30 November 2007. The plasticity of synapses—their ability to change their structure and function in response to activity—is the basis for learning, memory, and associated cognitive skills. Even as the list of neurological conditions that feature defects in plasticity has grown to include mental retardation, depression, drug addiction, and schizophrenia, our understanding of this process is incomplete. Researchers have been unable so far to connect the dots of synaptic potentiation, a transformation that starts with activation of one type of glutamate receptor (the NMDA receptor), continues through reorganization of the synaptic cytoskeleton, and ends with the synaptic enrichment of another glutamate receptor, the AMPA type. Now, Peter Penzes and colleagues at the Northwestern University Feinberg School of Medicine in Chicago, Illinois, have found a molecular missing link that ties the two receptors together directly via the actin cytoskeleton and signaling molecules that regulate it.
In a paper published in the November 21 issue of Neuron, the researchers present evidence that kalirin-7, an activator of the small GTPase Rac-1, is required for both morphological and functional remodeling of synapses in mature cortical neurons. Kalirin-7, they show, is activated by NMDA receptor activation, and associates with AMPA receptors to regulate their density in synapses. The protein thus defines a signaling pathway required for activity-dependent synaptic plasticity, a process the malfunction of which may contribute to schizophrenia. Of particular interest to schizophrenia researchers, kalirin-7 was previously shown to interact with the product of the schizophrenia gene,
DISC1 (Millar et al., 2003), and expression of the protein (also known as Duo) is reduced in prefrontal cortex in brains from schizophrenia patients (see SRF related news story).
On the way to altering synapse function, activation of NMDA-type glutamate receptors first causes an enlargement of dendritic spines, the structures that bear synapses. In the new work, lead authors Zhong Xie and Deepak Srivastava trace the pathway controlling this spine enlargement in cultured cortical neurons. They confirm that the change requires activation of the small GTPase Rac-1, a central regulator of the actin cytoskeleton, as well as the activation of the calmodulin-dependent kinase II (CaMKII). They go on to identify kalirin-7, a brain-specific guanine exchange factor, as the substrate of CaMKII that mediates Rac-1 activation and the increase in spine size.
In addition to spine enlargement, kalirin-7 also promotes the increased AMPAR levels that occur in synapses after activation, they find. Surprisingly, the investigators find that kalirin-7 directly associates with the AMPAR, and that this association controls basal levels of the GluR1 receptor subunit and AMPAR-mediated synaptic transmission in mature cortical neurons. In the absence of kalirin-7, the neurons have fewer spines, and show changes in synapse structure, with lower levels of the GluR1 subunit of the AMPAR. Neurons lacking kalirin-7, or treated with a competitor peptide that blocks synaptic location of the protein, do not display increased synaptic strengthening after NMDAR stimulation.
According to the authors, the results demonstrate that normal levels of kalirin expression are required for NMDAR activity-dependent enhancement of AMPAR-mediated synaptic transmission. “Our results, together with the established important roles of the upstream regulators of kalirin-7 (NMDARs and CaMKII) and its targets (Rac-1 and actin) in plasticity, strongly suggest that kalirin-7 may be an important regulator of the experience-dependent modifications of forebrain circuits during postnatal development and may play an important role in learning and memory,” they write. The next step will be to generate kalirin-7-deficient animals to confirm the role of the protein in vivo.—Pat McCaffrey.
Xie Z, Srivastava DP, Photowala H, Kai L, Cahill ME, Woolfrey KM, Shum CY, Surmeier DJ, Penzes P. Kalirin-7 controls activity-dependent structural and functional plasticity of dendritic spines. Neuron. 2007 Nov 22;56(4):640-56. Abstract