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By proudly working with the Autism Fragile X Foundation


Anxiety areas in the brain

The Anxiety areas in the brain significantly interferes with social development and learning:

The hippocampus is the part of the brain that is involved in memory forming, organizing, and storing. It is a limbic system structure that is particularly important in forming new memories and connecting emotions and senses, such as smell and sound, to memories. The hippocampus is a horseshoe shaped paired structure, with one hippocampus located in the left brain hemisphere and the other in the right hemisphere.

The hippocampus acts as a memory indexer by sending memories out to the appropriate part of the cerebral hemisphere for long-term storage and retrieving them when necessary.

The hippocampus is involved in several functions of the body including:

* Consolidation of new memory

* Emotional Responses

* Navigation

* Spatial Orientation

* Controlling anxiety can greatly improve therapies:

* Current anti-anxiety drugs are broad acting and usually ineffective

                 * Valium, Prozac, amphetamines, anti-psychotics etc

                 * These drugs are considered “Hit or Miss”, singly or in combination

* Positive targeted drugs are needed:

                *NUNZIA - a targeted Blocker” 

NUNZIA is able to reduce the extra synapses which cause anxiety. When there is a rapid firing of synapse and the protein filters of the brain are functional, then anxiety occurs, but no or little affixations, but when the protein filters are not functional or functioning at full capacity, such as the FXMP protein, then anxiety can also produce affixations and other disorders, which are related to affixations or compulsory. We had thought that Fragile X or Autist people did not have the FXMP protein and was the root cause, but after much research, we did conclude that the FXMP protein filter was present, but not functioning at full capacity and functioned at different levels according the individual and therefore the consensus and conclusion was that the different levels of functionality of the FXMP could be the main cause of affixations and compulsory disorders at different levels in the individual.

Anxiety Systems and Disorders alone cause various problems, but when coupled with a malfunctioning FXMP protein the problems are exponential.

Symptoms of Anxiety:

According to the Mayo Clinic Staff: ( Symptoms of Anxiety)

Common anxiety signs and symptoms include:

   * Feeling nervous

   * Feeling powerless

   * Having a sense of impending danger, panic or doom

   * Having an increased heart rate

   * Breathing rapidly (hyperventilation)

   * Sweating

   * Trembling

   * Feeling weak or tired

   * Trouble concentrating or thinking about anything other than the present worry

Several types of anxiety disorders exist:

Separation anxiety disorder is a childhood disorder characterized by anxiety that is excessive for the developmental level and related to separation from parents or others who have parental roles.

Selective mutism is a consistent failure to speak in certain situations, such as school, even when you can speak in other situations, such as at home with close family members. This can interfere with school, work and social functioning.

Specific phobias are characterized by major anxiety when you're exposed to a specific object or situation and a desire to avoid it. Phobias provoke panic attacks in some people.

Social anxiety disorder (social phobia) involves high levels of anxiety, fear and avoidance of social situations due to feelings of embarrassment, self-consciousness and concern about being judged or viewed negatively by others.

Panic disorder involves repeated episodes of sudden feelings of intense anxiety and fear or terror that reach a peak within minutes (panic attacks). You may have feelings of impending doom, shortness of breath, heart palpitations or chest pain.

Agoraphobia is anxiety about, and often avoidance of, places or situations where you might feel trapped or helpless if you start to feel panicky or experience embarrassing symptoms, such as losing control.

Generalized anxiety disorder:

Includes persistent and excessive anxiety and worry about activities or events — even ordinary, routine issues. The worry is usually out of proportion to the actual circumstance, is difficult to control and interferes with your ability to focus on current tasks. It often occurs along with other anxiety disorders or depression.

Substance-induced anxiety disorder is characterized by prominent symptoms of anxiety or panic that are a direct result of abusing drugs, taking medications, being exposed to a toxic substance or withdrawal from drugs.

Anxiety disorder due to a medical condition includes prominent symptoms of anxiety or panic that are directly caused by a physical health problem.

Specified anxiety disorder and unspecified anxiety disorder are terms for anxiety or phobias that don't meet the exact criteria for any other anxiety disorders but are significant enough to be distressing and disruptive.

Other Disorders that NUNZIA can help:

Mayo Clinic Staff, ( OCD)

Factors that may increase the risk of developing or triggering obsessive-compulsive disorder include:

Family history: Having parents or other family members with the disorder can increase your risk of developing OCD stressful life events. If you've experienced traumatic or stressful events or you tend to react strongly to stress, your risk may increase. This reaction may, for some reason, trigger the intrusive thoughts, rituals and emotional distress characteristic of OCD.

Stressful events cause ANXIETY:


Mayo Clinic Staff ( OCD)

The cause of obsessive-compulsive disorder isn't fully understood. Main theories include:

Biology: OCD may be a result of changes in your body's own natural chemistry or brain functions. OCD may also have a genetic component, but specific genes have yet to be identified.

California Biotech has identified the chemistry function for Anxiety, which can trigger OCD.

Environment: Some environmental factors such as infections are suggested as a trigger for OCD, but more research is needed to be sure.


By Mayo Clinic Staff, continued

Individuals with obsessive-compulsive disorder may have additional problems. Some of the problems below may be associated with OCD — others may exist in addition to OCD but not be caused by it.

* Inability to attend work, school or social activities

* Troubled relationships

* Overall poor quality of life

* Anxiety disorders**

* Depression

* Eating disorders***

* Suicidal thoughts and behavior

* Alcohol or other substance abuse***

* Contact dermatitis from frequent hand-washing: if frequent hand–washing is an affixation, than it can be BOLD and Underlined and can be treated by NUNZIA.  

All Anxiety Disorders as stated above, have been found to be the basis of Autistic Spectrum of Disorders (ASD).  As it is well known ASD includes many disorders that we are familiar with, such as: Autism, Fragile X, ADD, ADHD, PTSD OCD; and including some disorders that are also anxiety and glutamate based, but we may not have known, that this disorders are part of the same spectrum, such as: MS, Parkinson, and Dementia. It has been proven in several studies through out the world over the last twenty plus years, as stated and verified in this summary of more than three hundred studies. 

General clinical implications

•o Autoimmunity and antibody interactions with glutamate receptors and their subunit genes

•o Excitotoxicity

•o Neurodegeneration

Conditions with demonstrated associations to glutamate receptors

•o Aching*

•o Attention deficit hyperactivity disorder (ADHD)*

•o Autism*

•o Diabetes*

•o Huntington's disease

•o Ischemia

•o Multiple sclerosis*

•o Parkinson's disease (Parkinsonism)*

•o Rasmussen's encephalitis

•o Schizophrenia

•o Seizures*

• Other diseases suspected of glutamate receptor link

•o Neurodegenerative diseases with a suspected excitotoxicity link

General clinical implications

Specific medical conditions and symptoms are discussed below.

Autoimmunity and antibody interactions with glutamate receptors and their subunit genes

Various neurological disorders are accompanied by antibody or autoantigen activity associated with glutamate receptors or their subunit genes (e.g. GluR3 in Rasmussen's encephalitis,[31] and GluR2 in nonfamilial olivopontocerebellar degeneration.[32] In 1994 GluR3 was shown to act as an autoantigen in Rasmussen's encephalitis, leading to speculation that autoimmune activity might underlie the condition.[33] Such findings "suggest" links between glutamate receptors and autoimmune interactions are possible and may be significant in some degenerative diseases,[32] however the exact role of such antibodies in disease manifestation is still not entirely known.[34]


Overstimulation of glutamate receptors causes neurodegeneration and neuronal damage through a process called excitotoxicity. Excessive glutamate, or excitotoxins acting on the same glutamate receptors, overactivate glutamate receptors (specifically NMDARs), causing high levels of calcium ions (Ca2+) to influx into the postsynaptic cell.[35]

High Ca2+ concentrations activate a cascade of cell degradation processes involving proteases, lipases, nitric oxide synthase, and a number of enzymes that damage cell structures often to the point of cell death.[36] Ingestion of or exposure to excitotoxins that act on glutamate receptors can induce excitotoxicity and cause toxic effects on the central nervous system.[37] This becomes a problem for cells, as it feeds into a cycle of positive feedback cell death.

Glutamate excitotoxicity triggered by overstimulation of glutamate receptors also contributes to intracellular oxidative stress. Proximal glial cells use a cystine/glutamate antiporter (xCT) to transport cystine into the cell and glutamate out. Excessive extracellular glutamate concentrations reverse xCT, so glial cells no longer have enough cystine to synthesize glutathione (GSH), an antioxidant.[38] Lack of GSH leads to more reactive oxygen species (ROSs) that damage and kill the glial cell, which then cannot reuptake and process extracellular glutamate.[39] This is another positive feedback in glutamate excitotoxicity. In addition, increased Ca2+ concentrations activate nitric oxide synthase (NOS) and the over-synthesis of nitric oxide (NO). High NO concentration damages mitochondria, leading to more energy depletion, and adds oxidative stress to the neuron as NO is a ROS.[40]


In the case of traumatic brain injury or cerebral ischemia (e.g., cerebral infarction or hemorrhage), acute neurodegeneration caused by excitotoxicity may spread to proximal neurons through two processes. Hypoxia and hypoglycemia trigger bioenergetic failure; mitochondria stop producing ATP energy. Na+/K+-ATPase can no longer maintain sodium/potassium ion concentration gradients across the plasma membrane. Glutamate transporters (EAATs), which use the Na+/K+ gradient, reverse glutamate transport (efflux) in affected neurons and astrocytes, and depolarization increases downstream synaptic release of glutamate.[41] In addition, cell death via lysis or apoptosis releases cytoplasmic glutamate outside of the ruptured cell.[42] These two forms of glutamate release cause a continual domino effect of excitotoxic cell death and further increased extracellular glutamate concentrations.

Glutamate receptors' significance in excitotoxicity also links it to many neurogenerative diseases. Conditions such as exposure to excitotoxins, old age, congenital predisposition, and brain trauma can trigger glutamate receptor activation and ensuing excitotoxic neurodegeneration. This damage to the central nervous system propagates symptoms associated with a number of diseases.[43]

Conditions with demonstrated associations to glutamate receptors

A number of diseases in humans have a proven association with genetic mutations of glutamate receptor genes, or autoantigen/antibody interactions with glutamate receptors or their genes. Glutamate receptors and impaired regulation (in particular, those resulting in excessive glutamate levels) are also one cause of excitotoxicity (described above), which itself has been implicated or associated with a number of specific neurodegenerative conditions where neural cell death or degradation within the brain occurs over time.[39][43]

Excessive synaptic receptor stimulation by glutamate is directly related to a many conditions. Magnesium is one of many antagonists at the glutamate receptor, and magnesium deficiencies have demonstrated relationships with many glutamate receptor-related conditions.[44]

Glutamate receptors have been found to have an influence in ischemia/stroke, seizures, Parkinson's disease, Huntington's disease, and aching,[45] addiction[46] and an association with both ADHD[47] and autism.[48]

In most cases these are areas of ongoing research.


Hyperalgesia is directly involved with spinal NMDA receptors. Administered NMDA antagonists in a clinical setting produce significant side effects, although more research is being done in intrathecal administration.[37] Since spinal NMDA receptors link the area of pain to the brain's pain processing center, the thalamus, these glutamate receptors are a prime target for treatment. One proposed way to cope with the pain is subconsciously through the visualization technique.[49]

Attention deficit hyperactivity disorder (ADHD)

In 2006 the glutamate receptor subunit gene GRIN2B (responsible for key functions in memory and learning) was associated with ADHD.[50] This followed earlier studies showing a link between glutamate modulation and hyperactivity (2001),[51][51] and then between the SLC1A3 solute carrier gene-encoding part of the glutamate transporter process that mapped to a chromosome (5p12) noted in multiple ADHD genome scans.[52]

Further mutations to four different metabotropic glutamate receptor genes were identified in a study of 1013 children with ADHD compared to 4105 controls with non-ADHD, replicated in a subsequent study of 2500 more patients. Deletions and duplications affected GRM1, GRM5, GRM7 and GRM8. The study concluded that "CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts (P = 2.1 × 10−9)", "over 200 genes interacting with glutamate receptors [. .] were collectively affected by CNVs", "major hubs of the (affected genes') network include TNIK50, GNAQ51, and CALM", and "the fact that children with ADHD are more likely to have alterations in these genes reinforces previous evidence that the GRM pathway is important in ADHD".[47]

A SciBX article in January 2012 commented that "UPenn and MIT teams have independently converged on mGluRs as players in ADHD and autism. The findings suggest agonizing mGluRs in patients with ADHD".[53]


The etiology of autism may include excessive glutamatergic mechanisms. In small studies, memantine has been shown to significantly improve language function and social behavior in children with autism.[54][55] Research is underway on the effects of memantine in adults with autism spectrum disorders.[56]

A link between glutamate receptors and autism was also identified via the structural protein ProSAP1 SHANK2 and potentially ProSAP2 SHANK3. The study authors concluded that the study "illustrates the significant role glutamatergic systems play in autism" and "By comparing the data on ProSAP1/Shank2−/− mutants with ProSAP2/Shank3αβ−/− mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype."[48]


Diabetes is a peculiar case because it is influenced by glutamate receptors present outside of the central nervous system, and it also influences glutamate receptors in the central nervous system.

Diabetes mellitus, an endocrine disorder, induces cognitive impairment and defects of long-term potential in the hippocampus, interfering with synaptic plasticity. Defects of long-term potential in the hippocampus are due to abnormal glutamate receptors, to be specific the malfunctioning NMDA glutamate receptors during early stages of the disease.[57]

Research is being done to address the possibility of using hyperglycemia and insulin to regulate these receptors and restore cognitive functions. Pancreatic islets regulating insulin and glucagon levels also express glutamate receptors.[27] Treating diabetes via glutamate receptor antagonists is possible, but not much research has been done. The difficulty of modifying peripheral GluR without having detrimental effects on the central nervous system, which is saturated with GluR, may be the cause of this.

Huntington's disease

In 2004, a specific genotype of human GluR6 was discovered to have a slight influence on the age of onset of Huntington's disease.[58]

In addition to similar mechanisms causing Parkinson's disease with respect to NMDA or AMPA receptors, Huntington's disease was also proposed to exhibit metabolic and mitochondrial deficiency, which exposes striatal neurons to the over activation of NMDA receptors.[37] Using folic acid has been proposed as a possible treatment for Huntington's due to the inhibition it exhibits on homocysteine, which increases vulnerability of nerve cells to glutamate.[59] This could decrease the effect glutamate has on glutamate receptors and reduce cell response to a safer level, not reaching excitotoxicity.


During ischemia, the brain has been observed to have an unnaturally high concentration of extracellular glutamate.[60] This is linked to an inadequate supply of ATP, which drives the glutamate transport levels that keep the concentrations of glutamate in balance.[61] This usually leads to an excessive activation of glutamate receptors, which may lead to neuronal injury. After this overexposure, the postsynaptic terminals tend to keep glutamate around for long periods of time, which results in a difficulty in depolarization.[61] Antagonists for NMDA and AMPA receptors seem to have a large benefit, with more aid the sooner it is administered after onset of the neural ischemia.[37]

Multiple sclerosis

Inducing experimental autoimmune encephalomyelitis in animals as a model for multiple sclerosis(MS) has targeted some glutamate receptors as a pathway for potential therapeutic applications.[62] This research has found that a group of drugs interact with the NMDA, AMPA, and kainate glutamate receptor to control neurovascular permeability, inflammatory mediator synthesis, and resident glial cell functions including CNS myelination. Oligodendrocytes in the CNS myelinate axons; the myelination dysfunction in MS is partly due to the excitotoxicity of those cells. By regulating the drugs which interact with those glutamate receptors, regulating glutamate binding may be possible, and thereby reduce the levels of Ca2+ influx. The experiments showed improved oligodendrocyte survival, and remyelination increased. Furthermore, CNS inflammation, apoptosis, and axonal damage were reduced.[62]

Parkinson's disease (Parkinsonism)

Late onset neurological disorders, such as Parkinson's disease, may be partially due to glutamate binding NMDA and AMPA glutamate receptors.[37] In vitro spinal cord cultures with glutamate transport inhibitors led to degeneration of motor neurons, which was counteracted by some AMPA receptor antagonists such as GYKI 52466.[37] Research also suggests that the metabotropic glutamate receptor mGlu4 is directly involved in movement disorders associated with the basal ganglia through selectively modulating glutamate in the striatum.[63]

Rasmussen's encephalitis

In 1994, GluR3 was shown to act as an autoantigen in Rasmussen's encephalitis, leading to speculation that autoimmune activity might underlie the condition.[33]


In schizophrenia, the expression of the mRNA for the NR2A subunit of the NMDA glutamate receptor was found to be decreased in a subset of inhibitory interneurons in the cerebral cortex.[64] This is suggested by upregulation of GABA, an inhibitory neurotransmitter. In schizophrenia, the expression of the NR2A subunit of NDMA receptors in mRNA was experimentally undetectable in 49-73% in GABA neurons that usually express it. These are mainly in GABA cells expressing the calcium-buffering protein parvalbumin (PV), which exhibits fast-spiking firing properties and target the perisomatic (basket cells) and axo-axonic (chandelier cells) compartments of pyramidal neurons.[64] The study found the density of NR2A mRNA-expressing PV neurons was decreased by as much as 50% in subjects with schizophrenia. In addition, density of immunohistochemically labeled glutamatergic terminals with an antibody against the vesicular glutamate transporter vGluT1 also exhibited a reduction that paralleled the reduction in the NR2A-expressing PV neurons. Together, these observations suggest glutamatergic innervation of PV-containing inhibitory neurons appears to be deficient in schizophrenia.[64] Expression of NR2A mRNA has also been found to be altered in the inhibitory neurons that contain another calcium buffer, calbindin, targeting the dendrites of pyramidal neurons,[65] and the expression of the mRNA for the GluR5 kainate receptor in GABA neurons has also been found to be changed in organisms with schizophrenia.[66] Current research is targeting glutamate receptor antagonists as potential treatments for schizophrenia. Memantine, a weak, nonselective NMDA receptor antagonist, was used as an add-on to clozapine therapy in a clinical trial. Refractory schizophrenia patients showed associated improvements in both negative and positive symptoms, underscoring the potential uses of GluR antagonists as antipsychotics.[67] Furthermore, administration of noncompetitive NMDA receptor antagonists have been tested on rat models. Scientists proposed that specific antagonists can act on GABAergic interneurons, enhancing cortical inhibition and preventing excessive glutamatergic transmission associated with schizophrenia. These and other atypical antipsychotic drugs can be used together to inhibit excessive excitability in pyramidal cells, decreasing the symptoms of schizophrenia.[68]


Glutamate receptors have been discovered to have a role in the onset of epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors helps counteract the epileptic symptoms.[69] Since glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing, so applying an antagonist to these receptors helps in preventing convulsions.[70]

Other diseases suspected of glutamate receptor link

Neurodegenerative diseases with a suspected excitotoxicity link

Neurodegenerative diseases suspected to have a link mediated (at least in part) through stimulation of glutamate receptors:[35][71]

•• AIDS dementia complex *

•• Alzheimer's disease *

•• Amyotrophic lateral sclerosis

•• Combined systems disease (vitamin B12 deficiency)

•• Depression/anxiety *

•• Drug addiction, tolerance, and dependency *

•• Glaucoma

•• Hepatic encephalopathy

•• Hydroxybutyric aminoaciduria

•• Hyperhomocysteinemia and homocysteinuria

•• Hyperprolinemia

•• Lead encephalopathy

•• Leber's disease

•• MELAS syndrome


•• Mitochondrial abnormalities (and other inherited or acquired biochemical disorders)

•• Neuropathic pain syndromes (e.g. causalgia or painful peripheral neuropathies)

•• Nonketotic hyperglycinemia

•• Olivopontocerebellar atrophy (some recessive forms)

•• Essential tremor

•• Rett syndrome

•• Sulfite oxidase deficiency

•• Wernicke's encephalopathy

Synapse signaler: Small Cell Receptors: NUNZIA ia a Blocker

With California Biotech’s NUNZIA drug being able to block the cause of ANXIETY in the area of the brain that deals with the following:

* Forming new memories and connecting emotions and senses, such as smell and sound, to memories

* Consolidation of new memory

* Emotional Responses

* Navigation

* Spatial Orientation

NUNZIA works with the Hippocampus part of the brain.

Mayo Clinic Staff, ( OCD)

Annu Rev Psychol. Author manuscript; available in PMC 2010 Dec 30. PMCID: PMC3012424


Published in final edited form as:

Annu Rev Psychol. 2010; 61: 111–C3.

doi: 10.1146/annurev.psych.093008.100359

Structural Plasticity and Hippocampal Function

Benedetta Leuner and Elizabeth Gould

Author information ► Copyright and License information ►

The publisher's final edited version of this article is available at Annu Rev Psychol

See other articles in PMC that cite the published article.


NUNZIA works with the Hippocampus part of the brain.

The hippocampus is a region of the mammalian brain that shows an impressive capacity for structural reorganization. Preexisting neural circuits undergo modifications in dendritic complexity and synapse number, and entirely novel neural connections are formed through the process of neurogenesis. These types of structural change were once thought to be restricted to development. However, it is now generally accepted that the hippocampus remains structurally plastic throughout life. This article reviews structural plasticity in the hippocampus over the lifespan, including how it is investigated experimentally. The modulation of structural plasticity by various experiential factors as well as the possible role it may have in hippocampal functions such as learning and memory, anxiety, and stress regulation are also considered. Although significant progress has been made in many of these areas, we highlight some of the outstanding issues that remain.

Keywords: adult neurogenesis, anxiety, learning, memory, synapse

Regressive events also sculpt hippocampal circuitry during development—pruning of dendritic branches occurs on the granule cells during this time (Rahimi & Claiborne 2007). Similar events occur throughout the hippocampus—postnatal development of dendritic arbors and the formation of dendritic spines followed by dendritic pruning and synapse elimination are also features of the pyramidal neuron population (Liu et al. 2005).

(A, B) Photomicrographs of newly born neurons (arrows) in the dentate gyrus of an adult rat labeled with BrdU (red) coexpressing (A) NeuN (green), a marker of mature neurons or (B) TuJ1 (green), a marker of immature and mature neurons. Scale bars, 10 ... 

(A, B) Photomicrographs of newly born neurons (arrows) in the dentate gyrus of an adult rat labeled with BrdU (red) coexpressing (A) NeuN (green), a marker of mature neurons or (B) TuJ1 (green), a marker of immature and mature neurons. Scale bars, 10 ...

Negative Versus Positive Stress

Stressors are typically defined in terms of their ability to activate the hypothalamic-pituitary-adrenal (HPA) axis and ultimately increase glucocorticoid levels (reviewed in Ulrich-Lai & Herman 2009). Most experiences known to cause HPA axis activation are aversive. Exposure to aversive stressors adversely influences numerous aspects of hippocampal structure.

With few exceptions (Bain et al. 2004, Snyder et al. 2009a, Thomas et al. 2007), new cell production in the dentate gyrus is inhibited by a variety of acute and chronic aversive experiences, including both physical and psychosocial stressors (reviewed in Mirescu & Gould 2006). Stress-induced suppression of cell proliferation has been demonstrated in various species (mouse, rat, tree shrew, monkey) and occurs throughout life, with similar results reported for the early postnatal period, young adulthood, and aging (Coe et al. 2003; Gould et al. 1997, 1998; Simon et al. 2005; Tanapat et al. 1998, 2001; Veenema et al. 2007). When stressor exposure occurs during development, the effects are enduring and can persist into adulthood (Lemaire et al. 2000, Lucassen et al. 2009, Mirescu et al. 2004). However, it is unclear whether stress experienced in adulthood has a long-lasting influence on hippocampal neurogenesis. Prolonged effects of stress on new neuron production (Heine et al. 2004, Malberg & Duman 2003, Pham et al. 2003) and survival (Koo & Duman 2008, Thomas et al. 2007, Westenbroek et al. 2004) have been observed. Yet, others have shown that the influence of stress on adult neurogenesis is temporary, decreasing cell proliferation and immature neuron production without altering the number of new neurons that survive to maturity (Mirescu et al. 2004, Snyder et al. 2009a, Tanapat et al. 2001). The reason for these discrepancies is unknown but may be related to the duration or intensity of the stressor or timing of BrdU labeling or sacrifice relative to the stressful experience.

In addition to suppressing neurogenesis, aversive stressful experiences alter dendritic architecture in the hippocampus. For example, repeated stress in adulthood induces retraction of CA3 pyramidal neuron dendrites as well as a loss of synapses in adult male rats and tree shrews (Magariños et al. 1996, McKittrick et al. 2000, Stewart et al. 2005). Within hours of stressor onset, dendritic spine density in the CA3 region is also reduced (Chen et al. 2008). The effects of stress on dendritic architecture in other hippocampal regions have been less well-studied. Chronic stress causes dendritic regression and spine synapse loss in the dentate gyrus and CA1 (Hajszan et al. 2009, Sousa et al. 2000). Acute stress also alters dendritic spine density on CA1 pyramidal cells of adult rats, but the direction of the effect is dependent on the sex of the animal, increasing the number of dendritic spines in males but decreasing the number of dendritic spines in females (Shors et al. 2001a).

Some evidence demonstrates that glucocorticoids regulate structural plasticity in the hippocampus and are the primary mediator underlying the detrimental effects of aversive stress on hippocampal structure. First, an inhibition of neurogenesis occurs in response to natural changes in glucocorticoids across the lifespan. Neurogenesis in the dentate gyrus is maximal during the early postnatal period, when levels of circulating glucocorticoids are low (Gould et al. 1991b) but diminished during life stages when glucocorticoids are elevated, including aging and the postpartum period (Cameron & McKay 1999; Kuhn et al. 1996; Leuner et al. 2007a,b). Second, glucocorticoid administration during the early postnatal period and in adulthood suppresses neurogenesis (Cameron & Gould 1994, Gould et al. 1991b). Conversely, removal of circulating glucocorticoids by bilateral adrenalectomy increases neurogenesis in adult and aged rats (Cameron & Gould 1994, Cameron & McKay 1999) and prevents the stress-induced reduction in neurogenesis (Mirescu et al. 2004, Tanapat et al. 2001). Third, blocking glucocorticoid receptors can reverse the reduction in neurogenesis after glucocorticoid treatment (Mayer et al. 2006) or stressor exposure (Oomen et al. 2007). Like neurogenesis, the stress-induced atrophy of CA3 pyramidal neurons is prevented by pharmacological blockade of the glucocorticoid stress response and can be mimicked by exogenous glucocorticoid administration (Magariños & McEwen 1995, Woolley et al. 1990b).

Physical Activity :

It is becoming increasingly clear, however, that glucocorticoids are not the sole factor mediating the suppressive action of stress on hippocampal structure (Gould et al. 1997, Koo & Duman 2008, Van der Borght et al. 2005a) and that the effects of glucocorticoids on structural plasticity are complex. Notably, conditions associated with elevated glucocorticoids do not necessarily have detrimental effects on structural plasticity and in some cases, those conditions can be beneficial. Physical activity is an example of this paradox—despite substantial elevations in circulating glucocorticoids, running enhances adult neurogenesis (Stranahan et al. 2006, van Praag et al. 1999, Zhao et al. 2006) and dendritic architecture (Eadie et al. 2005, Stranahan et al. 2007) in the hippocampus.


This effect persists until the new neurons are at least two months old (Leuner et al. 2004). Other hippocampus-dependent tasks, such as long-delay eye blink conditioning, as well as spatial learning in the Morris water maze and conditioned food preference, also increase the number of newborn cells. (Ambrogini et al. 2000, Döbrössy et al. 2003, Dupret et al. 2007, Gould et al. 1999b, Hairston et al. 2005, Lemaire et al. 2000, Leuner et al. 2006a, Olariu et al. 2005).

In addition to differences in BrdU injection protocols and training paradigms employed, the maturity of the labeled adult-born cells at the time of learning may determine whether and how learning alters them. Both spatial learning and trace eyeblink conditioning encourage the survival of new cells born about one week prior to training, when these cells are immature but already differentiated into neurons (Ambrogini et al. 2000, Dupret et al. 2007, Epp et al. 2007, Gould et al. 1999b, Hairston et al. 2005). In contrast, some studies suggest that spatial learning induces the death of cells that are less mature (i.e., ≤4 days of age; Dupret et al. 2007, Mohapel et al. 2006), whereas others show that the death of older and perhaps more mature cells occurs (i.e., ≥10 days of age; Ambrogini et al. 2004). Therefore, learning may have a differential capacity to influence neurogenesis depending on the age of the cell. This is consistent with observations showing that experience-induced modulation of adult neurogenesis occurs at a critical period during an immature stage (Tashiro et al. 2007).

The purpose of a learning-induced enhancement of neurogenesis remains to be fully determined. One possibility is that these newborn neurons can contribute to learning and memory by creating a neural representation of previous experience (Aimone et al. 2009). Work showing that neurons made to survive by exposure to an enriched environment are preferentially activated at a later time to the same, but not a different, experience lends some support to the possibility that such a process takes place (Tashiro et al. 2007).

Experimental Approaches to Study the Role of Structural Plasticity in Hippocampal Function

Several strategies have been used to link structural change to hippocampal function. One is correlative and involves evaluating whether there is a positive relationship between structural plasticity and hippocampal function. Another is more direct and involves blocking structural changes and examining whether hippocampal functions are altered. With respect to adult neurogenesis, the depletion of newborn cells has been achieved pharmacologically by systemic administration of the antimitotic agent methylazoxymethanol (MAM; Bruel-Jungerman et al. 2005, Shors et al. 2001b) or the DNA-alkylating agent temozolomide (TMZ; Garthe et al. 2009) as well as by central infusion of the mitotic blocker cytosine arabinoside (AraC; Mak et al. 2007). However, none of these agents diminish the number of newborn neurons exclusively within the dentate gyrus. Irradiation is another approach to block hippocampal neurogenesis and when applied focally, spares neurogenesis in the rest of the brain (Clelland et al. 2009, Santarelli et al. 2003, Saxe et al. 2006, Winocur et al. 2006). One downside common to all of these methods is their nonspecific side effects that may complicate the interpretation of results (Dupret et al. 2005, Monje et al. 2003). Genetic ablation of dividing progenitors may be less susceptible to this criticism, but again assessing behavioral consequences is difficult because inhibition of the dividing precursors is not restricted to the dentate gyrus (Garcia et al. 2004, Saxe et al. 2006). For this reason, virus-based strategies have been developed to prevent neurogenesis exclusively in the dentate gyrus at a specific time in adulthood (Clelland et al. 2009, Jessberger et al. 2009). However, the possibility that postmitotic neurons are affected by the virus and may contribute to behavioral alterations cannot be ruled out. Most recently, inducible genetic approaches to ablate specific populations of adult-generated neurons in a temporally and spatially precise manner have been used (Imayoshi et al. 2008, Revest et al. 2009, Zhang et al. 2008), although these too are not without practical drawbacks.

A Possible Role in Learning and Memory

The role of the hippocampus in learning and memory has long been recognized. However, the hippocampus has been associated with a range of learning tasks (e.g., trace conditioning, contextual fear conditioning, social transmission of food preference, spatial navigation, and object recognition, to name a few) that do not readily fall into a single category, making a unifying theory of hippocampal function difficult to pin down. One reason for this may be related to findings from recent studies incorporating a subregional analysis of the hippocampus that suggests a heterogeneous distribution of function within its different subfields (reviewed in Rolls & Kesner 2006) as well as along the septotemporal axis (reviewed in Bannerman et al. 2004, Moser & Moser 1998). Despite this complexity, it has been proposed that learning and memory might require structural changes in the hippocampus (reviewed in Lamprecht & LeDoux 2004, Nottebohm 2002). In support of this, numerous positive correlations between learning and structural plasticity have been demonstrated.

In rodents, a variety of conditions that decrease adult neurogenesis in the dentate gyrus are associated with learning impairments. These include stress, increased levels of circulating glucocorticoids, and aging (Drapeau et al. 2003, Montaron et al. 2006). Similarly, adverse prenatal or early-life experiences produce persistent reductions in neurogenesis and reduced learning abilities in adulthood (Lemaire et al. 2000). Conversely, conditions that increase neurogenesis, such as environmental enrichment and physical exercise, also tend to enhance performance on hippocampal-dependent learning tasks (Kempermann et al. 1997; van Praag et al. 1999, 2005). There are also a number of studies that have found no correlation or even a negative correlation between neurogenesis and learning (reviewed in Leuner et al. 2006b). However, it is important to keep in mind that a positive correlation between the number of new neurons and learning performance implies a relationship between neurogenesis and learning, although not necessarily a causal one. Another issue to consider is that the time course for alterations in cell production may not correspond to changes in learning abilities. For example, it seems unlikely that the production of new cells would have an immediate effect on processes involved in learning because the cells probably require a certain level of differentiation to have an impact on behavior. Perhaps an even more important consideration, and one that is impossible to discount, is the fact that many of the factors known to affect neurogenesis alter other aspects of brain structure, such as dendritic architecture and synapse number. Since these types of changes are also likely to be involved in hippocampal-dependent learning, it is difficult to interpret correlations between new neurons and learning.

Because of the caveats associated with correlative studies, other work has attempted to demonstrate a casual relationship between learning and neurogenesis, but these too have yielded mixed findings (Leuner et al. 2006b). Reducing or blocking hippocampal neurogenesis disrupts various hippocampal-dependent forms of learning and memory (Clelland et al. 2009; Dupret et al. 2008; Garthe et al. 2009; Hernandez-Rabaza et al. 2009; Jessberger et al. 2009; Imayoshi et al. 2008; Madsen et al. 2003; Raber et al. 2004; Rola et al. 2004; Saxe et al. 2006; Shors et al. 2001b, 2002; Snyder et al. 2005; Winocur et al. 2006; Zhang et al. 2008). Recent findings further suggest that the correct differentiation and integration of new neurons may be necessary for acquisition of new information and the recall of memories consolidated in tasks previously performed (Farioli-Vecchioli et al. 2008). However, a large number of studies have failed to demonstrate an involvement of newly generated cells in hippocampal-dependent learning (Hernandez-Rabaza et al. 2009, Jessberger et al. 2009, Shors et al. 2002, Snyder et al. 2005, Zhang et al. 2008), and there is at least one demonstration of enhanced learning following the suppression of neurogenesis (Saxe et al. 2007). These discrepancies can be attributed to numerous factors, including the animal species and strain tested and the method of ablation, as well as the specifics of the design, analysis, and interpretation of the learning paradigm employed (Garthe et al. 2009).

Literature Cited


Glutamate as a Neurotransmitter - An overview

by Niels Chr. Danbolt

It took a long time to realize that glutamate is a neurotransmitter

It may sound astonishing, but it took the scientific community a long time to realize that glutamate is a neurotransmitter although it was noted already 70 years ago that glutamate is abundant in the brain and that it plays a central role in brain metabolism. Ironically, the reason for the delay seems to have been its overwhelming importance. Brain tissue contains as much as 5 - 15 mmol glutamate pr kg, depending on the region, more than of any other amino acid. Glutamate is one of the ordinary 20 amino acids which are used to make proteins and takes parts in typical metabolic functions like energy production and ammonia detoxification in addition to protein synthesis. It was hard to believe that a compound with so many functions and which is present virtually everywhere in high concentrations could play an additional role as transmitter...

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Glutamate as a Neurotransmitter