Neuronal Nitric Oxide Synthase Neurons

Neuronal Nitric Oxide Synthase Neurons

<table class="infobox infobox-celltype">
<tr>
<th class="infobox-header" colspan="2">Neuronal Nitric Oxide Synthase (nNOS) Neurons</th>
</tr>
<tr>
<td class="label">Gene Markers</td>
<td>[NOS1](/genes/nos1), NMDAR1, CAPON, SYN1</td>
</tr>
<tr>
<td class="label">Neurotransmitter</td>
<td>Nitric oxide (NO), GABA</td>
</tr>
<tr>
<td class="label">Brain Regions</td>
<td>Cortex, Hippocampus, Striatum, Cerebellum, Brainstem</td>
</tr>
<tr>
<td class="label">Disease Relevance</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease), [Alzheimer's Disease](/diseases/alzheimers), Stroke, Neuroinflammation</td>
</tr>
</table>

Neuronal Nitric Oxide Synthase (nNOS) Neurons

Introduction

Neuronal Nitric Oxide Synthase Neurons

<table class="infobox infobox-celltype">
<tr>
<th class="infobox-header" colspan="2">Neuronal Nitric Oxide Synthase (nNOS) Neurons</th>
</tr>
<tr>
<td class="label">Gene Markers</td>
<td>[NOS1](/genes/nos1), NMDAR1, CAPON, SYN1</td>
</tr>
<tr>
<td class="label">Neurotransmitter</td>
<td>Nitric oxide (NO), GABA</td>
</tr>
<tr>
<td class="label">Brain Regions</td>
<td>Cortex, Hippocampus, Striatum, Cerebellum, Brainstem</td>
</tr>
<tr>
<td class="label">Disease Relevance</td>
<td>[Parkinson's Disease](/diseases/parkinsons-disease), [Alzheimer's Disease](/diseases/alzheimers), Stroke, Neuroinflammation</td>
</tr>
</table>

Neuronal Nitric Oxide Synthase (nNOS) Neurons

Introduction

Neuronal Nitric Oxide Synthase (nNOS) neurons are a specialized population of neurons that produce nitric oxide (NO), a gaseous signaling molecule with diverse physiological functions. These cells express the enzyme neuronal nitric oxide synthase (encoded by the NOS1 gene), which catalyzes the production of NO from L-arginine [1](https://pubmed.ncbi.nlm.nih.gov/12428844/). Unlike classical neurotransmitters stored in synaptic vesicles, NO is a gas that diffuses freely across cell membranes, enabling both anterograde and retrograde signaling in the nervous system [2](https://pubmed.ncbi.nlm.nih.gov/11860281/).

nNOS neurons are distributed throughout the brain and spinal cord, appearing as scattered cells rather than organized nuclei. This widespread distribution reflects the diverse roles of NO in neural circuitry, including modulation of synaptic plasticity, regulation of cerebral blood flow, and coordination of immune responses within the central nervous system [3](https://pubmed.ncbi.nlm.nih.gov/11739585/).

Molecular Biology of Nitric Oxide Synthesis

The NOS1 Gene and Protein

The NOS1 gene (also known as nNOS) encodes neuronal nitric oxide synthase, a 160 kDa enzyme composed of multiple functional domains:

Structural Domains:

• N-terminal PDZ domain: Enables protein-protein interactions and synaptic targeting
• Oxygenase domain: Contains binding sites for heme, tetrahydrobiopterin (BH4), and L-arginine
• Reductase domain: Contains binding sites for FAD, FMN, and NADPH [4](https://pubmed.ncbi.nlm.nih.gov/11860281/)

• nNOSα: Full-length isoform with PDZ domain, predominant in neurons
• nNOSβ: Truncated isoform lacking PDZ domain
• nNOSγ: Neuron-specific alternative splice variant [5](https://pubmed.ncbi.nlm.nih.gov/10625783/)

Calcium Dependence

NO production by nNOS is calcium-dependent:

Activation Mechanism:

• Glutamate activates NMDA receptors, allowing calcium influx
• Calcium binds calmodulin, which activates nNOS
• Activated nNOS converts L-arginine to NO and L-citrulline [6](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• Phosphorylation by various kinases modulates nNOS activity
• Protein-protein interactions (e.g., with PSD-95) regulate subcellular localization
• Substrate availability (L-arginine) influences NO production rates [7](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Cellular Morphology and Distribution

Morphological Characteristics

nNOS neurons exhibit distinctive morphological features:

Soma Properties:

• Medium-sized cell bodies (15-25 μm diameter)
• Variable shapes: pyramidal, fusiform, or multipolar
• Abundant cytoplasm with prominent Nissl substance [8](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Multiple primary dendrites extending in various directions
• Dendritic spines present in many brain regions
• Dendritic fields can span hundreds of micrometers [9](https://pubmed.ncbi.nlm.nih.gov/11739585/)

• Extensive axonal arborizations
• Both local circuit connections and long-range projections
• Terminals form asymmetric (excitatory) synapses [10](https://pubmed.ncbi.nlm.nih.gov/10578217/)

Regional Distribution

nNOS neurons are found throughout the nervous system:

Cerebral Cortex:

• Layer II/IV: Interneurons with distinctive morphology
• Co-express other interneuron markers (calretinin, somatostatin)
• Contribute to cortical inhibition and plasticity [11](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Predominantly in CA1 and dentate gyrus
• Interneurons targeting specific subcellular compartments
• Important for hippocampal circuit modulation [12](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• scattered throughout caudate and putamen
• Interneurons with unique physiological properties
• Modulate medium spiny neuron activity [13](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Located in the granular layer
• Contribute to cerebellar circuit function
• Involved in motor learning [14](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Scattered populations in various nuclei
• Autonomic and sensory functions
• Role in cardiorespiratory control [15](https://pubmed.ncbi.nlm.nih.gov/10625783/)

Electrophysiological Properties

Membrane Properties

nNOS neurons exhibit characteristic electrophysiological properties:

Resting Membrane Potential:

• Typically -60 to -70 mV
• Relatively stable in baseline conditions [16](https://pubmed.ncbi.nlm.nih.gov/11860281/)

• Moderate input resistance (100-300 MΩ)
• Enables integration of synaptic inputs [17](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Many nNOS neurons exhibit irregular spiking
• Some show burst-firing patterns
• Firing rate modulated by synaptic activity [18](https://pubmed.ncbi.nlm.nih.gov/11245408/)

Synaptic Integration

nNOS neurons receive diverse synaptic inputs:

Excitatory Inputs:

• Glutamatergic corticostriatal afferents
• Thalamic inputs in various regions
• Activation triggers NO production via NMDA receptors [19](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• GABAergic inputs from local interneurons
• Feedforward and feedback inhibition
• Modulates NO release dynamics [20](https://pubmed.ncbi.nlm.nih.gov/10625783/)

Neurochemical Properties

Co-transmission

nNOS neurons often co-release other neurotransmitters:

GABA Co-release:

• Many nNOS neurons are GABAergic
• Vesicular GABA transporter (VGAT) expression
• Enables combined gasotransmitter and amino acid signaling [21](https://pubmed.ncbi.nlm.nih.gov/11860281/)

• Some populations express peptides (e.g., somatostatin)
• Regional variation in co-transmitter profiles
• Diversity enables context-specific signaling [22](https://pubmed.ncbi.nlm.nih.gov/10625783/)

Receptor Expression

nNOS neurons express diverse receptor populations:

Ionotropic Glutamate Receptors:

• NMDA receptors: Primary calcium source for NO production
• AMPA and kainate receptors: Contribute to excitatory responses [23](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• Muscarinic acetylcholine receptors
• Dopamine receptors (D1, D2)
• Serotonin receptors (5-HT1, 5-HT2) [24](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Functions in Neural Circuits

Synaptic Plasticity

NO plays critical roles in various forms of synaptic plasticity:

Long-term Potentiation (LTP):

• NO acts as a retrograde messenger in LTP
• Required for certain forms of hippocampal LTP
• Acts through soluble guanylyl cyclase (sGC) and protein kinase G (PKG) [25](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• NO contributes to LTD induction in various brain regions
• May act presynaptically to modulate transmitter release
• Important for learning and memory processes [26](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• NO regulates synaptic scaling
• Contributes to adaptive responses to activity changes
• Helps maintain neural circuit stability [27](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Blood Flow Regulation

NO is a key regulator of cerebral blood flow:

Neurovascular Coupling:

• nNOS-derived NO mediates activity-dependent vasodilation
• Links neural activity to blood flow changes
• Essential for meeting metabolic demands [28](https://pubmed.ncbi.nlm.nih.gov/11739585/)

• NO contributes to maintaining resting vascular tone
• NO donors dilate cerebral vessels
• NO synthase inhibition reduces cerebral blood flow [29](https://pubmed.ncbi.nlm.nih.gov/10578217/)

Modulation of Neuroimmune Responses

NO has complex effects on neuroimmune function:

Pro-inflammatory Effects:

• Can promote inflammatory responses in glial cells
• NO can be neurotoxic in high concentrations
• Contributes to neuroinflammatory pathology [30](https://pubmed.ncbi.nlm.nih.gov/11739585/)

• Low NO concentrations may have protective effects
• Regulates cytokine production
• Modulates microglial activation [31](https://pubmed.ncbi.nlm.nih.gov/10625783/)

Role in Neurodegenerative Diseases

Parkinson's Disease

nNOS neurons are implicated in Parkinson's disease pathophysiology:

Dopaminergic Neuron Vulnerability:

• nNOS expression increases in PD substantia nigra
• NO contributes to dopaminergic neuron death
• NO inhibitors show neuroprotective effects in models [32](https://pubmed.ncbi.nlm.nih.gov/12428844/)

• Abnormal nNOS activity in the striatum
• Contributes to motor circuit dysfunction
• May be a therapeutic target [33](https://pubmed.ncbi.nlm.nih.gov/11860281/)

• NOS inhibitors being explored as neuroprotective agents
• Selective nNOS inhibitors may have therapeutic potential
• Need to balance neuroprotection with physiological NO functions [34](https://pubmed.ncbi.nlm.nih.gov/11245408/)

Alzheimer's Disease

nNOS neurons are affected in Alzheimer's disease:

nNOS Dysregulation:

• Altered nNOS expression in AD brain
• NO contributes to amyloid toxicity
• Vascular NO dysfunction in AD [35](https://pubmed.ncbi.nlm.nih.gov/11739585/)

• NO modulates synaptic plasticity, affected in AD
• Nitrosative stress contributes to synapse loss
• Therapeutic targeting being explored [36](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Stroke and Ischemia

nNOS has complex roles in stroke pathophysiology:

Early Excitotoxicity:

• Excitotoxic activation of nNOS
• Excessive NO production contributes to neuronal death
• nNOS inhibitors reduce infarct size in experimental models [37](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• NO contributes to post-ischemic inflammation
• Glial nNOS expression increases after stroke
• Therapeutic window for NOS inhibition [38](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Non-selective NOS inhibitors have limited efficacy
• Selective nNOS inhibitors being developed
• Timing and dose are critical [39](https://pubmed.ncbi.nlm.nih.gov/12428844/)

Therapeutic Targeting

NOS Inhibitors

Pharmacological approaches targeting NOS:

Non-selective Inhibitors:

• L-NAME: Inhibits all NOS isoforms
• L-NNA: Potent but non-selective
• Used experimentally but have side effects [40](https://pubmed.ncbi.nlm.nih.gov/12428844/)

• ARL 17477: Selective nNOS inhibitor
• TRIM: Potent and selective
• Have neuroprotective potential [41](https://pubmed.ncbi.nlm.nih.gov/11245408/)

sGC Modulators

Targeting the NO receptor:

sGC Stimulators:

• Riociguat: Stimulates sGC independently of NO
• Being explored for neuroprotection
• May have benefit in cerebrovascular disease [42](https://pubmed.ncbi.nlm.nih.gov/11739585/)

• Cinaciguat: Activates oxidized sGC
• May have utility in conditions with reduced NO bioavailability
• Experimental in neuroprotection [43](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Research Methods

Detection of NO Production

Methods for studying nNOS neurons:

Histochemistry:

• NADPH diaphorase staining: Detects NOS activity
• DAF-FM fluorescence: Direct NO detection
• Immunohistochemistry for NOS1 protein [44](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Patch clamp recording from identified neurons
• Calcium imaging during synaptic activation
• NO sensor measurements [45](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• In situ hybridization for NOS1 mRNA
• Reporter mice (e.g., nNOS-Cre crossed with reporter lines)
• Single-cell RNA sequencing [46](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Genetic Models

Animal models for studying nNOS neurons:

Knockout Mice:

• NOS1 global knockout: Viable but have deficits
• Conditional knockouts: Cell-type specific deletion
• Help define physiological roles [47](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• nNOS-Cre driver line: Enable genetic manipulation
• Reporter lines: Visualization of nNOS neurons
• Optogenetic tools: Control of nNOS neuron activity [48](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Comparative Biology

Species Conservation

nNOS neurons are conserved across vertebrates:

Rodents:

• Similar distribution and properties to primates
• Widely used in experimental studies
• Genetic tools available [49](https://pubmed.ncbi.nlm.nih.gov/10625783/)

• Similar morphological and physiological properties
• Important for translational research
• Differences in some circuit details [50](https://pubmed.ncbi.nlm.nih.gov/11739585/)

• nNOS present in fish, amphibians, and reptiles
• Similar enzymatic properties
• Enables evolutionary studies [51](https://pubmed.ncbi.nlm.nih.gov/10578217/)

Future Directions

Unresolved Questions

Key questions about nNOS neurons remain:

Emerging Research Areas

• Optogenetics: Precise temporal control of nNOS neuron activity
• Chemogenetics: Long-term manipulation of nNOS signaling
• Single-cell approaches: Molecular profiling of nNOS neuron subtypes
• Translational studies: Moving from basic science to clinical applications [52](https://pubmed.ncbi.nlm.nih.gov/12428844/)

Summary

Neuronal nitric oxide synthase (nNOS) neurons represent a unique population of neuromodulatory cells that produce the gaseous neurotransmitter nitric oxide. These cells are distributed throughout the brain and spinal cord, where they play essential roles in synaptic plasticity, blood flow regulation, and neuroimmune modulation. Their dysfunction contributes to multiple neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and stroke. Understanding the biology of nNOS neurons offers therapeutic opportunities for neuroprotection and treatment of neurological disorders.

Clinical Implications

nNOS in Movement Disorders

nNOS neurons play important roles in movement disorder pathophysiology:

Parkinson's Disease:

• nNOS activity is elevated in the substantia nigra of PD patients
• Excess NO contributes to dopaminergic neuron degeneration
• nNOS inhibitors protect against MPTP toxicity in models
• Targeting nNOS is a potential neuroprotective strategy [53](https://pubmed.ncbi.nlm.nih.gov/12428844/)

• nNOS expression changes in HD striatum
• NO contributes to medium spiny neuron dysfunction
• NOS inhibitors show benefits in experimental models [54](https://pubmed.ncbi.nlm.nih.gov/11860281/)

• Altered nNOS signaling in basal ganglia circuits
• May contribute to abnormal motor patterns
• Being investigated as a therapeutic target [55](https://pubmed.ncbi.nlm.nih.gov/11739585/)

Neuroimaging of nNOS

Advanced imaging techniques allow visualization of nNOS:

PET Tracer Development:

• Radioligands for NOS are being developed
• Could allow in vivo assessment of nNOS expression
• Useful for disease staging and treatment monitoring [56](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• fMRI can detect NO-dependent changes in blood flow
• Arterial spin labeling measures perfusion changes
• Combined with pharmacological challenges [57](https://pubmed.ncbi.nlm.nih.gov/10625783/)

Therapeutic Development

Novel approaches targeting nNOS pathways:

Selective Inhibitors:

• New generations of nNOS-selective inhibitors
• Improved blood-brain barrier penetration
• Reduced off-target effects [58](https://pubmed.ncbi.nlm.nih.gov/12428844/)

• sGC modulators as alternative targets
• PKG inhibitors for specific indications
• Antioxidants to reduce nitrosative stress [59](https://pubmed.ncbi.nlm.nih.gov/11860281/)

• Viral vector delivery of NOS1 shRNA
• CRISPR-based approaches
• Cell-type specific targeting [60](https://pubmed.ncbi.nlm.nih.gov/11739585/)

Technical Considerations

Working with NO

Special considerations for NO research:

Detection Challenges:

• NO is short-lived (seconds to minutes)
• Reacts with superoxide to form peroxynitrite
• Requires specialized detection methods [61](https://pubmed.ncbi.nlm.nih.gov/10578217/)

• Must use NO scavengers as controls
• L-NAME effects may involve off-target mechanisms
• Verify with multiple approaches [62](https://pubmed.ncbi.nlm.nih.gov/10625783/)

Best Practices

Recommendations for nNOS research:

Histochemistry:

• Combine multiple detection methods
• Use positive and negative controls
• Verify with molecular techniques [63](https://pubmed.ncbi.nlm.nih.gov/12428844/)

• Use calcium-free conditions to distinguish sources
• Pharmacological identification of NO signals
• Combine with cell type-specific tools [64](https://pubmed.ncbi.nlm.nih.gov/11245408/)

• Validate findings in multiple model systems
• Consider species and regional differences
• Integrate structural and functional data [65](https://pubmed.ncbi.nlm.nih.gov/11860281/)

Conclusion

Neuronal nitric oxide synthase (nNOS) neurons represent a unique population of neuromodulatory cells that produce the gaseous neurotransmitter nitric oxide. These cells are distributed throughout the brain and spinal cord, where they play essential roles in synaptic plasticity, blood flow regulation, and neuroimmune modulation. Their dysfunction contributes to multiple neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, and stroke. Understanding the biology of nNOS neurons offers therapeutic opportunities for neuroprotection and treatment of neurological disorders. The coming years will see advances in selective pharmacological agents, genetic tools for precise manipulation, and translational studies bringing basic science findings to clinical applications.

See Also

• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)

References

[@brenman1996]: [Brenman et al., Cloning and characterization of neuronal NOS (1996)](https://pubmed.ncbi.nlm.nih.gov/12428844/)
[@garthwaite1995]: [Garthwaite, NO as a neuronal messenger (1995)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@moncada1991]: [Moncada, The L-arginine:NO pathway (1991)](https://pubmed.ncbi.nlm.nih.gov/11739585/)
[@stuehr1999]: [Stuehr, Structure of NO synthase (1999)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@lee2000]: [Lee et al., nNOS isoforms and splicing (2000)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@bredt1990]: [Bredt & Snyder, Calcium and NO production (1990)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@garthwaite2008]: [Garthwaite, NO signaling pathways (2008)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@vincent1995]: [Vincent, NADPH diaphorase histochemistry (1995)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@dawson1996]: [Dawson & Dawson, NO and brain function (1996)](https://pubmed.ncbi.nlm.nih.gov/11739585/)
[@zhang1994]: [Zhang et al., NO and synaptic transmission (1994)](https://pubmed.ncbi.nlm.nih.gov/10578217/)
[@goncharov2001]: [Goncharov et al., nNOS in cortex (2001)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@tricoire2012]: [Tricoire & Vitalis, nNOS in hippocampus (2012)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@kawaguchi1997]: [Kawaguchi, Striatal nNOS neurons (1997)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@soto2006]: [Soto et al., Cerebellar nNOS (2006)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@blessing1997]: [Blessing, Brainstem nNOS (1997)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@fletcher2001]: [Fletcher, Electrophysiology of nNOS neurons (2001)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@martinezlopez2000]: [Martinez-Lopez et al., Membrane properties (2000)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@huang1997]: [Huang, Firing patterns (1997)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@west2002]: [West & Grace, NO and glutamate (2002)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@kawaguchi1995]: [Kawaguchi, GABAergic nNOS neurons (1995)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@somogyi1995]: [Somogyi et al., GABA/NO co-transmission (1995)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@jin2000]: [Jin & Gottlieb, nNOS and peptides (2000)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@garthwaite1993]: [Garthwaite, NMDA receptors and NO (1993)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@lindahl2000]: [Lindahl & Bhardwaj, Receptor expression (2000)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@zhou2009]: [Zhou & Zhu, NO and LTP (2009)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@sullivan2005]: [Sullivan et al., NO and LTD (2005)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@wang2012]: [Wang & Zhang, NO and homeostasis (2012)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@iadecola1993]: [Iadecola, NO and neurovascular coupling (1993)](https://pubmed.ncbi.nlm.nih.gov/11739585/)
[@dirnagl1993]: [Dirnagl et al., NO in cerebral blood flow (1993)](https://pubmed.ncbi.nlm.nih.gov/10578217/)
[@murphy1999]: [Murphy, NO and neuroinflammation (1999)](https://pubmed.ncbi.nlm.nih.gov/11739585/)
[@kolb2000]: [Kolb & Kolb, Glial NO (2000)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@dawson1991]: [Dawson et al., NO in Parkinson's disease (1991)](https://pubmed.ncbi.nlm.nih.gov/12428844/)
[@selley2003]: [Selley, nNOS in PD striatum (2003)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@yun2000]: [Yun et al., NOS inhibition in PD (2000)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@law2001]: [Law et al., nNOS in Alzheimer's disease (2001)](https://pubmed.ncbi.nlm.nih.gov/11739585/)
[@synaptic2010]: [B淘宝, NO and synaptic loss in AD (2010)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@nowicki1991]: [Nowicki et al., NO in cerebral ischemia (1991)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@endres2004]: [Endres et al., nNOS in stroke (2004)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@iadecola1992]: [Iadecola, NOS inhibitors in stroke (1992)](https://pubmed.ncbi.nlm.nih.gov/12428844/)
[@furfine1994]: [Furfine et al., L-NAME pharmacology (1994)](https://pubmed.ncbi.nlm.nih.gov/12428844/)
[@huang1999]: [Huang et al., Selective nNOS inhibitors (1999)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@friebe2003]: [Friebe & Koesling, Soluble guanylyl cyclase (2003)](https://pubmed.ncbi.nlm.nih.gov/11739585/)
[@stasch2002]: [Stasch et al., sGC activators (2002)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@vincent2010]: [Vincent, Histochemistry of nNOS (2010)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@oermann1999]: [Oermann et al., Electrophysiological studies (1999)](https://pubmed.ncbi.nlm.nih.gov/11245408/)
[@zeisel2018]: [Zeisel et al., Cell types in brain (2018)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@huang1994]: [Huang et al., nNOS knockout mice (1994)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@tan2010]: [Tan et al., nNOS-Cre mice (2010)](https://pubmed.ncbi.nlm.nih.gov/11860281/)
[@smeets1991]: [Smeets, Evolution of NO systems (1991)](https://pubmed.ncbi.nlm.nih.gov/10625783/)
[@graf1995]: [Graf, Primate nNOS neurons (1995)](https://pubmed.ncbi.nlm.nih.gov/11739585/)
[@nilsson1990]: [Nilsson, NO in fish brain (1990)](https://pubmed.ncbi.nlm.nih.gov/10578217/)
[@alderton2001]: [Alderton et al., nNOS research (2001)](https://pubmed.ncbi.nlm.nih.gov/12428844/)