Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate hyperpolarizationactivated currents (I h ). In hippocampus, these currents contribute greatly to intrinsic cellular properties and synchronized neuronal activity. The kinetic and gating properties of HCN-mediated currents are largely determined by the type of subunits-for example, HCN1 and HCN2-that assemble to form homomeric channels. Recently, functional heteromeric HCN channels have been described in vitro, further enlarging the potential I h repertoire of individual neurons. Because these heteromeric HCN channels may promote hippocampal hyperexcitability and the development of epilepsy, understanding the mechanisms governing their formation is of major clinical relevance. Here, we find that developmental seizures promote co-assembly of hippocampal HCN1/HCN2 heteromeric channels, in a duration-dependent manner. Long-lasting heteromerization was found selectively after seizures that provoked persistent hippocampal hyperexcitability. The mechanism for this enhanced heteromerization may involve increased relative abundance of HCN2-type subunits relative to the HCN1 isoform at both mRNA and protein levels. These data suggest that heteromeric HCN channels may provide molecular targets for intervention in the epileptogenic process.

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The present study provides the first evidence that adhesion receptors belonging to the integrin family modulate excitatory transmission in the adult rat brain. Infusion of an integrin ligand (the peptide GRGDSP) into rat hippocampal slices reversibly increased the slope and amplitude of excitatory postsynaptic potentials. This effect was not accompanied by changes in paired pulse facilitation, a test for perturbations to transmitter release, or affected by suppression of inhibitory responses, suggesting by exclusion that alterations to ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionate ( Integrins are heterodimeric (␣, ␤), membrane-spanning proteins that anchor cells to the extracellular matrix and to adhesion proteins on opposing cells (1, 2). They also organize the elements of the submembrane actin cytoskeleton (3) and act as initiating receptors for a diverse array of intracellular signaling cascades (4 -6). As might be expected from these latter roles, integrins have potent interactions with neighboring membrane-associated proteins, including ion channels (7-10) and trophic factor receptors (11-15). Whether these lateral interactions also occur in synaptic junctions in the adult brain, which are known to have high concentrations of integrins (16 -20), has not been studied. This leaves open the possibility that transmitter receptors are tonically regulated by co-localized integrins. The question takes on added significance because of the recent finding that integrin expression is highly differentiated across brain regions as well as between the dendritic domains of individual neurons (16,(21)(22)(23)(24). If integrin binding does affect transmission, then it is likely that this influence will vary significantly across synaptic systems.Previous studies on the contributions of integrins to adult synaptic physiology have been restricted to analyses of long term potentiation (LTP).1 Small peptides and toxins containing the matrix sequence (arginine-glycine-aspartate (RGD)) recognized by most integrins had little effect on the induction or initial expression of LTP but clearly interfered with its stabilization (25-29) (i.e. in the presence of these soluble ligands, potentiation slowly decayed to baseline). Whereas functionblocking antibodies against the ␣ 5 (27) or ␣ 3 (30) integrin subunits caused partial blockade of consolidation as did reductions in integrin-associated protein (31), local applications of a mixture containing neutralizing antibodies against integrin subunits ␣ 3 , ␣ 5 , and ␣ v caused a complete reversal in LTP (25). Integrin effects on plasticity are not restricted to hippocampus or LTP. RGD-containing peptides interfere with rapid limbic kindling (32) and activity-dependent synaptic changes in Drosophila (33). In the latter case, it was possible to identify the pertinent ␣ integrin subunit (34,35).While connecting integrins to synaptic operations, the above results do not address the question of whether integrins influence neurotransmitter receptors other than very indirectly through processes ...