Grant reports

2015

The rescue of FMRP-related presynaptic long-term potentiation, social interaction, learning and memory deficits in Fmr1 knockout mice

This lab has used a previous FXRFC grant to characterize the phenomenon of long term potentiation (LTP) of synaptic strength, and its correlation with learning and memory function in mice. Dr. Zhuo’s lab reported that the Fragile X mouse model exhibits altered postsynaptic LTP in a part of the brain that is critical for learning and memory, known as the anterior cingulate cortex (ACC) . As well, they found that Fragile X mice have a deficit in fear learning behaviour.  Although postsynaptic mechanisms (ie. mechanisms in the receiving neuron) have been studied in Fragile X mice, the presynaptic mechanisms of LTP were unclear (ie. mechanisms in the sending neuron). To address this gap in knowledge, a new procedure was developed for inducing presynaptic LTP (pre-LTP) in the ACC, and some molecular mechanisms involved in this process were identified. When pre-LTP stimulation was applied to Fragile X mice, pre-LTP was observed to be defective. Preliminary data are suggestive that after induction of pre-LTP, the distribution of parts of an enzyme known as of PKA (Protein Kinase A) in the pre-synapse is abnormal. This can in turn adversely affect neuronal plasticity and communication between neurons.

The FXRFC has renewed this grant so that Dr. Zhuo’s lab can continue to characterize and compare the pre-LTP in normal mice to that of Fragile X mice. They will also study the functional  roles of arachadonic acid (ARA) in synaptic plasticity, the molecular mechanisms involved, and effects on social behaviour in Fragile X mice. The proposed new objective for this lab in the coming year will be to attempt to improve social interaction and fear learning deficits in Fmr1 KO mice. The effects of oral treatment and microinjection of ARA will be compared.

A definitive method for FMRP Measurement in Fragile X syndrome individuals

All of the core symptoms of Fragile X syndrome are caused by the absence of FMRP (Fragile X Mental Retardation Protein) in the brain cells of affected individuals.  This in turn is a direct result of a mutation in the FMR1 gene that renders it incapable of directing the production of FMRP. Researchers now know that there is no direct correlation between the size or length of the FMR1 mutation and the severity symptoms in individuals with Fragile X. However there is a direct correlation between the levels of FMRP in the peripheral blood, and the degree of intellectual disability. 

With a previous grant from the FXRFC, this lab has been developing a simple, accurate technique to measure FMRP levels in the platelets in the peripheral blood.  The goal is to make it easier to diagnose affected individuals, predict cognitive function and develop a new tool to measure the effectiveness of future treatments.  With this grant renewal the Corbin lab will start applying their technique by putting platelet extracts from the bank of blood samples that they presently have on hand through the full procedure that they have developed.

Electrophysiological biomarkers of altered brain plasticity in children with fragile X syndrome

Recent failures of a series of clinical trials that targeted specific receptors on brain cells (mGluR5 and GABA receptors) underscore the importance of finding better outcome measures to assess whether or not a new treatment for fragile X is actually working.  Scientists refer to these outcome measures as “biomarkers” because they connect the alterations in the structural and functional abnormalities of brain cells with the impairments in cognitive and behavioural responses seen in people with fragile X.  These are also objective measurable quantities, which means that they can appear in blood samples or are physiologic variables like brainwaves seen on electroencephalograms (EEG’s).

This lab will be conducting two non-invasive electrophysiological tests that can be used in treatment evaluation. The first involves measuring evoked potentials (electrical spikes that represent brainwave activity).  These are the results of additive synaptic transmission activity measured at the scalp in response to external stimulation. Increased amplitude of the signal is observed when increased numbers of neurons discharge. The second involves quantification of a phenomenon known as repetition suppression (RS) – a reduction of neural response that is often observed when stimuli are presented more than once.

Patients with fragile X syndrome show alterations in brain responses to external stimulation. Consistent with previous reports, this lab has found that individuals with fragile X syndrome do not show RS, which can be found in chronological and developmental age matched controls who show a decrease in brain responses with stimulus repetition. Deficits in RS are believed to be caused by disruptions in brain processes such as synaptic pruning and lateral inhibition and likely underlie learning deficits in fragile X syndrome. The applicants propose that this striking lack of RS will also be found in fragile X patients under 6 years of age.