Post synaptic density protein 95 (PSD-95) is a postsynaptic adaptor protein coupling the NMDA receptor to downstream signalling pathways underlying plasticity. Mice carrying a targeted gene mutation of PSD-95 show altered behavioural plasticity including spatial learning, neuropathic pain, orientation preference in visual cortical cells, and cocaine sensitisation. These behavioural effects are accompanied by changes in long-term potentiation of synaptic transmission. In vitro studies of PSD-95 signalling indicate that it may play a role in regulating dendritic spine structure. Here, we show that PSD-95 mutant mice have alterations in dendritic spine density in the striatum (a 15% decrease along the dendritic length) and in the hippocampus (a localised 40% increase) without changes in dendritic branch patterns or gross neuronal architecture. These changes in spine density were accompanied by altered expression of proteins known to interact with PSD-95, including NR2B and SAP102, suggesting that PSD-95 plays a role in regulating the expression and activation of proteins found within the NMDA receptor complex. Thus, PSD-95 is an important regulator of neuronal structure as well as plasticity in vivo.

Dendritic spines are important structures which receive synaptic inputs in many regions of the CNS. The goal of this study was to test the hypothesis that numbers of dendritic spines are significantly reduced on spiny neurones in basal ganglia regions in Parkinson's disease as we had shown them to be in a rat model of the disease [Exp Brain Res 93 (1993) 17]. Postmortem tissue from the caudate and putamen of patients suffering from Parkinson's disease was compared with that from people of a similar age who had no neurological damage. The morphology of Golgi-impregnated projection neurones (medium-sized spiny neurones) was examined quantitatively. The numerical density of dendritic spines on dendrites was reduced by about 27% in both nuclei. The size of the dendritic trees of these neurones was also significantly reduced in the caudate nucleus from the brains of PD cases and their complexity was changed in both the caudate nucleus and the putamen. Dendritic spines receive crucial excitatory input from the cerebral cortex. Reduction in both the density of spines and the total length of the remaining dendrites is likely to have a grave impact on the ability of these neurones to function normally and may partly explain the symptoms of the disorder.

It has been shown that dendritic spine density of medium sized spiny neurons in the neostriatum is reduced by about 19% in an animal model of Parkinson's disease (unilateral 6-hydroxydopamine lesion in rats) (Ingham el al., 1993). Recent results show an even greater reduction of spines (>20%) in the caudate and putamen on these neurons in Parkinson's disease patients. The spines receive input from axons originating mainly from the cortex, which form asymmetric synapses. Stimulation of these corticostriatal fibres leads to excitation of neostriatal neurons in a manner modifiable by dopamine. A similar reduction of asymmetric synapses (19%) in the neostriatum deprived of dopaminergic input compared with the intact side (Ingham et al., 1998) suggests this excitatory input is lost along with the spines. In the same study it was found that the numerical density of a sub-population of asymmetric synapses with discontinuous or complex synaptic specialisations was significantly increased. Such synapses would be expected to have increased efficacy and may be the morphological correlate of the proposed increase in excitation into the neostriatum in Parkinson's disease. A second unbiased, stereological study of the animal model suggests that both changes occur on neurons projecting indirectly via the globus pallidus to output nuclei of the basal ganglia.