The Hyperpolarization-Activated Current Determines Synaptic Excitability, Calcium Activity and Specific Viability of Substantia Nigra Dopaminergic Neurons

Abstract

Differential vulnerability between Substantia Nigra pars compacta (SNpc) and Ventral Tegmental Area (VTA) dopaminergic (DAergic) neurons is a hallmark of Parkinson’s disease (PD). Understanding the molecular bases of this key histopathological aspect would foster the development of much-needed disease-modifying therapies. Non-heterogeneous DAergic degeneration is present in both toxin-based and genetic animal models, suggesting that cellular specificity, rather than causing factors, constitutes the background for differential vulnerability. In this regard, we previously demonstrated that MPP+, a neurotoxin able to cause selective nigrostriatal degeneration in animal rodents and primates, inhibits the Hyperpolarization-activated current (Ih) in SNpc DAergic neurons and that pharmacological Ih antagonism causes potentiation of evoked Excitatory post-synaptic potentials (EPSPs). Of note, the magnitude of such potentiation is greater in the SNpc subfield, consistent with higher Ih density. In the present work, we show that Ih block-induced synaptic potentiation leads to the amplification of somatic calcium responses (SCRs) in vitro. This effect is specific for the SNpc subfield and largely mediated by L-Type calcium channels, as indicated by sensitivity to the CaV 1 blocker isradipine. Furthermore, Ih is downregulated by low intracellular ATP and determines the efficacy of GABAergic inhibition in SNpc DAergic neurons. Finally, we show that stereotaxic administration of Ih blockers causes SNpc-specific neurodegeneration and hemiparkinsonian motor phenotype in rats. During PD progression, Ih downregulation may result from mitochondrial dysfunction and, in concert with PD-related disinhibition of excitatory inputs, determine a SNpc-specific disease pathway.

Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels: An Emerging Role in Neurodegenerative Diseases

“…It is worth noting that unilateral ZD7288 injection into the SNc of adult rats prominently increased the number of apomorphine-induced rotations and reduced the immunofluorescence intensity of tyrosine hydroxylase-positive neurons. These effects were not observed in VTA neurons (Carbone et al, 2017).…”

“…Direct pharmacological suppression of I h through ZD7288 (50 μM) also increased the decay time and amplitude of eEPSPs, and this response was more prominent in SNc than in VTA neurons (Masi et al, 2015). ZD7288 also significantly reduced the amplitude of evoked inhibitory post-synaptic potentials (eIPSPs) (Carbone et al, 2017). Therefore, I h blockage likely enhances synaptic excitability through a dual mechanism in SNc dopaminergic neurons, specifically, by potentiating excitatory inputs and weakening inhibitory inputs.…”

Harnessing ionic mechanisms to achieve disease modification in neurodegenerative disorders

“…Because no association between HCN mutations and PD have been discovered so far, it remains to be determined whether HCN LOF participates in the pathogenic cascade of clinical PD and how genetic or sporadic PD-triggers induce HCN LOF. In this respect, it was demonstrated the HCN current is negatively modulated by acute inhibition of mitochondrial ATP production, an effect resembling that induced by low intracellular cAMP [53]. It is plausible that metabolic stress and reduced ATP production result in reduced cAMP synthesis in preclinical stages of PD.…”

“…Furthermore, the electrophysiological effects exerted by pharmacological inhibition of HCN current, as well as the ensuing somatic Ca 2+ inflow, is larger in vulnerable SNc as compared to resistant VTA DAergic neurons [52]. Finally, it was shown that chronic inhibition of HCN current attained with local administration of two distinct HCN blockers, causes DAergic neuronal death in the SNc, but not in the VTA, of normal adult rats [53]. Based on their results, the authors speculate that HCN current may undergo loss of function (LOF) during the early phases of disease progression, possibly as a consequence of metabolic fatigue, and drive Ca 2+ -mediated toxicity, thus representing an SNcspecific pathogenic pathway.…”

“…In PD models, both normal electrical properties (Ca V 1.3-mediated dendritic Ca 2+ activity) or acquired alterations (i.e. aberrant firing rate, increased synaptic excitability) resulting from the activation of specific disease pathways (αsynuclein signalling, UPS inhibition, metabolic stress) have been implied in the selective vulnerability of midbrain dopaminergic neurons [38,39,53,137]. In particular, Ca 2+ activity is emerging as a pathogenic component with broad relevance in PD forms with multiple aetiologies [41,43,46].…”