With an $80,000 grant from FRAXA Research Foundation over 2 years, Drs. Jay Gibson and Kimberly Huber from the University of Texas at Southwestern examined if the defected inhibitory neurotransmission was a primary or secondary symptom of Fragile X to determine where future treatment targets should be focused.
by Jay Gibson, PhD, 10/1/2006
The study is designed to answer a crucial question in Fragile X research: whether the defect in inhibitory neurotransmission is a primary Fragile X symptom or a secondary effect arising from misregulation of the mGluR pathways. If it is primary, then drugs which block mGluR are not likely to effectively treat this aspect of Fragile X. If, on the other hand, it is a secondary effect, then this adds more evidence supporting the mGluR Theory.
Cortical neurons in Fragile X patients and from mouse models of Fragile X syndrome have elongated dendritic spines as well as a higher density of spines. Synaptic plasticity alterations have also been identified. However, altered behavior and epilepsy in Fragile X syndrome are not directly mediated by such properties, but rather by the strength and temporal properties of synaptic connections between different neuron types. The basic synaptic connectivity of neuronal circuits must differ in Fragile X patients, but to date, no data exist addressing this issue. Furthermore, once a synaptic connectivity difference is found, how does this relate to the altered brain function in patients?
We have discovered a decrease in the excitatory synaptic strength onto a specific subclass of inhibitory neurons, the Parvalbumin (Parv+) neuron, in the mouse model of Fragile X syndrome (Fmr1 knockout mice). This was observed using electrophysiological methods in brain slices of primary somatosensory cortex. This decrement in excitatory drive would be expected to result in less activation of Parv+ neurons in vivo. This could lead to sensory hypersensitivity and perhaps epilepsy in Fragile X patients. If this is a general cortical deficit which occurs in higher order cortical areas as well, it could also underlie cognitive deficits in patients.
We are examining this deficit in greater detail. Because Group 1 metabotropic glutamate receptor (mGluR) signaling is known to regulate somatosensory cortical development and is also enhanced in Fmr1 KO mice, we plan to test the hypothesis that enhanced mGluR5 activity contributes to this cortical circuitry deficit.
Related research by Dr. Gibson can be found at https://profiles.utsouthwestern.edu/profile/50230/jay-gibson.html