Disorders in the function of the hippocampus, a brain region important for declarative learning and memory, have been implicated in a variety of psychiatric and neurological disorders, including Alzheimer's disease, schizophrenia, depression and epilepsy. Long-term synaptic plasticity in hippocampal circuits has been widely implicated in both learning and memory and as an underlying cause of disease. However, comparatively little is known about how the integrative membrane properties of hippocampal neurons contribute to spatial information processing or disease processes. This proposal focuses on the contribution to spatial learning and memory of the HCN1 hyperpolarization-activated channel, which is highly expressed in the dendrites of hippocampal CA1 pyramidal neurons where it regulates synaptic integration. HCN1 is of further interest as its level of expression is dynamically regulated by neural activity. Indeed, downregulation of HCN1 during seizures has been proposed to contribute to development of epilepsy. The role of HCN1 in brain function was previously studied in a line of mice in which HCN1 was deleted selectively in the forebrain. Surprisingly, these mice showed an enhancement in spatial learning and memory. This behavioral effect was associated with an enhancement in synaptic transmission and long-term potentiation (LTP) at the direct cortical, temperoammonic (TA) inputs to CA1 neurons, which terminate on the distal CA1 dendrites where HCN1 expression is normally greatest. These results indicate that HCN1 provides an inhibitory constraint on both synaptic plasticity at the TA synapses and on spatial learning and memory. However, the mechanism by which HCN1 constrains these processes is not known. Moreover, relatively little is known about synaptic plasticity or its behavioral significance at the TA synapses, compared to the wealth of information on synaptic plasticity at the major Schaffer collateral inputs to CA1 neurons. This proposal represents a multidisciplinary study, combining in vivo recordings of CA1 neuronal activity with hippocampal slice recordings of TA synaptic plasticity and two-photon imaging of calcium in distal CA1 dendrites, to address the following questions: How does HCN1 deletion enhance LTP at TA synapses? Does it alter the firing in the distal dendrites of calcium spikes - events that have been implicated in LTP? Is TA LTP associated with dynamic changes in HCN1 expression in the distal dendrites and does this alter synaptic transmission? Does HCN1 constrain spatial learning and memory by affecting the in vivo encoding of spatial information in CA1 neurons? By focusing on the role of a specific ion channel that is enriched in a specific region of CA1 neuron dendrites, this study will help elucidate the role of HCN1 and the defined synaptic element that it regulates in the encoding of spatial memory. Such studies may validate the HCN1 channel as a potential target for novel therapies for epilepsy, age-related memory loss, major depression, schizophrenia and related diseases of hippocampal function.
|Thuault, Sebastien J; Malleret, Gael; Constantinople, Christine M et al. (2013) Prefrontal cortex HCN1 channels enable intrinsic persistent neural firing and executive memory function. J Neurosci 33:13583-99|
|Piskorowski, Rebecca; Santoro, Bina; Siegelbaum, Steven A (2011) TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron 70:495-509|
|Giocomo, Lisa M; Hussaini, Syed A; Zheng, Fan et al. (2011) Grid cells use HCN1 channels for spatial scaling. Cell 147:1159-70|
|Hussaini, Syed A; Kempadoo, Kimberly A; Thuault, Sebastien J et al. (2011) Increased size and stability of CA1 and CA3 place fields in HCN1 knockout mice. Neuron 72:643-53|
|Chevaleyre, Vivien; Siegelbaum, Steven A (2010) Strong CA2 pyramidal neuron synapses define a powerful disynaptic cortico-hippocampal loop. Neuron 66:560-72|
|Santoro, Bina; Piskorowski, Rebecca A; Pian, Phillip et al. (2009) TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 62:802-13|
|George, Meena S; Abbott, L F; Siegelbaum, Steven A (2009) HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K(+) channels. Nat Neurosci 12:577-84|