Predictive genetic testing for Huntington's disease (HD) has revealed early cognitive deficits in asymptomatic gene carriers, such as altered working memory, executive function and impaired recognition memory. The perirhinal cortex processes aspects of recognition memory and the underlying mechanism is believed to be long-term depression (LTD) of excitatory neurotransmission, the converse of long-term potentiation (LTP). We have used the R6/1 mouse model of HD to assess synaptic plasticity in the perirhinal cortex. We report here a progressive derailment of both LTD and short-term plasticity at perirhinal synapses. Layer II/III neurones gradually lose their ability to support LTD, show early nuclear localization of mutant huntingtin and display a progressive loss of membrane integrity (depolarization and loss of cell capacitance) accompanied by a reduction in the expression of D1 and D2 dopamine receptors visualized in layer I of the perirhinal cortex. Importantly, abnormalities in both short-term and long-term plasticity can be reversed by the introduction of a D2 dopamine receptor agonist (Quinpirole), suggesting that alterations in dopaminergic signalling may underlie early cognitive dysfunction in HD.

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by progressive motor, psychiatric and cognitive decline. Marked neuronal loss occurs in the cortex and striatum. HD is inherited in an autosomal dominant fashion and caused by a trinucleotide repeat expansion (CAG) in the gene encoding the protein huntingtin. Predictive genetic testing has revealed early cognitive deficits in asymptomatic gene carriers at a time when there is little evidence for cell death, suggesting that impaired cognition results from a cellular or synaptic deficit, such as aberrant synaptic plasticity. Altered hippocampal long-term potentiation has been reported in mouse models of HD; however, the relationship between synaptic dysfunction and phenotype progression has not previously been characterized. We examined the age-dependency of aberrant hippocampal synaptic plasticity in the R6/1 mouse model of HD. Long-term depression (LTD) is a developmentally regulated form of plasticity, which normally declines by early adulthood. Young R6/1 mice follow the same pattern of LTD expression as controls, in that they express LTD in the first weeks of life, and then lose the ability with age. Unlike controls, R6/1 synapses later regain the ability to support LTD. This is associated with nuclear localization of mutant huntingtin, but occurs months prior to the formation of nuclear aggregates. We present the first detailed description of a progressive derailment of a functional neural correlate of cognitive processing in HD.

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The amygdala provides the medial prefrontal cortex (mPFC; areas 25, 32, and 24b) with salient emotional information. This study investigated the synaptic connectivity of identified amygdalocortical boutons (ACBs; labeled anterogradely following injections of Phaseolus vulgaris leucoagglutinin into the basolateral nucleus of the amygdala), with the dendritic processes of identified layer 5 corticospinal neurons in the rat mPFC. The corticospinal (CS) neurons in the mPFC had been retrogradely labeled with rhodamine fluorescent latex microspheres and subsequently intracellularly filled with biotinylated lucifer yellow to visualize their basal and apical dendrites. Two main classes of mPFC CS neurons were identified. Type 1 cells had apical dendrites bearing numerous dendritic spines with radiate basal dendritic arbors. Type 2 cells possessed apical dendrites with greatly reduced spine densities and a broad range of basal dendritic tree morphologies. Identified ACBs made asymmetric synaptic junctions with labeled dendritic spines and the labeled apical and basal dendritic shafts of identified CS neurons. On average, eight ACBs were closely associated with the labeled basal dendritic arbors of type 1 CS neurons and five ACBs with type 2 CS basal dendrites. The mean Scholl distance of ACBs from CS somata (for both types 1 and 2 cells) was 66 μm-coinciding with a region containing the highest length density of CS neuron basal dendrites. These results indicate that neurons in the BLA can monosynaptically influence CS neurons in the mPFC that project to autonomic regions of the thoracic spinal cord and probably to other additional subcortical target regions, such as the lateral hypothalamus.

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