can see how that would have some relevance to pretty much any condition that we treat the cortical striatal glutamate pathways is another one that's a descending pathway and it comes from cortical pyramidal neurons and projects to the striatal complex and it terminates on gaba neurons destined for a relay station and another part of the striatal complex that's the globus pallidus which you might remember the globus pallidus interna and externa when we were talking about motor control the hippocampal and nucleus accumbens pathway projects from those areas the hippocampus and the nucleus accumbens and it's theorized that this pathway is in particularly important to schizophrenia and similar to the corticostriatal glutamate pathway this pathway also terminates on gaba neurons that are in turn projecting to a relay station in the globus pallidus the thalamocortical glutamate pathway brings information from that thalamus area to the cortex often to process sensory information the corticothalamic glutamate pathway which is the fifth one projects directly back to the thalamus where it may direct the manner in which neurons react to that sensory information so then you have this direct and indirect corticocortical pathway so the direct corticocortical pathway is present on the cortex and these pyramidal neurons can excite each other within the cerebral cortex with direct synaptic input from their own neurotransmitter glutamate where with the indirect way they are inhibited via that indirect input from the gaba interneurons so just as a point to clarify some of the anatomy here whenever we're talking about these pyramidal neurons that's generally what we're thinking about whenever we talk about any kind of a neuron it is these large pyramid-shaped or triangular-shaped cell bodies and they make up about 75 percent of the cortical neurons in the brain and these pyramidal neurons receive signals from other brain regions as well as from local inter neurons and those interneurons which are typically gaba neurons inhibit the pyramidal neurons and they reduce the likelihood that those neurons will fire so the gaba interneurons sort of have this policing quality to them if you will they kind of prevent things from getting out of control they're inhibitory so this picture here that you're looking at it is showing you a really close-up version of those cortical pyramidal neurons and their communication with a gaba interneuron so this first box that you can see it's that box number one it shows that glutamate being released from that pyramidal neuron and it's binding to an nmda receptor that's on that gaba interneuron gaba is then released from that interneuron and it binds to a gaba receptor particularly an alpha-2 subtype that's located on the axon of another glutamate pyramidal neuron and so when that gaba binds that alpha-2 subunit on that glutamate pyramidal neuron it inhibits that neuron from releasing downstream glutamate so it sort of puts the breaks and blocks that downstream glutamate release so with schizophrenia then something appears to be wrong with the genetic programming of these particular gaba interneurons specifically in that prefrontal cortex and it has to do with this calcium binding protein that's called parvalbumin these parvalbumin containing gaba interneurons appear to be faulty post-synaptic partners to the incoming glutamate input from those pyramidal neurons there in the prefrontal cortex and thus they sort of form this defective nmda receptor containing synaptic connections within that incoming pyramidal neuron so they have these hypo functioning nmda receptors on their dendrites defective synapses between the glutamate neuronal axons and the gabara interneuronal dendrites and therefore it's this faulty glutamate information coming in to the gaba interneuron so this disconnectivity might be genetically programmed from a variety of faulty genes that all kind of come together to form these particularly faulty nmda synapses so what happens then how well the parvalbumin containing gaba interneurons in that prefrontal cortex in patients with schizophrenia have other problems as a consequence of this problematic connectivity they have deficits and an enzyme that makes their own neurotransmitter gaba so this enzyme is gad67 which is glutamic acid decarboxylase and this is one of the most consistent findings in schizophrenia research the gad67 is a form of messenger rna that encodes for that enzyme glutamic acid decarboxylase so with there being deficits then the body compensates by increasing the postsynaptic amount of that alpha-2 subunit containing gaba-a receptors which you see in that box there where it's red there's way more gaba receptors there on that postsynaptic axon so when the gaba doesn't bind to those extra alpha 2 gaba receptors on its axon then the pyramidal neuron is not inhibited so instead it's disinhibited meaning then it's overactive and therefore too much glutamate gets released downstream so the reason why anyone has been looking at these hypo functioning nmda glutamate receptors is because they can be connected to the pre-existing dopamine hypothesis of schizophrenia and the positive and negative symptoms that occur in schizophrenia can be connected to the glutamate hypofunctioning which we had previously thought was only due to the dopamine hypothesis so remember if you will that according to the dopamine hypothesis of schizophrenia too much dopamine activity in that mesolimbic pathway is what's causing the positive symptoms of schizophrenia so in this picture here you'll see it at the very top that smaller picture is showing you that the mesolimbic pathway is the dopamine pathway that is between the nucleus accumbens and the ventral tegmental area so the way that that's connected to the nmda receptors is through one of the glutamate pathways so remember on that one slide with the many glutamate pathways that there's the corticobrain stem glutamate pathway and it's important because it regulates output of glutamate from the cortex to the ventral tegmental area so that's intriguing because it directly innervates the dopamine neurons that are projecting from that ventral tegmental area to the nucleus accumbens which we know as the mesolimbic dopamine pathway so by directly innervating those dopamine neurons they stimulate those dopamine neurons so then if that glutamate neuron was overly active because of those nmda receptors being hypoactive and unable to inhibit that glutamate activity then that hyperactive glutamate release would then downstream lead to excessive dopamine particularly on that mesolimbic pathway so that's one way that the dopamine excess can happen so the other way that dopamine excess happens is through this complex sort of four neuron circuit that involves the hippocampus the nucleus accumbens the ventral tegmental area and the globus pallidus so in this diagram the picture that's on the left that's marked a it's representing how it should normally be functioning so under normal circumstances glutamate is released in the ventral hippocampus and then it binds to normal functioning nmda receptors on a gaba interneuron which then stimulates the release of gaba that gaba then binds that receptors on a pyramidal glutamate neuron and that neurons projecting to the nucleus accumbens so by that gaba sort of inhibiting that activity on that neuron projecting to the nucleus accumbens it prevents excessive amounts of glutamate being released there so then with normal amounts of glutamate being released into the nucleus accumbens it allows for normal activation of gaba neurons that are projecting from that nucleus accumbens to the globus pallidus so there since there's this normal activation of the gaba neuron happening there that globus pallidus projects to the ventral tegmental area remember that's where the dopamine pathway that mesolimbic dopamine pathway is also located so under normal circumstances that just leads to normal activation of that mesolimbic dopamine pathway which also projects from the ventral tegmental area to the nucleus accumbens so it's kind of a cycle there so then on the right hand side this is the problematic uh hypo functioning pathway and how that is broken down so it all again starts in that ventral hippocampal area but what if that nmda receptor and the gaba interneurons there are hypoactive well then the pathway there from that ventral hippocampus to the nucleus accumbens is going to be overly active that glutamate is going to be excessive because there's no inhibition happening from gaba activity there so then when that overactive nucleus accumbens with the glutamate activity being overactive there that means excessive amounts of glutamate are going to be projected over to the globus pallidus from the nucleus accumbens and where there's that excess glutamate activity there the globus pallidus is going to send that excess glutamate activity to that ventral tegmental area and so then we're kind of back to square one with the previous slide where that dopamine activity then will get stimulated because there's no disinhibition of the mesolympic dopamine pathway happening there so without that kind of breaking action that excess glutamate will lead to excess dopamine and then that gets released back to the nucleus accumbens so that mesolimbic pathway will light up with that excess dopamine activity so the nmda hypo functioning hypothesis can also be linked to the dopamine hypothesis and the way that negative symptoms of schizophrenia are expressed so if you recall the negative symptoms of schizophrenia according to the dopamine hypothesis traditionally was believed because there was a deficiency of dopamine activity in the mesocortical pathway not enough dopamine was happening there so with this figure on the left hand side where it says a it's showing you how things should normally go so the glutamate projections that are happening in the cortical brainstem are going to be different than the ones that are happening in the mesolimbic area so different glutamate neurons regulate different populations of dopamine neurons so that cortico brainstem glutamate pathway that's destined to regulate the mesocortical dopamine neurons in the ventral tegmental area do not do so in a direct way like it is happening in the mesolimbic pathway they they do it in an indirect way so the glutamate neurons that are regulating the mesocortical dopamine neurons are indirectly innervating the inhibitory gaba into neuron and that neuron itself is innervating the mesocortical dopamine neurons so it's like you have this in between step here so then if you have abnormalities there that's kind of looking at part b you can see where the problem will arise under normal circumstances if you activate those particular glutamate neurons that then activate the gaba interneurons they would then inhibit mesocortical dopamine neurons so too much glutamate activity because of a faulty nmda hypo functioning neuron upstream would lead to downstream hypoactivity of that mesocortical dopamine neuron which then would lead to too little dopamine release so in summary and as a bottom line psychosis may in part be caused by dysfunction of glutamate synapses at specific sites and those specific sites that we believe are involved in this would be those nmda receptors that are hypofunctional located on gaba interneurons in the prefrontal cortex and we see that related to neurodevelopmental changes and abnormalities that are associated with schizophrenia or due to neurodegenerative abnormalities like we see in alzheimer's and other dementias and with the toxicity or intoxication of certain drugs like ketamine and pcp in the way that they act by blocking the nmda receptor in an antagonistic way but all of that combined explains how the glutamate dysfunction may cause the downstream higher levels of dopamine in the various pathways that have classically contributed to our dopamine hypothesis and our and the way we've understood that as it relates to psychosis and schizophrenia