Thursday, January 3, 2013

NMDA Receptors Essential For Brain 'Pruning'

Several years after we are born, our brains house a tangle of neurons which are eventually pared down to form intricate and efficient neural networks as we learn and develop. The astonishing rate at which our nervous system can process a barrage of incoming stimuli- light, sound, a math equation on a blackboard, seeing a friend passing by- and direct the appropriate responses is a testament to its complexity and efficiency.

Neurons form elaborate circuits through which electrical and chemical 'signals' are relayed as a form of communication between our brains and the rest of our body. When a neuron is 'excited', an electrical impulse travels the length of the neuron before being converted into a chemical 'message' which is sent into the space between neurons known as the synapse. These chemical messengers- known as neurotransmitters- then act on neighboring neurons to either transmit the excitatory signal or prevent its transmission.

Neurons and the junctions between them form intricate circuits which can be re-activated when recalling a memory or something that was read in a book, for instance. In the same way that we lift weights to strengthen our muscles, repeated activation of a neural circuit makes it stronger. During the refinement of neural circuits, only the strong survive- weak and redundant synapses are cleared away in favor of stronger circuits. This neural 'pruning' persists well into our twenties, with weaker connections being removed to make way for stronger connections, increasing the efficacy of the transmission of impulses among neurons.

Comparison of synaptic density at birth, 7 years of age, and 15 years of age. Image credit:

Faulty pruning may be a major factor in disorders such as autism and schizoprenia, underlining the importance of this process and its regulation. In a recent paper published in the Proceedings of the National Academy of Sciences, researchers led by Zhong Wei-Zhang at Jackson Laboratory in Maine found that the N-methyl-D-aspartate receptor (NMDAR) may be important for pruning weak and redundant synapses.

Glutamate, one of the most abundant neurotransmitters, is released by some neurons and travels across the synapse where it acts on NMDARs on neighboring neurons. NMDARs in particular seem to be crucial for learning and memory at a cellular level. To investigate the effect of loss of NMDARs on neural circuit refinement, Zhang and his team analyzed a region of the brain known as the thalamus in mouse models which had lost NMDARs in some synapses but retained it at others. This allowed them to determine the direct effects of loss of NMDARs at the synapse- synapses in which NMDARs had been lost could be compared side-by-side with synapses which retained NMDARs in the same brain. In previous experiments it has been demonstrated that interfering with NMDAR activity or reducing NMDAR numbers at the synapses disrupted pruning in the brain, however, it was not clear whether these effects were direct or indirect effects of the researchers' manipulations.

Zhang and his team found that at synapses where NMDARs were lost, three or more neighboring neurons were often found clustered at the synapse, in contrast with the single neurons most commonly found next to synapses which had retained NMDARs. This indicated that redundant synapses were not being cleared away properly. The strength of synapses with NMDARs, moreover, was on average significantly higher than the strength of nearby synapses without NMDARs. They also examined pruning of a specific type of neuron and found that significantly more neurons remained at mutant synapses lacking NMDARs. These findings demonstrated the importance of NMDARs  in the pruning process, however, the specifics of the regulation of neural circuit refinement by NMDARs are still unclear. While it is believed that NMDARs may function in strengthening the synapse by supporting an increase in another type of glutamate receptor, the work of Zhang and his team  confirm the role of NMDARs in neural circuit refinement and encourage further investigation into the role of NMDARs in this important process.

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