From Neuroscience Karolinska Institutet, Stockholm, Sweden Extra- and Intracellular Electrotonic Conductance of Signals and its Significance for Synaptic Plasticity

Electrical signals play a pivotal role in the normal function of most if not all organisms. Understanding the electrophysiological principles that govern electrical signaling is essential for insights into normaland pathological processes in cell biology. The main aim of the current thesis is to provide a novel perspective on the way in which a passive electrical signal may participate in shaping the cellular response in the nervous system (e.g. for memory and learning) and in the cardiovascular system (cardiac contractility). A second aim is to demonstrate that some of these novel theoretical predictions may be of importance in living tissue under normal as well as pathological conditions. These aims have been obtained through a combination of theoretical and empirical studies in isolated cardiac muscle and brain slices. The initial studies show that a theoretical model of cardiac muscle, which may initially appear counter-intuitive (virtual electrodes predicted by the bidomain model), may actually be used to modulate intracellular calcium dynamics and modify the contraction of the cardiac muscle in normal conditions as well as in pathological conditions (paper I). I have then investigated whether similar principles could be applied to neuronal function, which has led to the development of the Cable-In-Cable (CIC) theory (paper II and paper III). The CIC theory represents a passive cable theory that is an extension of the conventional cable theory. The CIC theory suggests that post-synaptic potentials may be more accurately described by a system of cable within cable, where synaptic currents travel simultaneously in the medium between the cell membrane and the ER, and within the ER lumen. The CIC theory suggests a novel pathway by which the synaptic activity can modulate the activity of the cell nucleus (paper II). Additionally, the CIC theory suggests that synapses located on dendritic spines may code a second level of information (paper III), introducing a second dimension of synaptic plasticity. Synaptic plasticity, a dynamic refinement of synaptic efficacy, is generally regarded as a cellular correlate for particular forms of learning and memory. The majority of the experimental evidence for synaptic plasticity in the cortex relates to excitatory connections onto pyramidal cells. The primary postsynaptic target for these connections is the dendritic spines. The capability of dendritic spines to implement the Hebbian rule of synaptic plasticity has been addressed here through a combination of theoretical modeling and paired patch clamp recordings from cortical pyramidal neurons (unitary synaptic connections). Paper IV suggests that the Hebbian learning rule in a unitary synaptic connection is determined by free calcium dynamics within a temporal window of about 15-20 ms following the synaptic signal. Finally, synaptic plasticity (LTP) in healthy brain slices and in a transgenic animal model of Alzheimer disease was studied using patch clamp recording from cortical pyramidal neurons (paper V). This study suggested that synaptic plasticity is impaired at the onset of the disease, when the microcircuits architecture is still intact but the levels of the soluble β amyloid are elevated. This study shows that soluble β amyloid impairs LTP by diminishing the increase in the AMPA fraction of the synaptic signal. Specifically, the study shows that selective amplification of the AMPA fraction of the synaptic signal is capable of rescuing synaptic plasticity in vitro at the onset of Alzheimer-like disease. In summary, this thesis combines theoretical studies and empirical in vitro studies to introduce a new perspective to the way a passive electrical signal and intracellular calcium dynamics may participate in shaping cellular response in the cortical neurons and in the myocardium. LIST OF PUBLICATIONS I. SHEMER I*, Brunckhorst CB*, Mika Y, Ben-Haim SA, Burkhoff D. Cardiac contractility modulation by non-excitatory currents: studies in isolated cardiac muscle. Eur J Heart Fail. 2006 Jan;8(1):7-15. II. SHEMER I, Brinne B, Tegnér J, Grillner S. Electrotonic Signals Along Intracellular Membranes May Interconnect Dendritic Spines and Nucleus. PLoS Comput Biol. 2008 Mar 28;4(3):e1000036 III. SHEMER I and Grillner S. Cable-In-Cable theory predicts a second level of synaptic plasticity in spiny neurons. PLoS Computational Biology (submitted) IV. SHEMER I*, Zilberter M*, Holmgren H, Zilberter Y. Calcium Dynamics within a Short Temporal Window Determines Spike-timing-dependent Plasticity in Synapses between Layer 2/3 Pyramidal Cells. Cerebral Cortex (submitted) V. SHEMER I*, Holmgren C*, Min R, Fülöp L, Zilberter M, Sousa KM, Farkas T, Härtig W, Penke B, Burnashev N, Tanila H, Zilberter Y, Harkany T. Nonfibrillar beta-amyloid abates spike-timing-dependent synaptic potentiation at excitatory synapses in layer 2/3 of the neocortex by targeting postsynaptic AMPA receptors. Eur J Neurosci. 2006 Apr;23(8):2035-47. * Denotes equal contribution