The overall objective of the Research Group is to understand synapse formation and function, how synapses are changed by experience, and to pinpoint the synaptic circuits that are affected in brain disorders. The broad know-how of the group, ranging from molecular genetics, cell biology, in vivo electrophysiology and behavior, allows for an integrative multi-level approach to tackle our scientific questions and our hypotheses. Following are some examples of ongoing projects in the group and the strategies being employed to address them:
Compartmentalized regulation of protein synthesis and function is crucial during neuronal development and in synaptic plasticity. Future goals aim to: (a) unravel the role of local protein synthesis using in vivo models; (b) investigate the role of hnRNPK as a translational regulator under physiological and pathological conditions, such as in epilepsy; (c) study the role of the ubiquitin-proteasome system at the synapse, which may constitute an additional regulatory mechanism for fine-tuning of the synaptic proteome; (d) develop, in conjunction with Dr. Noo Li Jeon (Seoul National University, Korea), novel microfluidic chambers as tools to address new biological questions.
Hormones that regulate energy metabolism such as leptin and ghrelin also affect higher brain function. The orexigenic hormone ghrelin in particular enhances hippocampal-dependent memory retention. We propose to examine a neurobiological substrate of the effect of ghrelin on cognition, by testing the possibility that its cognitive benefits are associated with increased glutamatergic transmission (we recently published our studies on this aspect: (Ribeiro et al. PNAS, 2013), with altered dendritic spine density and morphology, and with structural plasticity of dendritic spines in the hippocampus. Our findings will provide mechanistic insight about the cognitive enhancing effects of ghrelin, and establish a framework to understand a possible link between the regulation of energy metabolism and learning.
Synaptic circuits of neuropsychiatric disorders: CACNG2/Stargazin is an AMPAR auxiliary protein involved in receptor trafficking at synapses. We are generating knock-in mouse lines carrying pathological CACNG2 mutations that have been identified in human patients to test our hypothesis that unbalanced synaptic homeostatic plasticity may be a hallmark of schizophrenia. In parallel, we are also implementing optogenetics and in vivo recording techniques in mice, to assist in dissecting the synaptic circuits of social behaviors. Specifically we aim to assess the role of frontal cortico-striatal synaptic connectivity in the regulation of affiliative social behaviors.
In contrast to the role of glutamate in ischemic damage, which is largely documented, pre- and post-synaptic alterations in inhibitory neurotransmission remain poorly understood. We will benefit from the know-how available in the investigation of the traffic of glutamate receptors to characterize the molecular mechanisms involved in down-regulation of GABAergic synaptic transmission at the post-synaptic level in brain ischemia. Additional studies will be carried out to: (a) determine whether brain ischemia leads to a general downregulation of trophic support to neurons, as suggested from our studies on the downregulation of BDNF signaling (J Neurosci 32, 4610-4622) and (b) characterize the events operating downstream of the inhibition of the ubiquitin-proteasome system in the cascade leading to neuronal death in brain ischemia (Biochim Biophys Acta 1832, 263-74).
One emerging theme in the Synapse Biology unit, with the integration of its newer members, is the potential to offer a layered approached to the study of proteins and genes and study their role in synaptic physiology and neuronal survival, to their effects on circuitry function and behavior.