Parvalbumin: Why You Can't Supplement For Fish

All About Parvalbumin

 
 

Basics Of Parvalbumin

Parvalbumin (PV) is a protein that acts as a magnesium/calcium buffer that plays a role in many physiological processes, namely cell-cycle regulation, second messenger production, muscle contraction, organization of microtubules and phototransduction. R

GABAergic neurons expressing parvalbumin (PV+-neurons) are the most common (40% of all) interneurons in the cortex and play a role in attention, sensory gating, social memory and more. R

Parvalbumin And Fish

Parvalbumin may explain the benefits of fish that we are unable to obtain from Omega 3 supplementation.

Cold water fish, such as herring, cod, carp, redfish, sockeye salmon and red snapper, have particularly high levels of parvalbumin. R R

Fish during and right after summer have higher levels of parvalbumin due to increased sun exposure and metabolic activity. R

High Vs Low Levels Of Parvalbumin In Disease

 
 https://www.nature.com/articles/mp201747

https://www.nature.com/articles/mp201747

 

High PV Levels

  • Vitamin A Deficiency R

Low levels of PV or PV Dysfunction:

  • Aging R
  • Anxiety R
  • Autism R R R R
  • Bipolar Disorder R
  • Cancer R
  • Chronic Stress R R
  • Decreased metabolic state (inside cells) R
  • Depression R
  • Diabetes and hyperglycemia R
  • Enhances susceptibility to epileptic seizure R R
  • Gulf War Illness R
  • HIV R
  • Impaired development R
  • Inadequate production of Fibroblast growth factor-2 (FGF-2) R
  • Metals exposure R
  • Neuroinflammation R
  • Parkinson's Disease R
  • PTSD (following prolonged stress) R
  • Schizophrenia and Psychosis R R R

Benefits And Biological Roles Of Parvalbumin

1. Parvalbumin And The Flow State

The reticular thalamic nucleus (RTN, also known as the reticular formation) acts as the gatekeeper for sensory information. R

The RTN is covered by Parvalbumin (PV)-positive neurons which when activated can send GABA-mediated inhibitory projections to the RTN. R

Activating PV in the RTN may help put you in the "flow state". R

2. Increases Cognition, Memory And Myelination

 
 https://www.cell.com/cell/abstract/S0092-8674(15)01557-3

https://www.cell.com/cell/abstract/S0092-8674(15)01557-3

 

In the medial prefrontal cortex (mPFC), activation of PV neurons increases cognitive function and improves goal-directed behavior. R

PV neurons in the PFC are required for spatial working memory as well as cognitive flexibility. R

In the hippocampus, PV is necessary for new rule learning and acquiring/retaining information on new skills. R R

PV neurons are necessary for memory consolidation (via neocotrical-hippocampal). R

Stimulation of PV interneurons in the mPFC can significantly enhance axonal myelinationR R

3. Reduces Neuroinflammation

Microglial activation can cause cytokine storms and thus neuroinflammation and PV over-expression can decrease this activation of microglia (via allowing an increased calcium buffering capacity). R

4. Plays A Role In Sleep

Adenosine A2A Receptors (A2ARs) are necessary for adenosine-induced sleep. R

A2ARs are innervated with PV neurons in the External Glovus Pallidus (GPe) and are necessary for promotion of NREM sleep. R 

5. Combats Parkinson Disease

PV has been shown to inhibit the formation of certain protein structures closely associated with Parkinson's Disease (PD), such as alpha-synuclein. R

PV creates amyloid structures that bind together with the alpha-synuclein protein (around 68.44%), rendering them harmless and reducing high levels to develop in the brain. R R

PV also can increase Glial-Derived Neurotrophic Factor (GDNF) in the striatum, which may be therapeutic for PD. R

In the olfactory of PD models, in accordance with alpha-synuclien levels, parvalbumin expression is uprgulated as a protective mechanism, but may become exhausted. R

In the amygdala, alpha-synuclien bound to parvalbumin may cause anhedonia (more on PV and emotional processing below). R

6. May Combat Alzheimer's Disease

As a calcium binding protein, fish parvalbumins can bind to amyloid aggregates, such as Amyloid-Beta (AB) plaque, a major pathology seen in Alzheimer's Disease (AD). R R R

7. Reduces Seizure Activity

Loss of PV can enhance seizure susceptibility, whereas higher levels have been linked to lower rates of seizures. R

8. Plays A Role In Schizophrenia

 
 https://www.ncbi.nlm.nih.gov/pubmed/24027504

https://www.ncbi.nlm.nih.gov/pubmed/24027504

 

Within the prefrontal cortex (PFC), impaired PV signaling has been implicated in schizophrenia pathology. R

For example, increased oxidative stress can cause PV dysfunction thus leading to schizophrenic symptoms. R

9. May Reduce Autism Symptoms

Multiple animal models have shown low PV expression to replicate the similar core symptoms of Autism Spectrum Disorder (ASD). R R

PV may be able to improve ASD-relevant behavioral impairments. R

For example, Shank2 is an abundant postsynaptic scaffolding protein implicated in ASD, and in models of Shank2 deletion from PV neurons, there is hyperactivity, enhanced self-grooming and suppressed brain excitation. R

10. May Combat Gulf War Illness

Combined exposure to the nerve gas antidote pyridostigmine bromide (PB), pesticides and stress during the Persian Gulf War-1 (PGW-1) are presumed to be among the major causes of Gulf War Illness (GWI).

In rat models that have been exposed to GWI-related chemicals and mild stress, there are lower levels of PV and Neuropeptide Y (NPY) expressing hippocampal GABA-ergic neurons. R

Reduced numbers of these interneurons may be one of the major causes of cognitive dysfunction and reduced neurogenesis observed in GWI. R

11. Regulates Electrolyte Balance And Bone Density

Parvalbumin (PV) expression in the kidneys plays a role in electrolyte balance by acting on calcium (Ca2+) signaling. R

Proper PV-Ca2+ signaling is necessary for the beneficial effect of certain diuretic on bone mineral density (BMD). R

12. May Improve Opioid Withdrawal

By activating cyclic AMP (cAMP), PV may help with opioid withdrawal. R

13. Balances Mood, Anxiety, and Chronic stress

PV cells are very sensitive to stressR

Chronic stress can reduce PV levels, which may correlate with increased depressive-like behavior. R

For example, in animal models chronic stress (low circulating levels of corticosterone/glucocoritcoids via the HPA-hippocampus axis causing a glutathione deficict) causes PV dysfunction of GABA/Ca signalling, which may lead to decreased mood. R

Loss of PV function from excess stress in the hippocampus has shown in animal models to induce anhedonia. R

In animal models, activation of PV neurons in the hippocampus through exercise causes reduced anxiety. R

14. Required For Amphetamines Reward

PV is required for amphetamies to have psychostimulant-induced behavioral adaptations such as sensitization and reward. R R

15. Plays A Role In Vision

PV plays a role in regulating spatio-temporal patterning of activity in the visual cortex. R

16. May Regulate Pain And Fear

PV plays a role in fear learning and amygdala plasticity. R

The amygdala is a bilateral temporal lobe brain region which plays an important role in emotional processing. R

There are significantly more PV neurons in the left basolateral amygdala compared to the right, with a significant difference specifically in the posterior subdivision, which could help explain how different hemispheres of the amygdala processes what is painful vs what is fearful stimuli. R

17. Plays A Role In Muscle Activation

Lower levels of PV in muscles can enhance fast-twitch muscle fibers and improve fatigue resistance. R R

18. May Combat Cancer

In tumor cells, PV can inhibit the cell growth and induce cell death (via AKT/GSK3beta). R

My Experience With Fish Vs Fish Oil Supplementation

I've noticed supplementing fish oil always gives me adverse reactions no matter what source, time of year, type of extract, DHA/EPA ratio, etc.

On the other hand, I get no ill reaction from eating fish (mostly salmon) and increased ability to focus on projects the during following day of eating.

    Ways To Increase Parvalbumin And Protect PV Neurons

     
     

    What Increases Parvalbumin:

    Things To Avoid:

    • Blue light - needs proper timing as blue light causes spikes in PV R
    • Chronic stress - reduces PV in hippocampus, although NRF2 activation may be able to relieve some oxidative stress R R
    • Endotoxemia (via lipopolysaccharides during development) and sepsis (via NOX2) R R R
    • Hearing damage R
    • Hypoxia - 25–30% decrease in PV+GABAergic inhibitory neurons in the cerebral cortex of mice with hypoxia R
    • Ketamine - damages PV neurons R
    • Lead R R
    • Maternal Alcohol Consumption - although lithium may help prevent some downside effects on PV neurons R
    • Maternal Hypothyroidism - adequate levels of thyroid hormone is necessary for PV in the anterioir hypothalmic area R
    • MMP9 R
    • Phencyclidine (PCP) - damages PV neurons R R
    • Premature birth - still speculation R
    • rTMS R
    • Sugar - reduces cognitive function via PV prefrontal and hippocampal neruons R
    • TBI (especially at a younger age) - NOX2 inhibition may protect against PV loss R R

    Caveats

    Parvalbumin (beta-1) is a cause of some fish allergies, so if you have a fish allergy, it's probably best to avoid fish but try other ways to increase PV. R

    Concerning fish allergies, reason why paravalbumin can be allergenic is dependent of the formation of amyloid by parvalbumins (such as rGad m 1) and its degradation resistance in the body. R

    Mechanism Of Action

    Simple:

    • Increases AKT R
    • Increases cAMP R
    • Increases CREB R
    • Increases Erk1/2 R
    • Increases GABA R
    • Increases GAD67 R R
    • Increases GDNF R
    • Increases GSK3beta R
    • Reduces Alpha-Synuclein R

    Advanced:

    • Most of the PV+ cells in the central nervous system belong to the group of interneurons (Golgi type 2), and only a small part belong to long axon neurons (Golgi type 1), while there is a reversed situation at the level of the peripheral nervous system. R
    • PV+ interneurons comprise two main morphological subtypes: basket cells, which target the soma and proximal dendrites of pyramidal cells, and chandelier neurons, which target the initial segment of the pyramidal cell axon and may limit most effectively the firing of principal cells. R
    • Dopamine D2 receptor deletion from parvalbumin interneurons in mouse causes an impaired inhibitory activity in the ventral hippocampus and a dysregulated dopaminergic system. R
    • Synapses from parvalbumin-expressing interneurons onto hippocampal pyramidal neurons are regulated by neuronal firing, signaling through L-type calcium channels. Synapses from somatostatin-expressing interneurons are regulated by NMDA receptors, signaling through R-type calcium channels. R
    • From a mitochondrial POV, Complexes I, IV, and V in layer 3 pyramidal and PV cells was significantly lower in subjects with schizophrenia relative to unaffected comparison subject. R
    • Parvalbumin interneurons constrain the size of the lateral amygdala engram. R
    • PV modulates nicotinic acetylcholine receptors (nachrs) via Lynx1. R
    • How does PV bind to amyloid? - "Acid proteins capable of nucleating Ca2+ and displaying aggregation capacity play key roles in the formation of calcium carbonate biominerals. The helix-loop helix EF-hands are the most common Ca2+-binding motifs in proteins. Calcium is bound by the loop region. These motifs are found in many proteins that are regulated by calcium. Gad m 1, an Atlantic cod β-parvalbumin isoform, is a monomeric EF-hand protein that acts as a Ca2+ buffer in fish muscle; the neutral and acid apo-forms of this protein can form amyloids." R

    Genetics

    PVALB

    rs4820255

    • C Alleles - Increased desire, arousal, orgasm and pain for women. R

    rs4821535

    • G Alleles - Increased desire, arousal, orgasm and pain for women. R

    rs2284024

    • T Alleles - Increased desire, arousal, orgasm and pain for women. R

    rs5750311

    • G Alleles - Increased desire, arousal, orgasm and pain for women. R
    • C Alleles - associated with Bone Density R

    rs739031

    • T Alleles - Increased desire, arousal, orgasm and pain for women. R

    rs4821536

    • T Alleles - Increased desire, arousal, orgasm and pain for women. R

    rs2022068

    • A Alleles - associated with Pit and Fissure surface dental caries R