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Understanding decline of brain function
Research helps explain disorders such as schizophrenia

The research group led by Professor Toshio Ohshima of the Waseda University Faculty of Science and Engineering focused on cyclin-dependent kinase 5 (Cdk5), which is the protein related to the formation of spines in the mechanisms of synapses (joints between neurons). These allow neurons to transmit information inside the brain, and the spines (spiny structures on the dendrites of neurons) take the role of receiving neurotransmitters. The research has clarified that Cdk5 is required for forming and maintaining the spines*1 and that the degradation of the functions of Cdk5 leads to the decline in the efficiency of synaptic transmission and the memorizing and learning functions*2. In the case of neuropsychiatric disorders, such as schizophrenia, the decrease in spine density has been detected. If the higher brain functions are normal, spines are formed healthily and spine density is kept constant. As part of the mechanism for controlling the spine density of nerve synapses has been elucidated, it is expected that the pathological clarification of neuropsychiatric disorders will progress.

*1 These results were published online by the British journal “Cerebral Cortex” on November 17.
Cyclin-Dependent Kinase 5 Regulates Dendritic Spine Formation and Maintenance of Cortical Neuron in the Mouse Brain

*2 This outcome was achieved through collaborative research with the Laboratory of Behavioral Genetics of RIKEN Brain Science Institute (senior team leader: Shigeyoshi Itohara), and published online by the open-access journal “Molecular Brain” on November 18.
Cdk5/p35 functions as a crucial regulator of spatial learning and memory

(1) What we have learned through research so far

Our brains perform high-level functions by neurons transmitting information. The exchange of such information requires the structure called a synapse*1, and the information receiving side is a special structure called a spine*2, to streamline the transmission. The decrease in spine density has been detected in neuropsychiatric disorders, such as schizophrenia, and so it is essential to form healthy spines and maintain spine density for keeping higher brain functions. However, the mechanism of this control is yet to be clarified. The results of the experiments using cultured neurons, etc., suggested the involvement of cyclin-dependent kinase 5 (Cdk5), but the relation between Cdk5 and the formation and maintenance of spines in the living brain had not been investigated.

(2) Findings of this research

It was found that Cdk5 is necessary for forming and maintaining spines and that the functional degradation of Cdk5 induces decline in efficiency of synaptic transmission, and memory and learning functions. Thus, part of the mechanism for controlling spine density of nerve synapses has been elucidated.

(3) Newly developed method for this research

The conditional knockout method adopted for this research is a technique for triggering a genetic defect on a specific cell or tissue at a specific time. As for the target gene in this study, disruption in the prenatal period will induce early death in mice. It affects formation of the brain, and so by triggering the genetic defect after the brain is formed, it is possible to study more specific functions.

(4) Outcome and knowledge obtained through this research

By using the genetic modification technique called conditional knockout, the research group compared spine densities when the target gene is disrupted before the formation of spines and after the formation of spines. As Cdk5 is activated when it is bound to p35 or p39, the genes of both p35 and p39 were disrupted. As a result, it was observed that synapse density decreased in the neurons of the “hippocampus”*3 and the “cerebral cortex” related to memory and learning, no matter whether the target gene was disrupted before or after the formation of spines (Fig. 1). This indicates that Cdk5 is necessary for forming and maintaining synopses. It was confirmed that spine density decreases further when the genes of both p35 and p39 in the neurons of the hippocampus CA1 region are disrupted to weaken the activation of Cdk5, compared with the case where the gene of the activation subunit p35 only is disrupted (Fig. 2).

It was also clarified, through collaborative research with the Itohara Laboratory of RIKEN Brain Science Institute (senior team leader: Shigeyoshi Itohara), that disruption of p35, the subunit for activating Cdk5, in the adult brain, the efficiency of synaptic transmission declines (Fig. 3) and spatial memory degrades (Fig. 4) in the Morris water maze test*4, in addition to the decrease in synapse density.

(5) Ripple effects and social impact of this research

From these results, it was found that Cdk5 plays important roles for realizing the high-order brain functions by forming and maintaining spines. Since Cdk5 is a kinase that phosphorylates other proteins, by identifying phosphorylated proteins (substrates), it would be possible to shed light on more detailed control mechanisms. The relation between Cdk5 and neuropsychiatric disorders has been reported. For instance, the relation between schizophrenia and the functional degradation of Cdk5 has been reported. Since synapse density decreases also in this disease, it is expected that by identifying the matrix protein of Cdk5, etc., it will be possible to clarify neuropsychiatric pathology, including schizophrenia.

(6) Future issues

It has been reported that the agent for inhibiting the activities of Cdk5 in insulin-secreting cells helps secrete insulin, and so this is being studied as a treatment for diabetes. If the matrix proteins related to formation and maintenance of spines are identified, there is a possibility that the development of more specific medicines will contribute to the treatment of neuropsychiatric disorders such as schizophrenia. Going forward, it will be necessary to study the detailed mechanisms for Cdk5’s control of spine density.

Glossary
1. Synapse
A joint between neurons. The neurons connected by synapses constitute a neural network. At a synapse, neurotransmitters such as glutamic acid are emitted from the axon tips of neurons, i.e., the presynaptic region, and received by the spines of neurons, i.e., the postsynaptic region, to transmit information.
2. Spine
A spike-shaped structure on the dendrite of a neuron. A special structure in the postsynaptic region, where there are receptors for receiving neurotransmitters and various molecules for signal transmission inside cells.
3. Hippocampus
Area of the brain which plays important roles for spatial learning and long-lasting memory. The name hippocampus means sea horse in Latin, after its curved, elongated shape. Neurons located in its CA1, CA2, CA3 and dentate gyrus regions form a network.
4. Morris water maze test
This method was invented by Dr. Richard Morris for evaluating the spatial memory and learning ability of rodents, including mice and rats. In a circular pool (diameter: 1 m) with turbid water, a submerged platform is placed so that a mouse can escape the water. A mouse is put into the pool, so that it learns the location of the platform based on the spatial layout of objects around the pool. After repeating for about seven days, the platform is removed and the mouse observed to determine whether it remembers the former location of the platform.
Diagrams

Figure 1 Decrease in spine density was observed in cases where the subunit for activating Cdk5 was disrupted before the formation of spines (upper panel) and after the formation of spines (lower panel).

Figure 2 Gradual decrease in spine density was detected in two cases, where only p35, the subunit for activating Cdk5, was disrupted in the CA1 region of the hippocampus (left panel), and where p35 and p39 were disrupted (right panel).

Figure 3 Decline in the efficiency of synaptic transmission and the induction of long-term suppression of synapses were observed when p35, the subunit for activating Cdk5, was disrupted in the adult brain.

Figure 4 The results of the Morris water maze test indicate that the disruption of p35, the subunit for activating Cdk5, in the adult brain causes disorders in spatial learning (left panel) and spatial memory (right panel).

Links

Department of Life Science & Medical Bioscience, School of Advanced Science and Engineering, Waseda University

Oshima Laboratory of Waseda University

Laboratory for Behavioral Genetics, RIKEN Brain Science Institute