Introduction

Gene discovery is only the first step towards understanding the pathology of any underlying disease. Clear understanding of any disease requires an integration of diverse approaches; ranging from molecular and cellular neuroscience probing for mechanistic functions, pathways and circuits to cognitive level assessment explaining the functional context. State of the art molecular biology tools to manipulate genes in-vivo offers a unique opportunity to study the molecular and cellular architecture of a neuron, and how this design is altered with changes in synaptic activity. This basic knowledge is essential before one can evaluate how genotype affects the phenotype.

Research efforts in the last two decades has shed light into the properties of neurons as signaling units and on the functional organization and plasticity of synaptic networks. Synaptic activity modulates signaling cascades originating at the synapse that ultimately elicit response inside the nucleus, which are often again relayed back to the synapse. However, synapses are highly specialized structures with a distinct distribution of proteins specific to each synapse, whose function are governed by local activation of regulatory molecules which are ubiquitously expressed. The spatial and temporal distribution of a specific protein and the availability of its effecter molecule play a crucial role in this relay of information.

Kinase pathways activated at the post synaptic sites regulate the dynamics of gephyrin scaffold formation and maintenance. Blocking GSK3β kinase pathway by Lithium promotes gephyrin clustering and GABAergic synapse formation. However, activation of GSK3β pathway leads to gephyrin phosphorylation at Ser270 and Calpain-1 mediated degradation.


Existing evidence indicates that inhibitory neurotransmission in the CNS is affected in many neuro-developmental disorders, neuro-psychiatric disorders, alcohol addiction and also neuro-degenerative disorders. Pharmacological interventions for neurological disorders typically influence synaptic transmission by interfering with transmitter function or reuptake. New avenues in drug discoveries for neurological disorders require a fresh focus on signaling pathways downstream of neurotransmission. Hence, the focus of our research group is to identify signal cascades which effect GABAergic transmission in the brain, and potentially develop this knowledge to design biosensors to monitor synaptic homeostasis and functionally link different types of synapses within a network. Convergence of signaling molecules onto postsynaptic protein scaffolds to alter receptor function offers exciting new opportunity to study and understand the regulation of synaptic transmission.