Synaptic and circuit development in cerebral cortex in a mouse model of schizophrenia

Neurodevelopmental diseases occur because neuronal circuits are not wired up correctly early in life. In this collaborative PhD project between the Ashby and Fox labs, we will investigate how loss of the schizophrenia-related DISC1 gene impairs the synaptic processes that drive neuronal circuit assembly in the young brain using cutting-edge two-photon microscopy.

Project details
Neurodevelopmental disorders, such as schizophrenia and autism, are caused by abnormal maturation of neuronal synapses and circuits. This early life dysfunction leads to long-term disturbances of brain function into adulthood. We have recently discovered a functional phenotype for the DISC1 gene, which when mutated creates a high risk for mental health problems including schizophrenia, bipolar disorder, major clinical depression and autism. In mice that have DISC1 disrupted during a critical period of postnatal development (P7-9 in the mouse, third trimester in humans), we found that synaptic plasticity is abolished in adulthood and that synaptic development arrested at an early developmental stage on a subset of 2nd/3rd order dendrites in layer 2/3 neurons (Greenhill et al., 2015, Science 349; 424-427). Cortical layer 2/3 neurons are important for plasticity in the adult and therefore the loss of plasticity in adulthood may explain the many of cognitive symptoms associated with schizophrenia.

In this project, we will use advanced microscopy techniques already in use in the Bristol and Cardiff labs to assess development of the cortical circuit and development of the synaptic properties to explain the loss of plasticity in the DISC1 mice. In Cardiff, we will assess synaptic plasticity by imaging dendritic spines on 2nd/3rd order dendrites to measure their dynamics. Spine turnover normally increases rapidly following whisker deprivation and we will test how, when and where this plasticity is altered in DISC1 animals. In Bristol, we will use 2-photon imaging and glutamate uncaging in vivo and ex vivo to measure the functional properties of individual synapses. Measurement of the AMPA and NMDA receptor content of specific synapses on 2nd/3rd order dendrites versus those on neighbouring higher order dendrites will be used to define their synaptic maturation and plasticity (eg Ashby & Isaac, 2011, Neuron 70(3); 510-521). Explaining the differences between synapses on sub-branches of dendrites will be a key step in understanding the long-lasting pathology driven by critical period DISC1 disruption.

The studies are expected to lead not only to an understanding of why DISC1 produces a permanent plasticity impairment when disrupted during a critical period of development, but may also lead to a better understanding of plasticity compartmentalisation within neurons and the possibility of dendritic branch tagging in wild-types. Jointly supervised by Dr M Ashby (Bristol) and Prof K Fox (Cardiff)