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short-term memory tasks such as working memory, the mPFC also plays an important role in
long-term memories.
The cellular mechanisms underlying synaptic plasticity at mPFC synapses are similar to
those in other brain regions where synaptic plasticity has been well studied, such as the
hippocampus. Both LTD and LTP require a both rise in postsynaptic calcium, and they both
generally require activation of NMDA receptors. Furthermore, activation of PKA, MAP
kinase, CREB phosphorylation, and protein synthesis point to similar molecular mechanisms
underlying plasticity. While neuromodulation by dopamine has been well studied, the effects
of other neuromodulators such as 5-HT, acetylcholine and noradrenaline remain largely
elusive. Given that 5-HT in the mPFC is known to be essential for mood regulation, and
acetylcholine for cognitive abilities, elucidating the effects of these neuromodulators on
synaptic plasticity may provide insights into the cellular basis of these cognitive functions.
The most striking difference between synaptic plasticity in the mPFC and in other brain
regions is the similarity in induction protocols that induce LTP and LTD in the mPFC. All but
two studies (Milad and Quirk 2002; Huang et al. 2004) have evoked LTD with the same high
frequency stimulation both in vitro (Hirsch and Crepel 1990; Auclair et al. 2000) and in vivo
(Takita et al. 1999) that can induce LTP. The relationship between LTP and LTD in other
brain areas, such as the hippocampus and other cortical regions, is determined by the amount
of calcium influx during the induction protocol, with greater calcium rises associated with
LTP and lesser calcium rises associated with LTD (Dudek and Bear 1992; Kirkwood et al.
1993; Dudek and Friedlander 1996; Manabe 1997). The reason for the disparity in LTD
induction in the mPFC is not clear, but may be due to a higher NMDA receptor-mediated
contribution to basal synaptic transmission at synapses in the mPFC (Faber, unpublished
observations; Wang 2001), shifting the rules for synaptic plasticity induction. An
investigation into the properties of spike timing-dependent plasticity, in addition to calcium
imaging of spines and dendrites undergoing synaptic plasticity, would help to elucidate these
discrepancies.
Disorders of synaptic plasticity in the mPFC may contribute to the pathology of a range
of psychiatric disorders, including Alzheimer's disease, mental retardation, depression,
anxiety disorders, and drug addiction. Therefore it is crucial to understand the cellular
mechanisms underlying synaptic plasticity in the mPFC, to understand not only the
mechanisms underlying normal cognitive processes, the functioning of the mind and
“conscious” thought processes, but also to pave the way to the development of improved
therapies of neurological disorders, for which the current treatments are very poor.
A
CKNOWLEDGEMENTS
I would like to thank Jeremy Seamans and Satoru Otani for their useful comments on this
chapter.
