Cycle 2 project 4

Project 4: Septin-dependent structural plasticity of dendritic spines

 

PhD student: Monika Bańko, Poland
Home Institute:
Neuroscience Center Zürich; Principle Investigator: Helge Ewers
Host Institute: Bordeaux Neurocampus; Principle Investigator: Daniel Choquet

Executive Summary
A central feature of excitatory glutamatergic synapses in the brain is their ability to adjust their strength individually in response to stimuli. Glutamate receptors of the NMDA-type mediate synaptic plasticity by changing the number of APMA-type glutamate receptors in the postsynapse, which in term leads to a stronger or weaker response to glutamate release at this very synapse. This functional plasticity is generally accompanied by a structural plasticity of dendritic spines, the small, actin-rich protrusion from the dendrite stalk that harbor the excitatory synapses. Synaptic plasticity is thought to underlie learning and memory formation and problems with synaptic plasticity and spine morphology are found in many diseases of the nervous system. In schizophrenia, spines are morphologically aberrant[i] and glutamate receptor signaling is disturbed[ii],[iii]. While dysfunctional NMDAreceptor mediated synaptic plasticity seems to be central to schizophrenia, the exact molecular mechanisms acting on spine morphology and excitatory synapses that underlie the pathogenesis of this strongly disabling and complex disease are poorly understood.

New insight into synaptic and spine plasticity in health and disease may come from the investigation of the septins, a new protein family important for spine morphogenesis[iv],[v] that is involved in schizophrenia on the genetic[vi], expression[vii] and protein level[viii].

The septins are a conserved family of filament-forming GTPases[ix] that organize microtubuli and actin[x] in complex cellular events such as cytokinesis[xi] and cell migration[xii]. Some of the 13 septins common to mammals are tissue specific and several are expressed exclusively in the brain. Here, a complex of septins 5,7 and 11 is required for dendritic arborization in neurons. This complex later locates to dendritic spine necks and controls spine morphogenesis. Here it acts as a diffusion barrier to the lateral exchange of receptors between the spine head and the dendritic membrane. Strikingly, the assembly of septin complexes in heterologous cells is regulated by cdc42 and its Borg effectors[xiii], whose expression is misregulated in hippocampi of schizophrenia patients as well7. In agreement with a possible role in the expression of schizophrenia pathology, the downregulation of cdc42 reduces spine number resulting in less functional synapses[xiv], [xv], but how septin complex regulation in dendritic spines is executed is unknown.

We have now found that a reduction of septin7 expression results in lower amounts of NMDA-type glutamate receptors at synapses and that NMDAreceptor dependent structural plasticity of dendritic spines is strongly reduced when septin7 is knocked down by RNA interference. Furthermore, the number of spines is markedly reduced when septin7 is not present.

These preliminary results lead us to hypothesize that septin7 is important for synapse and spine plasticity. We aim to address the following questions by live-cell microscopy and electrophysiology: Is septin7 required for synaptic plasticity? Does the cdc42-Borg pathway control septin complex assembly in neurons and is this linked to plasticity? Do spines that have septin complexes at their necks bear stronger synapses?

The expected results will provide a new pathway for the execution of plasticity in dendritic spines and elucidate the control of septin complex assembly in dendritic spines.

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