Are NMDA spikes impaired in ‘mad’ mice?
PhD Research
Funding:
The full studentship (fees and stipend) is available to UK or EU students who have been resident in the UK for at least three years. Other EU participants may receive a fees only award.
Applicants capable of self-funding (UK, EU and international) are also welcome to apply.
Project details:
Secondary Supervisor: Dr Kerrie Thomas
Schizophrenia affects 1% of the population. It is hard to treat crippling ‘negative’ symptoms such as working memory deficits. Working memory is disrupted by glutamate NMDA receptor blockers, which also produce other schizophrenia-like symptoms in normal subjects. NMDA hypofunction is thought to be a key ‘final common pathway’ of numerous interacting genetic ‘defects’/predispositions and environmental stressors leading to schizophrenia.
In cerebral cortex, most excitatory synapses are onto dendritic spines on sub-micron diameter dendrites, whose active conductances are dominated by NMDA receptors; as few as 10 synaptic inputs into a dendrite can cause it to fire an ‘NMDA spike’ accompanied by a local calcium transient1,2.
Many schizophrenic brains exhibit thinning of the grey matter, caused by loss of dendrites and spines, which in turn could lead to NMDA hypofunction.
In a particular extended Scottish family, every family member with a disrupted DISC1 gene has either a severe psychiatric disorder or sub-clinical schizophrenia-like symptoms.
We will test whether NMDA spikes are impaired in several promising rodent models of schizophrenia, starting with mice transiently expressing defective DISC13. These animals exhibit working memory deficits, social withdrawal and reduced dendritic complexity – like human schizophrenics3.
We will perform whole-cell patch recording, 2-photon microscopy, calcium imaging and patterned glutamate uncaging experiments in brain slices. If we find impaired NMDA spikes in slices from ‘mad’ rodents, we will perform in vivo imaging experiments, to test for a corresponding loss of NMDA spike calcium transients. This would be an important break-through and could lead to new treatments for schizophrenia-like psychoses which cause untold suffering and, worldwide, cost something like UK GDP.
1. Major et al. (2008). J. Neurophysiol. 99:2584-601.
2. Schiller et al. (2000). Nature 404:285-289.
3. Li et al (2007). PNAS 104:18280-5.