Tadinada Satya Murthy, Walsh Emily N, Mukherjee Utsav, Abel Ted
Department of Neuroscience and Pharmacology, The University of Iowa, Iowa City, IA, USA.
Iowa Neuroscience Institute, The University of Iowa, Iowa City, IA, USA.
J Physiol. 2024 Dec 18. doi: 10.1113/JP286801.
cAMP signalling is critical for memory consolidation and certain forms of long-term potentiation (LTP). Phosphodiesterases (PDEs), enzymes that degrade the second messengers cAMP and cGMP, are highly conserved during evolution and represent a unique set of drug targets, given the involvement of these enzymes in several pathophysiological states including brain disorders. The PDE4 family of cAMP-selective PDEs exert regulatory roles in memory and synaptic plasticity, but the specific roles of distinct PDE4 isoforms in these processes are poorly understood. Building on our previous work demonstrating that spatial and contextual memory deficits were caused by expressing selectively the long isoform of the PDE4A subfamily, PDE4A5, in hippocampal excitatory neurons, we now investigate the effects of PDE4A isoforms on different cAMP-dependent forms of LTP. We found that PDE4A5 impairs long-lasting LTP induced by theta burst stimulation (TBS) while sparing long-lasting LTP induced by spaced four-train stimulation (4 × 100 Hz). This effect requires the unique N-terminus of PDE4A5 and is specific to this long isoform. Targeted overexpression of PDE4A5 in area CA1 is sufficient to impair TBS-LTP, suggesting that cAMP levels in the postsynaptic neuron are critical for TBS-LTP. Our results shed light on the inherent differences among the PDE4A subfamily isoforms, emphasizing the importance of the long isoforms, which have a unique N-terminal region. Advancing our understanding of the function of specific PDE isoforms will pave the way for developing isoform-selective approaches to treat the cognitive deficits that are debilitating aspects of psychiatric, neurodevelopmental and neurodegenerative disorders. KEY POINTS: Hippocampal overexpression of PDE4A5, but not PDE4A1 or the N-terminus-truncated PDE4A5 (PDE4A5Δ4), selectively impairs long-term potentiation (LTP) induced by theta burst stimulation (TBS-LTP). Expression of PDE4A5 in area CA1 is sufficient to cause deficits in TBS-LTP. Hippocampal overexpression of the PDE4A isoforms PDE4A1 and PDE4A5 does not impair LTP induced by repeated tetanic stimulation at the CA3-CA1 synapses. These results suggest that PDE4A5, through its N-terminus, regulates cAMP pools that are critical for memory consolidation and expression of specific forms of long-lasting synaptic plasticity at CA3-CA1 synapses.
环磷酸腺苷（cAMP）信号传导对于记忆巩固和某些形式的长时程增强（LTP）至关重要。磷酸二酯酶（PDEs）是降解第二信使cAMP和环鸟苷酸（cGMP）的酶，在进化过程中高度保守，鉴于这些酶参与包括脑部疾病在内的多种病理生理状态，它们代表了一组独特的药物靶点。cAMP选择性PDEs的PDE4家族在记忆和突触可塑性中发挥调节作用，但不同PDE4亚型在这些过程中的具体作用尚不清楚。基于我们之前的研究工作，即选择性地在海马兴奋性神经元中表达PDE4A亚家族的长亚型PDE4A5会导致空间和情境记忆缺陷，我们现在研究PDE4A亚型对不同cAMP依赖性LTP形式的影响。我们发现，PDE4A5会损害由theta爆发刺激（TBS）诱导的持久LTP，而对间隔四串刺激（4×100Hz）诱导的持久LTP没有影响。这种效应需要PDE4A5独特的N端，并且是该长亚型特有的。在CA1区靶向过表达PDE4A5足以损害TBS-LTP，这表明突触后神经元中的cAMP水平对TBS-LTP至关重要。我们的结果揭示了PDE4A亚家族亚型之间的内在差异，强调了具有独特N端区域的长亚型的重要性。增进我们对特定PDE亚型功能的理解将为开发亚型选择性方法治疗认知缺陷铺平道路，这些认知缺陷是精神疾病、神经发育障碍和神经退行性疾病令人衰弱的方面。要点：海马中过表达PDE4A5，而不是PDE4A1或N端截短的PDE4A5（PDE4A5Δ4），会选择性损害由theta爆发刺激（TBS-LTP）诱导的长时程增强。在CA1区表达PDE4A5足以导致TBS-LTP缺陷。海马中过表达PDE4A亚型PDE4A1和PDE4A5不会损害CA3-CA1突触处重复强直刺激诱导的LTP。这些结果表明，PDE4A5通过其N端调节对记忆巩固和CA3-CA1突触处特定形式的持久突触可塑性表达至关重要的cAMP池。
