One issue addressed in my lab is: What are the key synaptic proteins that regulate activity-development of the cerebral cortex and how do they regulate synaptic development?
The brain develops as a result of a complex interplay between genetic instruction (Nature) and experience (Nurture). Our laboratory is interested in genes that allow the brain to learn and store information during development.
At the heart of both childhood and adult learning and memory are the molecules that regulate the way neurons communicate, namely neurotransmitter receptors and their downstream signaling pathways.
Recently several forms of childhood cognitive impairment, including Fragile X Syndrome (FXS), have been shown to result from genetic alteration of genes encoding proteins that regulate glutamate receptors signaling and synaptic development.
FXS is the most common form of genetically inherited cognitive impairment with a prevalence of approximately 1:4000 boys and 1:8000 girls.
FXS results from genetic silencing of the fragile X mental retardation gene (Fmr1), which encodes the fragile X mental retardation protein (FMRP).
FMRP is a key regulator of synaptic development and belongs to a family of “synaptopathies” caused by genetic disruption of genes that encode synaptic proteins that result in altered synaptic development.
Other synaptic proteins being examined in the laboratory whose disruption leads to cognitive impairment in humans include SynGAP and SAP-102.
Finally we are examining the role of the Tuberous Sclerosis genes (Tsc1 and Tsc2) in cortical development.
The research projects in my laboratory are addressing several key issues:
James OT, Livesey MR, Qiu J, Dando O, Bilican B, Haghi G, Rajan R, Burr K, Hardingham GE, Chandran S, Kind PC, Wyllie DJ. (2014) Ionotropic GABA and glycine receptor subunit composition in human pluripotent stem cell-derived excitatory cortical neurones. J Physiol. 592(Pt 19):4353-63.
Filis P, Kind PC, Spears N. (2013) Implantation failure in mice with a disruption in Phospholipase C beta 1 gene: lack of embryonic attachment, aberrant steroid hormone signalling and defective endocannabinoid metabolism. Mol Hum Reprod. 19(5):290-301.
Wijetunge LS, Chattarji S, Wyllie DJ, Kind PC. (2012) Fragile X syndrome: from targets to treatments. Neuropharmacology. 68:83-96. Review.
McMahon AC, Barnett MW, O’Leary TS, Stoney PN, Collins MO, Papadia S, Choudhary JS, Komiyama NH, Grant SGN, Hardingham GE, Wyllie DJA and Kind PC (2012) Activity-dependent alternative promoter usage and alternative splicing enable SynGAP isoforms to exert opposing effects on synaptic strength. Nature Communications. 3.
Martel M-A, Ryan T, Bell KF, Fowler JH, McMahon A, Al-Mubarak B, Komiyama N, Horsburgh K, Kind PC, Grant SG, Wyllie DJ, Hardingham GE The subtype of GluN2 (2012) C-terminal domain determines the response to excitotoxic insults. Neuron. 74:543-556.
Till SM, Wijetunge LS, Seidel VG, Harlow E, Wright A, Bagni C, Contractor A, Gillingwater TH, Kind PC (2012) Genetic deletion of FMRP alters the trajectory of specific cellular processes during cortical development. Human Molecular Genetics. 21:2143-2156
Jaffer S, Vorobyov V, Kind PC, Sengpiel F (2012) Experience dependent regulation of functional maps in synaptic protein expression in cat visual cortex. Eur. J Neurosci. in press.
Kind PC, Sengpiel F, Beaver CJ, Kelly GM, Matthews RT and Mitchell DE (2012) Development and Activity- Dependent Expression of Aggrecan in the Cat Visual Cortex. Cerebral Cortex. in press.
Harlow EG, Till SM, Russell TA, Wijetunge LS, Kind PC and Contractor A (2010) Critical period plasticity is disrupted in the barrel cortex of Fmr1 knockout mice. Neuron, 65, 385-398.
Thomson RE, Kind PC, Graham NA, Etherson ML, Kennedy J, Fernandes AC, Marques CS, Hevner RF, Iwata T. (2009) Fgf receptor 3 activation promotes selective growth and expansion of occipitotemporal cortex. Neural Dev. 4:4.
Wijetunge L, Till S, Ingham C, Gillingwater T and Kind PC (2008) mGluR5 Regulates Glutamate-Dependent Development of the Mouse Somatosensory Cortex. J. Neurosci. 28:13028-13037.
Watson RF, Abdel-Majid RM, Barnett MW, Willis BS, Katsnelson A, Gillingwater TH, McKnight GS, Kind PC*, and Neumann PE (2006) Involvement of Protein Kinase A in Patterning of the Mouse Somatosensory Cortex. J. Neurosci. 17:5393-5361. *PC Kind is communication author.
Mitchell DE, Kind PC Sengpiel F, Murphy K (2006) Short periods of concordant binocular vision prevent the development of deprivation amblyopia. Eur. J. Neurosci. 23:2458-2466.
Barnett MW, Watson R, Vitalis T, Porter K, Komiyama NH, Stoney PN, Gillingwater TH, Grant SGN and Kind PC SynGAP regulates pattern formation in the trigeminal system of mice. J. Neurosci. 26:1355-1365.
Porter K, Komiyama NH, Vitalis T, Kind PC & Grant SGN (2005) Differential expression of two NMDA receptor interacting proteins, PSD-95 and SynGAP during mouse development. Eur. J. Neurosci. 21:351-362.
Spires TL, Molnar Z, Kind PC, Cordery PM, Upton AL, Blakemore C, Hannan AJ. (2005) Activity-dependent Regulation of Synapse and Dendritic Spine Morphology in Developing Barrel Cortex Requires Phospholipase C-b1 Signalling. Cereb. Cortex 15:385-393.
Mitchell DE, Kind PC, Sengpiel F, Murphy K. (2003) Brief daily periods of binocular vision prevent deprivation-induced acuity loss. Curr. Biol. 13:1704-8.
Sengpiel, F and Kind, PC (2002) The role of activity in the development of the visual system. Curr. Biol. 12:R818-826.
Vitalis T, Cases O, Gillies K, Hanoun N, Hamon M, Seif I, Gaspar P, Kind PC, and Price DJ (2002) Interactions between TrkB-signalling and serotonin excess in the developing murine somatosensory cortex: a role in tangential and radial organisation of thalamocortical axons. J. Neurosci. 22:4987-5000.
Kind PC, Mitchell DE, Ahmed B, Blakemore C, Bonhoeffer T and Sengpiel F (2002) Correlated binocular activity guides recovery from monocular deprivation. Nature 416:430-433.
Hannan AJ, Blakemore C, Katsnelson A, Huber K, Roder JK, Bear M, Kim D, Shin H and Kind PC (2001). Phospholipase C-?1, activated via mGluRs, mediates activity-dependent differentiation in cerebral cortex. Nat. Neurosci. 4, 282-288.
This article was published on Jan 29, 2015