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The Gut-Brain Axis, BDNF, NMDA and CNS Disorders

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Abstract

Gastro-intestinal (GI) microbiota and the ‘gut-brain axis’ are proving to be increasingly relevant to early brain development and the emergence of psychiatric disorders. This review focuses on the influence of the GI tract on Brain-Derived Neurotrophic Factor (BDNF) and its relationship with receptors for N-methyl-d-aspartate (NMDAR), as these are believed to be involved in synaptic plasticity and cognitive function. NMDAR may be associated with the development of schizophrenia and a range of other psychopathologies including neurodegenerative disorders, depression and dementias. An analysis of the routes and mechanisms by which the GI microbiota contribute to the pathophysiology of BDNF-induced NMDAR dysfunction could yield new insights relevant to developing novel therapeutics for schizophrenia and related disorders. In the absence of GI microbes, central BDNF levels are reduced and this inhibits the maintenance of NMDAR production. A reduction of NMDAR input onto GABA inhibitory interneurons causes disinhibition of glutamatergic output which disrupts the central signal-to-noise ratio and leads to aberrant synaptic behaviour and cognitive deficits. Gut microbiota can modulate BDNF function in the CNS, via changes in neurotransmitter function by affecting modulatory mechanisms such as the kynurenine pathway, or by changes in the availability and actions of short chain fatty acids (SCFAs) in the brain. Interrupting these cycles by inducing changes in the gut microbiota using probiotics, prebiotics or antimicrobial drugs has been found promising as a preventative or therapeutic measure to counteract behavioural deficits and these may be useful to supplement the actions of drugs in the treatment of CNS disorders.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

CNS:

Central nervous system

FOS:

Fructo-oligosaccharide

GABA:

Gamma-aminobutyric acid

GF:

Germ-free mice

GI:

Gastrointestinal

GOS:

Galacto-oligosaccharide

IL-10:

Interleukin 10

IL-1β:

Interleukin 1β

IL-6:

Interleukin 6

LTD:

Long term depression

LTP:

Long term potentiation

NMDA:

N-Methyl-d-aspartate

NMDAR:

N-Methyl-d-aspartate receptor

SCFA:

Short-chain fatty acid

SPF:

Specific pathogen-free

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Maqsood, R., Stone, T.W. The Gut-Brain Axis, BDNF, NMDA and CNS Disorders. Neurochem Res 41, 2819–2835 (2016). https://doi.org/10.1007/s11064-016-2039-1

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