Homeostatic Plasticity of Striatal Neurons Intrinsic Excitability following Dopamine Depletion

Abstract

The striatum is the major input structure of basal ganglia and is involved in adaptive control of behaviour through the selection of relevant informations. Dopaminergic neurons that innervate striatum die in Parkinson disease, leading to inefficient adaptive behaviour. Neuronal activity of striatal medium spiny neurons (MSN) is modulated by dopamine receptors. Although dopamine signalling had received substantial attention, consequences of dopamine depletion on MSN intrinsic excitability remain unclear. Here we show, by performing perforated patch clamp recordings on brain slices, that dopamine depletion leads to an increase in MSN intrinsic excitability through the decrease of an inactivating A-type potassium current, I A. Despite the large decrease in their excitatory synaptic inputs determined by the decreased dendritic spines density and the increase in minimal current to evoke the first EPSP, this increase in intrinsic excitability resulted in an enhanced responsiveness to their remaining synapses, allowing them to fire similarly or more efficiently following input stimulation than in control condition. Therefore, this increase in intrinsic excitability through the regulation of I A represents a form of homeostatic plasticity allowing neurons to compensate for perturbations in synaptic transmission and to promote stability in firing. The present observations show that this homeostatic ability to maintain firing rates within functional range also occurs in pathological conditions, allowing stabilizing neural computation within affected neuronal networks.

Striatal atrophy and dendritic alterations in a knock-in mouse model of Huntington's disease

“…Specifically, dopamine deficiency has been associated with a loss in spines in medium sized spiny neurons [4, 20, 21, 33, 46], and dopamine is being increasingly considered as a potential neuroprotective agent in HD [16, 29, 49]. Therefore, to determine whether alterations in DA transmissions could contribute to the morphological impairments we have observed in older mice, we performed an immunocytochemical stain for TH, a marker of nigrostriatal dopaminergic terminals in the striatum.…”

“…In the present study, we have measured immunoreactivity of TH, the rate-limiting enzyme of catecholamine synthesis and a marker for dopamine terminals in the striatum (which contains very few noradrenergic terminals). Interestingly, several studies have reported an association between striatal dopamine deficiency and spine loss in medium sized spiny neurons [4, 20, 21, 33, 46]. In fact, changes in dopamine function influencing striatal spines in HD could either be pre- or post-synaptic.…”

Upregulation of D2-class signaling in dopamine-denervated striatum is in part mediated by D3receptors acting on CaV2.1 channels via PIP2depletion

“…All increase in the E max for Ca 2ϩ current modulation by quinelorane after DA depletion (Prieto et al 2009) is virtually due to enhanced D 3 R-type modulation. Supersensitivity contributed by other receptor types belonging to the D 2 R class deserves its own study to relate their signaling with some excitability parameter (Azdad et al 2009). 4) Downregulation of D 3 nf variant in striatum accompanied the enhanced D 3 R-type activity.…”

Catecholamine autotoxicity. Implications for pharmacology and therapeutics of Parkinson disease and related disorders

“…As striatal dopaminergic terminals are lost, a variety of compensatory adjustments take place, such as increased DA release from remaining terminals (Snyder et al, 1990; Zigmond et al, 1990; Calne & Zigmond, 1991), decreased reuptake of released DA (Sossi et al, 2007), increased DA synthesis via TH (Loeffler et al, 1995; Bezard et al, 2000), upregulation of post-synaptic DA receptors (Perlmutter et al, 1987; Kaasinen et al, 2000), and increased excitability of the target striatal medium spiny neurons (Azdad et al, 2009). These adaptive changes, which exemplify compensatory activation of alternative effectors in homeostatic negative feedback loops (Goldstein, 2013), maintain dopaminergic functions until the loss of the terminals is advanced.…”