SUMMARY 1. In recent decades evidence has accumulated demonstrating the birth and functional integration of new neurons in specific regions of the adult mammalian brain, including the dentate gyrus of the hippocampus and the subventricular zone. 2. Studies in a variety of models have revealed genetic, envi- ronmental and pharmacological factors that regulate adult neurogenesis. The present review examines some of the molecular and cellular mechanisms that could be mediating these regulatory effects in both the normal and dysfunctional brain. 3. The dysregulation of adult neurogenesis may contribute to the pathogenesis of neurodegenerative disorders, such as Hunt- ington's, Alzheimer's and Parkinson's disease, as well as psy- chiatric disorders such as depresssion. Recent evidence supports this idea and, furthermore, also indicates that factors promoting

Reduced neuronal plasticity in the striatum, hippocampus, and neocortex is a common feature of transgenic mouse models of Huntington’s disease (HD). Doublecortin (DCX) and polysialylated neural cell adhesion molecule (PSA-NCAM) are associated with structural plasticity in the adult mammalian brain, are markers of newly formed neurons in the dentate gyrus of the adult hippocampus, and are highly expressed in primary olfactory (piriform) cortex. Animal studies have demonstrated that a reduction in plasticity in the piriform cortex is associated with a selective impairment in odour discrimination. Therefore, the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex were quantified as measures of plasticity in early stage (fifteen week old) R6/1 transgenic HD mice. The transgenic mice had a large reduction in the number of DCX and PSA-NCAM immunoreactive cells in the piriform cortex, similar to that previously reported in the R6/2 mice. We also tested whether odour discrimination, as well as identification and detection, were impaired in HD patients and found that patients (at a similar disease stage as the mice) had an impairment in odour discrimination and identification, but not odour detection. These results suggest that olfactory impairments observed in HD patients may be the result of reduced plasticity in the primary olfactory cortex.

1. In recent decades evidence has accumulated demonstrating the birth and functional integration of new neurons in specific regions of the adult mammalian brain, including the dentate gyrus of the hippocampus and the subventricular zone. 2. Studies in a variety of models have revealed genetic, environmental and pharmacological factors that regulate adult neurogenesis. The present review examines some of the molecular and cellular mechanisms that could be mediating these regulatory effects in both the normal and dysfunctional brain. 3. The dysregulation of adult neurogenesis may contribute to the pathogenesis of neurodegenerative disorders, such as Huntington's, Alzheimer's and Parkinson's disease, as well as psychiatric disorders such as depression. Recent evidence supports this idea and, furthermore, also indicates that factors promoting neurogenesis can modify the onset and progression of specific brain disorders, including Huntington's disease and depression.

Nektarios K. Mazarakis,1 Anita Cybulska-Klosowicz,2 Helen Grote,1 Terence Pang,3 Anton Van Dellen,1 Malgorzata Kossut,1 Colin Blakemore,1 and Anthony J. Hannan1,3 1University Laboratory of Physiology, University of Oxford, Oxford OX1 3PT, United Kingdom, 2Laboratory of Cortical Plasticity, Nencki Institute of Experimental Biology, 02-093 Warsaw, Poland, and 3Howard Florey Institute, University of Melbourne, Parkville, 3010 Victoria, Australia

SUMMARY1. Huntington's disease (HD) is a fatal autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. The dynamic mutation that causes the disease is common to numerous other brain disorders, which may share similar pathogenic mechanisms.2. Much progress has been made in the past decade in understanding how a trinucleotide (CAG) repeat expansion, encoding an expanded polyglutamine tract in the huntingtin protein, induces dysfunction at molecular and cellular levels. The present review integrates various lines of experimental evidence in an attempt to move towards a unifying mechanistic framework, which may explain the pathogenesis of HD, from molecular through to neuronal network and behavioural levels.3. Recent evidence, using transgenic mouse models, also suggests that environmental factors can modify the onset and progression of HD. The effects of specific environmental manipulations are discussed in the context of gene–environment interactions and experience‐dependent plasticity in the healthy and diseased brain, particularly the cerebral cortex.

In order to ascertain whether disturbances of neurogenesis occur in chronic neurodegenerative disorders, we assessed hippocampal cell proliferation in the R6/1 transgenic mouse model of Huntington's disease (HD). Using BrdU labelling for dividing cells at two different time points (5 and 20 weeks) in transgenic and wild type control mice, we have shown that cell proliferation in the hippocampus was similar in younger asymptomatic R6/1 mice and wild type controls, but that older R6/1 mice had significantly fewer BrdU+ cells than controls. Such a decrease in cell proliferation may be relevant to some of the deficits seen in these mice, although further work is needed to prove this.

Synaptic plasticity takes many molecular forms. In this week’s Journal, Lei and McBain explore two types of long-term depression (LTD) at CA3 inhibitory synapses between mossy fibers and stratum lucidum interneurons. Both types require influx of postsynaptic calcium, but whereas calcium-permeable AMPA-type glutamate receptors (CP-AMPARs), when present, are sufficient to induce LTD at some of these synapses, NMDA receptors (NMDARs) are required for LTD at synapses expressing calcium-impermeable (CI)-AMPARs. The authors used a three-pronged approach to determine the site of LTD expression in each case. They measured whether the two forms of LTD altered neurotransmitter release probability, the level of released glutamate fluctuations in the cleft, and/or AMPA receptor trafficking in the postsynaptic membrane. LTD expression appeared to be presynaptic at synapses with CP-AMPARs, whereas postsynaptic mechanisms, possibly calcium-evoked AMPAR endocytosis, mediated LTD evoked by CI-AMPARs and NMDARs. The parallel LTD mechanisms give a familiar answer to the question “presynaptic or postsynaptic?” It depends.

Huntington's disease (HD) is one of a group of neurodegenerative diseases caused by an expanded trinucleotide (CAG) repeat coding for an extended polyglutamine tract. The disease is inherited in an autosomal dominant manner, with onset of motor, cognitive, and psychiatric symptoms typically occurring in midlife, followed by unremitting progression and eventual death. We report here that motor presymptomatic R6/1 HD mice show a severe impairment of somatosensory-discrimination learning ability in a behavioral task that depends heavily on the barrel cortex. In parallel, there are deficits in barrel-cortex plasticity after a somatosensory whisker-deprivation paradigm. The present study demonstrates deficits in neocortical plasticity correlated with a specific learning impairment involving the same neocortical area, a finding that provides new insight into the cellular basis of early cognitive deficits in HD.