Defining the role of ciliary BBS proteins in neuroplasticity

Neuronal plasticity is among the most important areas of modern neuroscience research and one of the best existing cellular models for learning and memory. The hippocampus is a brain structure important for learning and the storage of memories. It has been shown that there is an area in hippocampus where new neurons are born even during adult life. New neurons integrate into existing networks and are important for developing new skills and memory. It has also recently emerged that memories and learning skills are "stored" in dendritic spines, mushroom like protrusions on the dendrites of nerve cells. Dendritic spines are very "plastic", that is, they change significantly in shape, volume, and number over a short time course. Because spines mostly comprise an actin cytoskeleton, they are dynamic, with the majority of spines able to change their shape within seconds to minutes following actin remodelling. New experiences and learning lead to the formation of new spines. It has been observed that malformed spines or reduced spine number can be associated with learning disabilities.

Recently, an exciting link between cilia/ciliary proteins and adult neurogenesis has emerged. Cilia are hair-like projections from the cell membrane. They are found on almost all eukaryotic cells. In the last decade it has been shown normal human functions such as ability to see, hear, smell, breathe, excrete, reproduce critically depend on correct ciliary function. It has been also shown that cilia are important for normal brain functions such as learning and memory. Normal cilia function depends on integrity of many proteins including BBS.
We have generated preliminary data indicating that there is a reduction in formation of adult new born neurons as well as reduction in dendritic spine number and density in Bbs mice model. These mice lack a functional BBS protein and therefore recapitulates the main features of human BBS and thus, will provide Here we propose to investigate how mutation in a single BBS protein might lead to the changes in neuroplasticity. We hypothesise that the absence of a fully functioning Bbs protein affects the formation of dendritic spines thus reducing the hippocampal capacity for information storage and effective learning.

Neuronal plasticity is among the most important areas of modern neuroscience research and one of the best existing cellular models for learning and memory. Dynamic changes in axon and dendritic growth, integration of adult new-born neurons into existing networks, synaptogenesis, and dendritic spine formation are just some examples of the molecular and cellular underpinnings of neuronal plasticity.
Recently, an exciting link between cilia and adult neurogenesis has emerged. Loss of cilia in adult progenitor cells leads to significant decrease of proliferation in hippocampal amplifying progenitors. Moreover, loss of ciliary protein Arl13b causes aberrant polarity of radial progenitors leading to the disruption of neuron organisation in cortex.
Cilia are microtubule-based, centriole-derived projections from the apical cell membrane. In the last decade it has been identified that normal human functions such as ability to see, hear, smell, breathe, excrete, reproduce and learn/remember critically depend on correct ciliary function.
Bardet-Biedl syndrome, BBS, proteins play an important role in cilia function being a core facilitators of ciliogenesis and cilia receptor trafficking. We, and others have previously shown that the BBS4 protein is involved in microtubular stabilisation suggesting involvement of BBS proteins in the regulation of the cytoskeleton and protein trafficking. In spite a well-defined role in ciliagenesis, the role of BBS proteins in neurogenesis and dendritic spine formation has not been investigated. In our preliminary experiments we have determined that Bbs4 and Bbs5 null mice have significantly reduced neurogenesis and dendritic spine formation in the dentate gyrus suggesting that there is an overall reduction in neuronal plasticity. Here we propose to investigate the molecular mechanisms of BBS proteins involvement in adult neurogenesis and synaptogenesis.

The proposed research will likely have immediate and long term impact on academic communities and clinical researchers. Even though it is not our primary goal to investigate a Bardet-Biedl syndrome patients neurophysiology, this study will have an impact on BBS patients, their clinicians, and the National Health and Social services
Academic community:
Although the proposed research project is multi-disciplinary in nature, we predict that the greatest impact for researchers will be in the cilia and neuro-biology fields. Cilia is a organell which is recognised to be vital for many normal human functions such as hearing, vision, taste, reproduction and learning and memory. The evidence of cilia profound significance lies in the fact that defects in cilia lead to a broad range of organ specific disorders: situs inversus, polycystic kidneys, retinal degeneration, obesity etc. However, little is known as to how defects in cilia function affect learning, memory and even psychiatric disease. This project will help to evaluate the potential link between neuronal plasticity and its impact on learning, memory and behaviour. Bbs mice might provide an excellent tool for the neurobiological studies of neuronal plasticity.
Bardet-Biedl patients and their clinicians
In this study we propose to investigate the role of BBS proteins in neuroplasticity. BBS proteins when mutated, cause Bardet-Biedl syndrome (BBS) which is a highly debilitating autosomal-recessive genetic disorder in which patients present with early-onset blindness, polydactyly, renal disease, obesity, diabetes and cognitive impairment. There is no cure. In addition to learning disabilities, the neuropsychiatric component of BBS comprises behavioural difficulties such as disinhibition, an inability to recognise social cues, obsessive-compulsive tendencies, anxiety and depression, autism and even psychosis. Most adult patients experience short-term memory deficits but relatively well-preserved long term memory.
For the clinicians, the knowledge of the underlying aetiology of the cognitive impairment in BBS patients is critical for how clinicians regard the intellectual development of these patients who currently have no strategy for improvement. For example, early recognition of the disorder by GPs, mid-wives or health visitors, and subsequent correct diagnosis by paediatricians and clinical geneticists is vital if affected children are to be given the appropriate and timely therapy.
National Health Service and Social Services
Approximately 500 patients attend the NHS nationally commissioned clinical service (led by P. Beales). Each BBS patient requires input from multiple services including ophthalmology, nephrology, urology, dietetics, endocrinology, clinical genetics, psychology and neurology. The BBS specialised service provides a one-stop shop clinic visit delivered by four NHS trusts; Birmingham Children's Hospital, Queen Elizabeth Hospital (Birmingham), Guys Hospital and Great Ormond Street Hospital (London). Genetic testing for each patient is also provided through this service. BBS patients require lifelong monitoring of their disease and treatment of organ-specific problems which is partly delivered through this service.
An important observation from the service is that learning disabilities and memory deficits are much less pronounced in the early years than during adolescence and adulthood indicating that these are not likely due to defects in embryonic development but decline with age. By investigating the role of BBS proteins in learning and memory, we could potentially develop early intervention programmes and targeted educational approaches for BBS syndrome patients.