Synaptic and circuit pathology in a mouse model of AP4 deficiency syndrome

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Nerve cells (neurons) are critical for brain function and when they go wrong this leads to neurological diseases. Key to their function is the nerve cells specialised shape which includes a large dendritic tree which receives connections from other neurons and a long thin axonal process which can connect to downstream neurons. Nerve cells can communicate with each other via specialised cell-cell contact sites called synapses where they release and detect neurotransmitters. The correct formation of axons and dendrites is a critical step that allows synapses to wire up and operate correctly. Synapses can change their strength in response to changes in neural activity, an important property for key brain functions such as cognition and learning and memory. Moreover if synapses do not wire correctly during development (for example because axons and dendrites don't properly form) or if the synapses go wrong later in life this can lead to devastating diseases including intellectual disability and epilepsy in addition to neuropsychiatric disorders like Schizophrenia and autism and neurodegenerative disorders like Alzheimer's diseases.Cells contain a series of lipid membrane bound 'organelle' compartments that play a key role in compartmentalising important processes at discrete locations within cell. Proteins, membrane and other cell constituents often need to be transported between different organelle compartments which is often carried out in transport carriers called vesicles by a process of membrane trafficking or 'cargo delivery'. By controlling the levels of signalling receptors on the neuronal surface and hence neuronal signalling vesicular trafficking is important for key steps during the developmental wiring up of the brain and then the operation of the synaptic connections. One key family of receptors that are transported to where they are needed in vesicles are the receptors for neurotransmitters (the chemical signalling molecules in the brain) and have a specialised role to bind neurotransmitters like GABA and glutamate that are released at synapses.A key goal of this proposal is to investigate how the regulation of the delivery of cargo between different organelles is performed, characterising the molecular properties of the protein AP4 which we think is crucial for regulating the homeostasis of organelle networks and for the regulation of receptor signalling. When the AP4 complex goes wrong in humans this leads to a devastiating neurological disorder, causing intellectual disability, brain structural alterations, epilepsy, in addition to spastic paraplegia and gait problems. However we still don't know how AP4 complex dysfunction leads to this devastating disease. In particular we want to know how AP4 complexes help brain cells to regulate membrane delivery and the number, activity and location of the key membrane proteins (such as neurotransmitter receptors) in the plasma membrane of brain cells to control neuronal signalling. Studying the molecular mechanisms that underlie these regulatory processes will allow us to better understand how the brain works under healthy conditions. In addition because disrupted cargo delivery is implicated in many neurodegenerative and neuropsychiatric diseases, our proposed work may also lead to an improved understanding of diseases where membrane trafficking and synaptic function are altered such as in epilepsy, stroke, Alzheimer's disease, motor neuron disease, Huntington's disease, schizophrenia and autism.