Thinking outside the synapse: glycine at extrasynaptic NMDA receptors.

In this issue, Papouin et al. show that glycine is the endogenous coagonist for extrasynaptic NMDA receptors (NMDARs), unlike at synapses where the coagonist is d-serine. By enzymatically degrading endogenous glycine, they begin to address the enigmatic physiological and pathological roles for extrasynaptic NMDARs.

d-Serine inhibits non-ionotropic NMDA receptor signaling.

NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g. d-serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results can be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of LTD induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker, MK801. Conversely, a saturating concentration of d-serine completely inhibited both LTD and spine shrinkage induced by glutamate binding in the presence of MK801. Using a FRET-based assay in cultured neurons, we further found that d-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in which d-serine inhibits ion flux-independent NMDAR signaling and plasticity, and thus d-serine availability could serve to modulate NMDAR signaling even when the NMDAR is blocked by magnesium.Significance Statement NMDARs are glutamate-gated cation channels that are key regulators of neurodevelopment and synaptic plasticity and unique in their requirement for binding of a co-agonist (e.g. d-serine) in order for the channel to open. NMDARs have been found to drive synaptic plasticity via non-ionotropic (ion flux-independent) signaling upon the binding of glutamate in the absence of co-agonist, though conflicting results have led to controversy. Here, we found that d-serine inhibits non-ionotropic NMDAR-mediated LTD and LTD-associated spine shrinkage. Thus, a major source of the contradictory findings might be attributed to experimental variability in d-serine availability. In addition, the developmental regulation of d-serine levels suggests a role for non-ionotropic NMDAR plasticity during critical periods of plasticity.

Excessive Laughter-like Vocalizations, Microcephaly, and Translational Outcomes in the Ube3a Deletion Rat Model of Angelman Syndrome.

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder characterized by intellectual disabilities, motor and balance deficits, impaired communication, and a happy, excitable demeanor with frequent laughter. We sought to elucidate a preclinical outcome measure in male and female rats that addressed communication abnormalities of AS and other neurodevelopmental disorders in which communication is atypical and/or lack of speech is a core feature. We discovered, and herein report for the first time, excessive laughter-like 50 kHz ultrasonic emissions in the Ube3amat-/pat+ rat model of AS, which suggests an excitable, playful demeanor and elevated positive affect, similar to the demeanor of individuals with AS. Also in line with the AS phenotype, Ube3amat-/pat+ rats demonstrated aberrant social interactions with a novel partner, distinctive gait abnormalities, impaired cognition, an underlying LTP deficit, and profound reductions in brain volume. These unique, robust phenotypes provide advantages compared with currently available mouse models and will be highly valuable as outcome measures in the evaluation of therapies for AS.SIGNIFICANCE STATEMENT Angelman syndrome (AS) is a severe neurogenetic disorder for which there is no cure, despite decades of research using mouse models. This study used a recently developed rat model of AS to delineate disease-relevant outcome measures to facilitate therapeutic development. We found the rat to be a strong model of AS, offering several advantages over mouse models by exhibiting numerous AS-relevant phenotypes, including overabundant laughter-like vocalizations, reduced hippocampal LTP, and volumetric anomalies across the brain. These findings are unconfounded by detrimental motor abilities and background strain, issues plaguing mouse models. This rat model represents an important advancement in the field of AS, and the outcome metrics reported herein will be central to the therapeutic pipeline.

Reduced d-serine levels drive enhanced non-ionotropic NMDA receptor signaling and destabilization of dendritic spines in a mouse model for studying schizophrenia.

Schizophrenia is a psychiatric disorder that affects over 20 million people globally. Notably, schizophrenia is associated with decreased density of dendritic spines and decreased levels of d-serine, a co-agonist required for opening of the N-methyl-d-aspartate receptor (NMDAR). We hypothesized that lowered d-serine levels associated with schizophrenia would enhance ion flux-independent signaling by the NMDAR, driving destabilization and loss of dendritic spines. We tested our hypothesis using the serine racemase knockout (SRKO) mouse model, which lacks the enzyme for d-serine production. We show that activity-dependent spine growth is impaired in SRKO mice, but can be acutely rescued by exogenous d-serine. Moreover, we find a significant bias of synaptic plasticity toward spine shrinkage in the SRKO mice as compared to wild-type littermates. Notably, we demonstrate that enhanced ion flux-independent signaling through the NMDAR contributes to this bias toward spine destabilization, which is exacerbated by an increase in synaptic NMDARs in hippocampal synapses of SRKO mice. Our results support a model in which lowered d-serine levels associated with schizophrenia enhance ion flux-independent NMDAR signaling and bias toward spine shrinkage and destabilization.

Postsynaptic Serine Racemase Regulates NMDA Receptor Function.

d-serine is the primary NMDAR coagonist at mature forebrain synapses and is synthesized by the enzyme serine racemase (SR). However, our understanding of the mechanisms regulating the availability of synaptic d-serine remains limited. Though early studies suggested d-serine is synthesized and released from astrocytes, more recent studies have demonstrated a predominantly neuronal localization of SR. More specifically, recent work intriguingly suggests that SR may be found at the postsynaptic density, yet the functional implications of postsynaptic SR on synaptic transmission are not yet known. Here, we show an age-dependent dendritic and postsynaptic localization of SR and d-serine by immunohistochemistry and electron microscopy in mouse CA1 pyramidal neurons. In addition, using a single-neuron genetic approach in SR conditional KO mice from both sexes, we demonstrate a cell-autonomous role for SR in regulating synaptic NMDAR function at Schaffer collateral (CA3)-CA1 synapses. Importantly, single-neuron genetic deletion of SR resulted in the elimination of LTP at 1 month of age, which could be rescued by exogenous d-serine. Interestingly, there was a restoration of LTP by 2 months of age that was associated with an upregulation of synaptic GluN2B. Our findings support a cell-autonomous role for postsynaptic neuronal SR in regulating synaptic NMDAR function and suggests a possible autocrine mode of d-serine action.SIGNIFICANCE STATEMENT NMDARs are key regulators of neurodevelopment and synaptic plasticity and are unique in their requirement for binding of a coagonist, which is d-serine at most forebrain synapses. However, our understanding of the mechanisms regulating synaptic d-serine availability remains limited. d-serine is synthesized in the brain by the neuronal enzyme serine racemase (SR). Here, we show dendritic and postsynaptic localization of SR and d-serine in CA1 pyramidal neurons. In addition, using single-neuron genetic deletion of SR, we establish a role of postsynaptic SR in regulating NMDAR function. These results support an autocrine mode of d-serine action at synapses.

Increased excitation-inhibition balance and loss of GABAergic synapses in the serine racemase knockout model of NMDA receptor hypofunction.

There is substantial evidence that both N-methyl-D-aspartate receptor (NMDAR) hypofunction and dysfunction of GABAergic neurotransmission contribute to schizophrenia, though the relationship between these pathophysiological processes remains largely unknown. Although models using cell-type-specific genetic deletion of NMDARs have been informative, they display overly pronounced phenotypes extending beyond those of schizophrenia. Here, we used the serine racemase knockout (SRKO) mice, a model of reduced NMDAR activity rather than complete receptor elimination, to examine the link between NMDAR hypofunction and decreased GABAergic inhibition. The SRKO mice, in which there is a >90% reduction in the NMDAR coagonist d-serine, exhibit many of the neurochemical and behavioral abnormalities observed in schizophrenia. We found a significant reduction in inhibitory synapses onto CA1 pyramidal neurons in the SRKO mice. This reduction increases the excitation/inhibition balance resulting in enhanced synaptically driven neuronal excitability without changes in intrinsic excitability. Consistently, significant reductions in inhibitory synapse density in CA1 were observed by immunohistochemistry. We further show, using a single-neuron genetic deletion approach, that the loss of GABAergic synapses onto pyramidal neurons observed in the SRKO mice is driven in a cell-autonomous manner following the deletion of SR in individual CA1 pyramidal cells. These results support a model whereby NMDAR hypofunction in pyramidal cells disrupts GABAergic synapses leading to disrupted feedback inhibition and impaired neuronal synchrony.NEW & NOTEWORTHY Recently, disruption of excitation/inhibition (E/I) balance has become an area of considerable interest for psychiatric research. Here, we report a reduction in inhibition in the serine racemase knockout mouse model of schizophrenia that increases E/I balance and enhances synaptically driven neuronal excitability. This reduced inhibition was driven cell-autonomously in pyramidal cells lacking serine racemase, suggesting a novel mechanism for how chronic NMDA receptor hypofunction can disrupt information processing in schizophrenia.

Sestd1 Encodes a Developmentally Dynamic Synapse Protein That Complexes With BCR Rac1-GAP to Regulate Forebrain Dendrite, Spine and Synapse Formation.

SEC14 and Spectrin domain-1 (Sestd1) is a synapse protein that exhibits a striking shift from the presynaptic to postsynaptic space as neurons mature postnatally in the mouse hippocampus. Hippocampal pyramidal neurons from mice with global genetic deletion of Sestd1 have reduced dendrite arbors, spines, and excitatory synapses. Electrophysiologically this correlates with cell-autonomous reductions in both AMPA- and NMDA-excitatory postsynaptic currents in individual hippocampal neurons from which Sestd1 has been deleted in vivo. These neurodevelopmental and functional deficits are associated with increased activation of the Rho family GTPases Rac1 and RhoA. Co-immunoprecipitation and mass spectrometry reveal that the Breakpoint Cluster Region protein, a Rho GTPase activating protein (GAP), forms complexes with Sestd1 in brain tissue. This complements earlier findings that Sestd1 can also partner with other Rho family GAPs and guanine nucleotide exchange factors. Our findings demonstrate that Sestd1 is a developmentally dynamic synaptic regulator of Rho GTPases that contributes to dendrite and excitatory synapse formation within differentiating pyramidal neurons of the forebrain.

Long-Term Depression Is Independent of GluN2 Subunit Composition.

NMDA receptors (NMDARs) mediate both long-term potentiation and long-term depression (LTD) and understanding how a single receptor can initiate both phenomena remains a major question in neuroscience. A prominent hypothesis implicates the NMDAR subunit composition, specifically GluN2A and GluN2B, in dictating the rules of synaptic plasticity. However, studies testing this hypothesis have yielded inconsistent and often contradictory results, especially for LTD. These inconsistent results may be due to challenges in the interpretation of subunit-selective pharmacology and in dissecting out the contributions of differential channel properties versus the interacting proteins unique to GluN2A or GluN2B. In this study, we address the pharmacological and biochemical challenges by using a single-neuron genetic approach to delete NMDAR subunits in conditional knock-out mice. In addition, the recently discovered non-ionotropic nature of NMDAR-dependent LTD allowed the rigorous assessment of unique subunit contributions to NMDAR-dependent LTD while eliminating the variable of differential charge transfer. Here we find that neither the GluN2A nor the GluN2B subunit is strictly necessary for either non-ionotropic or ionotropic LTD.SIGNIFICANCE STATEMENT NMDA receptors are key regulators of bidirectional synaptic plasticity. Understanding the mechanisms regulating bidirectional plasticity will guide development of therapeutic strategies to treat the dysfunctional synaptic plasticity in multiple neuropsychiatric disorders. Because of the unique properties of the NMDA receptor GluN2 subunits, they have been postulated to differentially affect synaptic plasticity. However, there has been significant controversy regarding the roles of the GluN2 subunits in synaptic long term depression (LTD). Using single-neuron knock-out of the GluN2 subunits, we show that LTD requires neither GluN2A nor GluN2B.

Non-Ionotropic NMDA Receptor Signaling Drives Activity-Induced Dendritic Spine Shrinkage.

The elimination of dendritic spine synapses is a critical step in the refinement of neuronal circuits during development of the cerebral cortex. Several studies have shown that activity-induced shrinkage and retraction of dendritic spines depend on activation of the NMDA-type glutamate receptor (NMDAR), which leads to influx of extracellular calcium ions and activation of calcium-dependent phosphatases that modify regulators of the spine cytoskeleton, suggesting that influx of extracellular calcium ions drives spine shrinkage. Intriguingly, a recent report revealed a novel non-ionotropic function of the NMDAR in the regulation of synaptic strength, which relies on glutamate binding but is independent of ion flux through the receptor (Nabavi et al., 2013). Here, we tested whether non-ionotropic NMDAR signaling could also play a role in driving structural plasticity of dendritic spines. Using two-photon glutamate uncaging and time-lapse imaging of rat hippocampal CA1 neurons, we show that low-frequency glutamatergic stimulation results in shrinkage of dendritic spines even in the presence of the NMDAR d-serine/glycine binding site antagonist 7-chlorokynurenic acid (7CK), which fully blocks NMDAR-mediated currents and Ca(2+) transients. Notably, application of 7CK or MK-801 also converts spine enlargement resulting from a high-frequency uncaging stimulus into spine shrinkage, demonstrating that strong Ca(2+) influx through the NMDAR normally overcomes a non-ionotropic shrinkage signal to drive spine growth. Our results support a model in which NMDAR signaling, independent of ion flux, drives structural shrinkage at spiny synapses. SIGNIFICANCE STATEMENT: Dendritic spine elimination is vital for the refinement of neural circuits during development and has been linked to improvements in behavioral performance in the adult. Spine shrinkage and elimination have been widely accepted to depend on Ca(2+) influx through NMDA-type glutamate receptors (NMDARs) in conjunction with long-term depression (LTD) of synaptic strength. Here, we use two-photon glutamate uncaging and time-lapse imaging to show that non-ionotropic NMDAR signaling can drive shrinkage of dendritic spines, independent of NMDAR-mediated Ca(2+) influx. Signaling through p38 MAPK was required for this activity-dependent spine shrinkage. Our results provide fundamental new insights into the signaling mechanisms that support experience-dependent changes in brain structure.

D-Serine inhibits non-ionotropic NMDA receptor signaling.

NMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g. d -serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results can be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of LTD induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker, MK801. Conversely, a saturating concentration of d -serine completely inhibited both LTD and spine shrinkage induced by glutamate binding in the presence of MK801. Using a FRET-based assay in cultured neurons, we further found that d -serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in which d -serine inhibits ion flux-independent NMDAR signaling and plasticity, and thus d -serine availability could serve to modulate NMDAR signaling even when the NMDAR is blocked by magnesium. Significance Statement: NMDARs are glutamate-gated cation channels that are key regulators of neurodevelopment and synaptic plasticity and unique in their requirement for binding of a co-agonist (e.g. d -serine) in order for the channel to open. NMDARs have been found to drive synaptic plasticity via non-ionotropic (ion flux-independent) signaling upon the binding of glutamate in the absence of co-agonist, though conflicting results have led to controversy. Here, we found that d -serine inhibits non-ionotropic NMDAR-mediated LTD and LTD-associated spine shrinkage. Thus, a major source of the contradictory findings might be attributed to experimental variability in d -serine availability. In addition, the developmental regulation of d -serine levels suggests a role for non-ionotropic NMDAR plasticity during critical periods of plasticity.

GluN3A subunit tunes NMDA receptor synaptic trafficking and content during postnatal brain development.

Signaling via N-methyl-d-aspartate receptors (NMDARs) is critical for the maturation of glutamatergic synapses, partly through a developmental switch from immature synapses expressing primarily GluN2B- and GluN3A-containing subtypes to GluN2A-rich mature ones. This subunit switch is thought to underlie the synaptic stabilization of NMDARs necessary for neural network consolidation. However, the cellular mechanisms controlling the NMDAR exchange remain unclear. Using a combination of single-molecule and confocal imaging and biochemical and electrophysiological approaches, we show that surface GluN3A-NMDARs form a highly diffusive receptor pool that is loosely anchored to synapses. Remarkably, changes in GluN3A subunit expression selectively alter the surface diffusion and synaptic anchoring of GluN2A- but not GluN2B-NMDARs, possibly through altered interactions with cell surface receptors. The effects of GluN3A on NMDAR surface diffusion are restricted to an early time window of postnatal development in rodents, allowing GluN3A subunits to control the timing of NMDAR signaling maturation and neuronal network refinements.

5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines.

Psychedelic compounds have displayed antidepressant potential in both humans and rodents. Despite their promise, psychedelics can induce undesired effects that pose safety concerns and limit their clinical scalability. The rational development of optimized psychedelic-related medicines will require a full mechanistic understanding of how these molecules produce therapeutic effects. While the hallucinogenic properties of psychedelics are generally attributed to activation of serotonin 2A receptors (5-HT2ARs), it is currently unclear if these receptors also mediate their antidepressant effects as several nonhallucinogenic analogues of psychedelics with antidepressant-like properties have been developed. Moreover, many psychedelics exhibit promiscuous pharmacology, making it challenging to identify their primary therapeutic target(s). Here, we use a combination of pharmacological and genetic tools to demonstrate that activation of 5-HT2A receptors is essential for tryptamine-based psychedelics to produce antidepressant-like effects in rodents. Our results suggest that psychedelic tryptamines can induce hallucinogenic and therapeutic effects through activation of the same receptor.

D-serine availability modulates prefrontal cortex inhibitory interneuron development and circuit maturation.

The proper development and function of telencephalic GABAergic interneurons is critical for maintaining the excitation and inhibition (E/I) balance in cortical circuits. Glutamate contributes to cortical interneuron (CIN) development via N-methyl-D-aspartate receptors (NMDARs). NMDAR activation requires the binding of a co-agonist, either glycine or D-serine. D-serine (co-agonist at many mature forebrain synapses) is racemized by the neuronal enzyme serine racemase (SR) from L-serine. We utilized constitutive SR knockout (SR-/-) mice to investigate the effect of D-serine availability on the development of CINs and inhibitory synapses in the prelimbic cortex (PrL). We found that most immature Lhx6 + CINs expressed SR and the obligatory NMDAR subunit NR1. At embryonic day 15, SR-/- mice had an accumulation of GABA and increased mitotic proliferation in the ganglionic eminence and fewer Gad1 + (glutamic acid decarboxylase 67 kDa; GAD67) cells in the E18 neocortex. Lhx6 + cells develop into parvalbumin (PV+) and somatostatin (Sst+) CINs. In the PrL of postnatal day (PND) 16 SR-/- mice, there was a significant decrease in GAD67+ and PV+, but not SST + CIN density, which was associated with reduced inhibitory postsynaptic potentials in layer 2/3 pyramidal neurons. These results demonstrate that D-serine availability is essential for prenatal CIN development and postnatal cortical circuit maturation.

Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors.

Decreased dendritic spine density in the cortex is a hallmark of several neuropsychiatric diseases, and the ability to promote cortical neuron growth has been hypothesized to underlie the rapid and sustained therapeutic effects of psychedelics. Activation of 5-hydroxytryptamine (serotonin) 2A receptors (5-HT2ARs) is essential for psychedelic-induced cortical plasticity, but it is currently unclear why some 5-HT2AR agonists promote neuroplasticity, whereas others do not. We used molecular and genetic tools to demonstrate that intracellular 5-HT2ARs mediate the plasticity-promoting properties of psychedelics; these results explain why serotonin does not engage similar plasticity mechanisms. This work emphasizes the role of location bias in 5-HT2AR signaling, identifies intracellular 5-HT2ARs as a therapeutic target, and raises the intriguing possibility that serotonin might not be the endogenous ligand for intracellular 5-HT2ARs in the cortex.

SOX2 is essential for astrocyte maturation and its deletion leads to hyperactive behavior in mice.

Children with SOX2 deficiency develop ocular disorders and extra-ocular CNS anomalies. Animal data show that SOX2 is essential for retinal and neural stem cell development. In the CNS parenchyma, SOX2 is primarily expressed in astroglial and oligodendroglial cells. Here, we report a crucial role of astroglial SOX2 in postnatal brain development. Astroglial Sox2-deficient mice develop hyperactivity in locomotion and increased neuronal excitability in the corticostriatal circuit. Sox2 deficiency inhibits postnatal astrocyte maturation molecularly, morphologically, and electrophysiologically without affecting astroglia proliferation. Mechanistically, SOX2 directly binds to a cohort of astrocytic signature and functional genes, the expression of which is significantly reduced in Sox2-deficient CNS and astrocytes. Consistently, Sox2 deficiency remarkably reduces glutamate transporter expression and compromised astrocyte function of glutamate uptake. Our study provides insights into the cellular mechanisms underlying brain defects in children with SOX2 mutations and suggests a link of astrocyte SOX2 with extra-ocular abnormalities in SOX2-mutant subjects.

Genetic analysis of neuronal ionotropic glutamate receptor subunits.

In the brain, fast, excitatory synaptic transmission occurs primarily through AMPA- and NMDA-type ionotropic glutamate receptors. These receptors are composed of subunit proteins that determine their biophysical properties and trafficking behaviour. Therefore, determining the function of these subunits and receptor subunit composition is essential for understanding the physiological properties of synaptic transmission. Here, we discuss and evaluate various genetic approaches that have been used to study AMPA and NMDA receptor subunits. These approaches have demonstrated that the GluA1 AMPA receptor subunit is required for activity-dependent trafficking and contributes to basal synaptic transmission, while the GluA2 subunit regulates Ca(2+) permeability, homeostasis and trafficking to the synapse under basal conditions. In contrast, the GluN2A and GluN2B NMDA receptor subunits regulate synaptic AMPA receptor content, both during synaptic development and plasticity. Ongoing research in this field is focusing on the molecular interactions and mechanisms that control these functions. To accomplish this, molecular replacement techniques are being used, where native subunits are replaced with receptors containing targeted mutations. In this review, we discuss a single-cell molecular replacement approach which should arguably advance our physiological understanding of ionotropic glutamate receptor subunits, but is generally applicable to study of any neuronal protein.

Potentiation of synaptic AMPA receptors induced by the deletion of NMDA receptors requires the GluA2 subunit.

Deletion of N-methyl-D-aspartate receptors (NMDARs) early in development results in an increase in the number of synaptic AMPA receptors (AMPARs), suggesting a role for NMDARs in negatively regulating AMPAR trafficking at developing synapses. Substantial evidence has shown that AMPAR subunits function differentially in AMPAR trafficking. However, the role of AMPAR subunits in the enhancement of AMPARs following NMDAR ablation remains unknown. We have now performed single-cell genetic deletions in double-floxed mice in which the deletion of GluN1 is combined with the deletion of GluA1 or GluA2. We find that the AMPAR enhancement following NMDAR deletion requires the GluA2 subunit, but not the GluA1 subunit, indicating a key role for GluA2 in the regulation of AMPAR trafficking in developing synapses.

The expanded biology of serotonin.

Serotonin is perhaps best known as a neurotransmitter that modulates neural activity and a wide range of neuropsychological processes, and drugs that target serotonin receptors are used widely in psychiatry and neurology. However, most serotonin is found outside the central nervous system, and virtually all of the 15 serotonin receptors are expressed outside as well as within the brain. Serotonin regulates numerous biological processes including cardiovascular function, bowel motility, ejaculatory latency, and bladder control. Additionally, new work suggests that serotonin may regulate some processes, including platelet aggregation, by receptor-independent, transglutaminase-dependent covalent linkage to cellular proteins. We review this new "expanded serotonin biology" and discuss how drugs targeting specific serotonin receptors are beginning to help treat a wide range of diseases.

The Role of Glutamate in Language and Language Disorders - Evidence from ERP and Pharmacologic Studies.

Current models of language processing do not address mechanisms at the neurotransmitter level, nor how pharmacologic agents may improve language function(s) in seemingly disparate disorders. L-Glutamate, the primary excitatory neurotransmitter in the human brain, is extensively involved in various higher cortical functions. We postulate that the physiologic role of L-Glutamate neurotransmission extends to the regulation of language access, comprehension, and production, and that disorders in glutamatergic transmission and circuitry contribute to the pathogenesis of neurodegenerative diseases and sporadic-onset language disorders such as the aphasic stroke syndromes. We start with a review of basic science data pertaining to various glutamate receptors in the CNS and ways that they may influence the physiological processes of language access and comprehension. We then focus on the dysregulation of glutamate neurotransmission in three conditions in which language dysfunction is prominent: Alzheimer's Disease, Fragile X-associated Tremor/Ataxia Syndrome, and Aphasic Stroke Syndromes. Finally, we review the pharmacologic and electrophysiologic (event related brain potential or ERP) data pertaining to the role glutamate neurotransmission plays in language processing and disorders.