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The ability of VSL#3 to restore the age-related deficit in LTP is associated with changes in brain genes expression

ABSTRACT: A deficit in synaptic plasticity is one of the many changes that occurs with age. Specifically the archetypal model of plasticity, long-term potentiation (LTP), is reduced in hippocampus of middle-aged and aged animals. Several factors are likely to contribute to this deficit including morphological changes like a net loss of neurons and loss of synapses with the consequent changes in receptor signalling. However it is also clear that ageing is associated with development of oxidative stress, and also inflammatory stress which is typified by increased activation of microglia. Recent evidence has indicated that probiotics exert anti-inflammatory in the gut. Specifically VSL#3, a proprietary probiotic comprising 8 Gram-positive bacterial strains, decreased markers of inflammation in the colon in an animal model of colitis. We considered that its anti-inflammatory effects might extend to brain and therefore that treatment of aged rats with VSL#3 might attenuate the age-related deficit in LTP. The evidence indicates that LTP was impaired in control-treated aged rats but sustained in aged rats which received VSL#3. This was accompanied by a modest decrease in markers of microglial activation and an increase in BDNF and synapsin . The microarray analysis demonstrated that VSL#3 treatment induces changes also in the expression of some brain genes.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE51381 | GEO | 2014/04/02

SECONDARY ACCESSION(S): PRJNA222855

REPOSITORIES: GEO

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Project description:Background: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5-/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function underlie the enhanced LTP we observe in the hippocampus of Cdkl5-/y rats. Methods: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 5 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology. Results: Our results indicate that CA1 hippocampal LTP is enhanced in slices prepared from juvenile, but not adult, Cdkl5-/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5-/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses. Conclusions: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity. Limitations: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brains regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD.

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The ability of VSL#3 to restore the age-related deficit in LTP is associated with changes in brain genes expression

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